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1
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Bryant N, Muehling LM, Wavell K, Teague WG, Woodfolk JA. Rhinovirus as a driver of airway T cell dynamics in children with treatment-refractory recurrent wheeze. JCI Insight 2025; 10:e189480. [PMID: 40337866 DOI: 10.1172/jci.insight.189480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/27/2025] [Indexed: 05/09/2025] Open
Abstract
Severe asthma in children is notoriously difficult to treat, and its immunopathogenesis is complex. In particular, the contribution of T cells and relationships to antiviral immunity remain enigmatic. Here, we coupled deep phenotyping with machine learning methods to elucidate the dynamics of T cells in the lower airways of children with treatment-refractory recurrent wheeze, and examine rhinovirus (RV) as a driver. Our strategy revealed a T cell landscape dominated by type 1 and type 17 CD8+ signatures. Interrogation of phenotypic relationships coupled with trajectory mapping identified T cell migratory and differentiation pathways spanning the blood and airways that culminated in tissue residency, and involved transitions between type 1 and type 17 tissue-resident types. These dynamics were reflected in cytokine polyfunctionality. Use of machine learning tools to cross-compare T cell populations that were enriched in the airways of RV-positive children with those induced in the blood following experimental RV challenge precisely pinpointed RV-responsive signatures that contributed to T cell migratory and differentiation pathways. Despite their rarity, these signatures were also detected in the airways of RV-negative children. Together, our results underscore the aberrant nature of type 1 immunity in the airways of children with recurrent wheeze, and implicate an important viral trigger as a driver.
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Affiliation(s)
- Naomi Bryant
- Department of Medicine
- Department of Microbiology, Immunology, and Cancer Biology, and
| | | | - Kristin Wavell
- Child Health Research Center, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - W Gerald Teague
- Child Health Research Center, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Judith A Woodfolk
- Department of Medicine
- Department of Microbiology, Immunology, and Cancer Biology, and
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2
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Sun Y, Sun Z, Fang B, Wang R, Liu Y, Li J, Lan H, Zhao W, Hung WL, Zhang M. Exploring the anti-inflammatory potential of Lacticaseibacillus paracasei postbiotics: Mechanistic insights and functional components. FOOD BIOSCI 2025; 65:106105. [DOI: 10.1016/j.fbio.2025.106105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
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3
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Kuklina EM. Mechanisms of Glucocorticoid Resistance in Nonclassical T Helper Populations Th17.1/Ex-Th17. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:188-199. [PMID: 40254398 DOI: 10.1134/s0006297924604222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 04/22/2025]
Abstract
The nonclassical population of Th1-polarized Th17 lymphocytes (Th17.1/ex-Th17) is currently in the focus of researchers' attention. These cells possess a unique proinflammatory potential and ability to penetrate blood-tissue barriers and play a key role in the pathogenesis of many inflammatory diseases, primarily autoimmune ones. Th1-polarized Th17 lymphocytes prevail in the autoimmune lesion foci and are considered to be a promising therapeutic target in these pathologies. At the same time, recent studies have shown another distinctive feature of Th1-polarized Th17 - their selective resistance to glucocorticoids. Since glucocorticoids are the first-line drugs for the treatment of the autoimmune disease exacerbation, understanding the causes of this phenomenon is crucial for predicting patients' response to therapy and improving the treatment effectiveness. This review analyzes the mechanisms of drug resistance of Th1-polarized Th17 cells, compares these mechanisms with those typical of nonpathogenic classical Th17 cells, and discusses the role of glucocorticoid resistance in the body's response to glucocorticoid therapy.
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Affiliation(s)
- Elena M Kuklina
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, Perm, 614081, Russia.
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4
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Chiarolla CM, Schulz AR, Meir M, Ferrara S, Xiao Y, Reu-Hofer S, Romero-Olmedo AJ, Falcone V, Hoffmann K, Büttner-Herold M, Prelog M, Rosenwald A, Hengel H, Lohoff M, Chang HD, Schlegel N, Mei HE, Berberich-Siebelt F. Pro-inflammatory NK-like T cells are expanded in the blood and inflamed intestine in Crohn's disease. Mucosal Immunol 2025; 18:162-175. [PMID: 39521274 DOI: 10.1016/j.mucimm.2024.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 10/28/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
Altered intestinal immune homeostasis leads to chronic inflammation in Crohn's disease (CD). To address disease- and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with CD and healthy donors' PBMCs. Chronic intestinal inflammation enforced activation, exhaustion, and terminal differentiation of CD4+ and CD8+ T cells and a relative enrichment of CD4+ regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4+FOXP3+HLA-DR+TIGIT- and CD4+FOXP3+CD56+, expressing pro-inflammatory IFN-γ upon in vitro stimulation. Some conventional T (Tcon) cells acquired NK-like features. In CD patients' blood, not well studied CD16+CCR6+CD127+ T cells appeared, being CD4+ or CD8+, a phenotype inducible on healthy T cells by CD blood plasma. Upon CD16-mediated antibody binding, they could attain effector function. These findings suggest an uncommon pro-inflammatory innate-like differentiation of Treg and Tcon cells with acquisition of non-specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.
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Affiliation(s)
- Cristina M Chiarolla
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Axel R Schulz
- Mass Cytometry Lab, German Rheumatism Research Center Berlin (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Michael Meir
- Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Sebastian Ferrara
- Mass Cytometry Lab, German Rheumatism Research Center Berlin (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Yin Xiao
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Simone Reu-Hofer
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Addi J Romero-Olmedo
- Institute of Medical Microbiology and Hospital Hygiene, Philipps University Marburg, Marburg, Germany
| | - Valeria Falcone
- Institute of Virology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Katja Hoffmann
- Institute of Virology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Maike Büttner-Herold
- Department of Nephropathology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Martina Prelog
- Department of Pediatrics, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Andreas Rosenwald
- Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany; Comprehensive Cancer Centre Mainfranken, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Hartmut Hengel
- Institute of Virology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
| | - Michael Lohoff
- Institute of Medical Microbiology and Hospital Hygiene, Philipps University Marburg, Marburg, Germany
| | - Hyun-Dong Chang
- Schwiete Laboratory for Microbiota and Inflammation, German Rheumatism Research Center Berlin (DRFZ), Leibniz Institute, 10117 Berlin, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Henrik E Mei
- Mass Cytometry Lab, German Rheumatism Research Center Berlin (DRFZ), a Leibniz Institute, Berlin, Germany
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5
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Xia X, Huang Z, Xu C, Fu H, Wang S, Tian J, Rui K. Regulation of intestinal tissue‑resident memory T cells: a potential target for inflammatory bowel disease. Cell Commun Signal 2024; 22:610. [PMID: 39695803 DOI: 10.1186/s12964-024-01984-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/05/2024] [Indexed: 12/20/2024] Open
Abstract
Tissue-resident memory T (TRM) cells are populations which settle down in non-lymphoid tissues instead of returning to secondary lymph organs after the antigen presentation. These cells can provide rapid on-site immune protection as well as long-term tissue damage. It is reported that TRM cells from small intestine and colon exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional and functional heterogeneity. In this review, we focus on the reason why they lodge in intestinal tract, their developmental plasticity of going back to to circulation, as well as their regulators associated with retention, maintenance, exhaustion and metabolism. We also elaborate their role in the inflammatory bowel disease (IBD) and discuss the potential therapeutic strategies targeting TRM cells.
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Affiliation(s)
- Xin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhanjun Huang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Chengcheng Xu
- Department of Nuclear Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hailong Fu
- Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shengjun Wang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jie Tian
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Lei X, Xiao R, Chen Z, Ren J, Zhao W, Tang W, Wen K, Zhu Y, Li X, Ouyang S, Xu A, Hu Y, Bi E. Augmenting antitumor efficacy of Th17-derived Th1 cells through IFN-γ-induced type I interferon response network via IRF7. Proc Natl Acad Sci U S A 2024; 121:e2412120121. [PMID: 39541355 PMCID: PMC11588128 DOI: 10.1073/pnas.2412120121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
The importance of CD4+ T cells in cancer immunotherapy has gained increasing recognition. Particularly, a specific subset of CD4+ T cells coexpressing the T helper type 1 (Th1) and Th17 markers has demonstrated remarkable antitumor potential. However, the underlying mechanisms governing the differentiation of these cells and their subsequent antitumor responses remain incompletely understood. Single-cell RNA sequencing (scRNA-seq) data reanalysis demonstrated the presence of Th171 cells within tumors. Subsequent trajectory analysis found that these Th171 cells are initially primed under Th17 conditions and then converted into IFN-γ-producing cells. Following the in vivo differentiation trajectory of Th171 cells, we successfully established in vitro Th171 cell culture. Transcriptomic profiling has unveiled a substantial resemblance between in vitro-generated Th171 cells and their tumor-infiltrating counterparts. Th171 cells exhibit more potent antitumor responses than Th1 or Th17 cells. Additionally, Th171chimeric antigen receptor T (CAR-T) cells eradicate solid tumors more efficiently. Importantly, Th171 cells display an early exhaustion phenotype while retaining stemness. Mechanistically, Th171 cells migrate faster and accumulate more in tumors in an extracellular matrix protein 1 (ECM1)-dependent manner. Furthermore, we show that IFN-γ up-regulated IRF7 to promote the type I interferon response network and ECM1 expression but decreased the exhaustion status in Th171 cells. Taken together, our findings position Th171 cells as a great candidate for improving targeted immunotherapies in solid malignancies.
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Affiliation(s)
- Xiaoyi Lei
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Ruipei Xiao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Zhe Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Jie Ren
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Wenli Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Wenting Tang
- Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou510515, China
| | - Kang Wen
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou510280, China
| | - Yihan Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Xinru Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
| | - Suidong Ouyang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan523808, China
| | - Abai Xu
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou510280, China
| | - Yu Hu
- Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou510515, China
| | - Enguang Bi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong510515, China
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou510280, China
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7
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Bryant N, Muehling LM, Wavell K, Teague WG, Woodfolk JA. Rhinovirus as a Driver of Airway T-Cell Dynamics in Children with Severe Asthma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.15.623877. [PMID: 39605344 PMCID: PMC11601360 DOI: 10.1101/2024.11.15.623877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Severe asthma in children is notoriously difficult to treat, and its immunopathogenesis is complex. In particular, the contribution of T cells and relationships to anti-viral immunity, remain enigmatic. Here, we coupled deep phenotyping with machine learning methods to resolve the dynamics of T cells in the diseased lower airways, and examined rhinovirus (RV) as a driver. Our strategy revealed a T-cell landscape dominated by type 1 and type 17 CD8+ signatures. Interrogation of phenotypic relationships coupled with trajectory mapping identified T-cell migratory and differentiation pathways spanning the blood and airways that culminated in tissue residency, and included transitions between type 1 and type 17 tissue-resident types. These T-cell dynamics were reflected in cytokine polyfunctionality in situ . Use of machine learning to cross-compare T-cell populations that were enriched in the airways of RV-positive children with those induced in the blood after RV challenge in an experimental infection model, precisely pinpointed RV-responsive signatures that mapped to T-cell differentiation pathways. Despite their rarity, these signatures were detected in the airways of uninfected children. Together, our results underscore the aberrant nature of type 1 immunity in the airways of children with severe asthma, and implicate an important viral trigger as a driver.
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8
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Clua‐Ferré L, Suau R, Vañó‐Segarra I, Ginés I, Serena C, Manyé J. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: A focus on inflammatory bowel disease. Clin Transl Med 2024; 14:e70075. [PMID: 39488745 PMCID: PMC11531661 DOI: 10.1002/ctm2.70075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/13/2024] [Accepted: 10/16/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage. MAIN TOPICS COVERED This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials. CONCLUSIONS Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice. HIGHLIGHTS The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC-EVs reduce intestinal inflammation by suppressing pro-inflammatory mediators (e.g., TNF-α, IL-1β, IL-6) and increasing anti-inflammatory factors (e.g., IL-4, IL-10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.
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Affiliation(s)
- Laura Clua‐Ferré
- Germans Trias i Pujol Research Institute IGTPInflammatory Bowel DiseasesBadalonaSpain
| | - Roger Suau
- Germans Trias i Pujol Research Institute IGTPInflammatory Bowel DiseasesBadalonaSpain
| | - Irene Vañó‐Segarra
- Hospital Universitari Joan XXIIIInstitut d'investigació sanitària Pere VirgiliTarragonaSpain
| | - Iris Ginés
- Hospital Universitari Joan XXIIIInstitut d'investigació sanitària Pere VirgiliTarragonaSpain
| | - Carolina Serena
- Hospital Universitari Joan XXIIIInstitut d'investigació sanitària Pere VirgiliTarragonaSpain
| | - Josep Manyé
- Germans Trias i Pujol Research Institute IGTPInflammatory Bowel DiseasesBadalonaSpain
- Centro de Investigación Biomédica en RedMadridSpain
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9
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Jin C, Jiang P, Zhang Z, Han Y, Wen X, Zheng L, Kuang W, Lian J, Yu G, Qian X, Ren Y, Lu M, Xu L, Chen W, Chen J, Zhou Y, Xin J, Wang B, Jin X, Qian P, Yang Y. Single-cell RNA sequencing reveals the pro-inflammatory roles of liver-resident Th1-like cells in primary biliary cholangitis. Nat Commun 2024; 15:8690. [PMID: 39375367 PMCID: PMC11458754 DOI: 10.1038/s41467-024-53104-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/02/2024] [Indexed: 10/09/2024] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients.
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Affiliation(s)
- Ciliang Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Penglei Jiang
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Zhaoru Zhang
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Yingli Han
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Xue Wen
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Kuang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangshan Lian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guodong Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyue Qian
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Yue Ren
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Miaomiao Lu
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingling Xu
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Weixin Chen
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiyang Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuwei Zhou
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinxia Xin
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Ben Wang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Xi Jin
- Depratment of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Pengxu Qian
- Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
| | - Yida Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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10
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Wolska M, Wypych TP, Rodríguez-Viso P. The Influence of Premature Birth on the Development of Pulmonary Diseases: Focus on the Microbiome. Metabolites 2024; 14:382. [PMID: 39057705 PMCID: PMC11279213 DOI: 10.3390/metabo14070382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 06/28/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Globally, around 11% of neonates are born prematurely, comprising a highly vulnerable population with a myriad of health problems. Premature births are often accompanied by an underdeveloped immune system biased towards a Th2 phenotype and microbiota dysbiosis. Typically, a healthy gut microbiota interacts with the host, driving the proper maturation of the host immunity. However, factors like cesarean section, formula milk feeding, hospitalization in neonatal intensive care units (NICU), and routine antibiotic treatments compromise microbial colonization and increase the risk of developing related diseases. This, along with alterations in the innate immune system, could predispose the neonates to the development of respiratory diseases later in life. Currently, therapeutic strategies are mainly focused on restoring gut microbiota composition using probiotics and prebiotics. Understanding the interactions between the gut microbiota and the immature immune system in premature neonates could help to develop novel therapeutic strategies for treating or preventing gut-lung axis disorders.
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Affiliation(s)
| | - Tomasz Piotr Wypych
- Laboratory of Host-Microbiota Interactions, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Ludwika Pasteura 3, 02-093 Warsaw, Poland; (M.W.); (P.R.-V.)
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11
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Sun D, Wang K, Chen Y, Zhang B, Tang J, Luo W, Liu J, Yu S. Immunological characteristics of CD103 +CD161 + T lymphocytes on chronic rhinosinusitis with nasal polyps. Cell Immunol 2024; 401-402:104842. [PMID: 38897020 DOI: 10.1016/j.cellimm.2024.104842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/25/2024] [Accepted: 06/10/2024] [Indexed: 06/21/2024]
Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.
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Affiliation(s)
- Danqi Sun
- Institute of Translational Medicine, The First People's Hospital of Foshan, 81 Lingnan Road, Foshan 528000, China; Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Kai Wang
- Department of Otolaryngology, The First People's Hospital of Foshan, 81 Lingnan Road, Foshan 528000, China
| | - Youmou Chen
- The General Hospital of Western Theater Command, No. 270, Rongdu Avenue, Chengdu 610083, China
| | - Beiying Zhang
- Institute of Translational Medicine, The First People's Hospital of Foshan, 81 Lingnan Road, Foshan 528000, China
| | - Jun Tang
- Department of Otolaryngology, The First People's Hospital of Foshan, 81 Lingnan Road, Foshan 528000, China
| | - Wei Luo
- Institute of Translational Medicine, The First People's Hospital of Foshan, 81 Lingnan Road, Foshan 528000, China
| | - Jia Liu
- Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
| | - Sifei Yu
- Institute of Translational Medicine, The First People's Hospital of Foshan, 81 Lingnan Road, Foshan 528000, China.
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12
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Hu X, Dong Y, Xie S, Song Y, Yu C, He Y, Wang Z, Hu Q, Ni Y, Ding L. Immune checkpoint CD161/LLT1-associated immunological landscape and diagnostic value in oral squamous cell carcinoma. J Pathol Clin Res 2024; 10:e353. [PMID: 38502058 PMCID: PMC10792702 DOI: 10.1002/cjp2.353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 03/20/2024]
Abstract
An active host adaptive response is characterized by the existence of programmed cell death protein 1 (PD-1)+ /IFN-γ+ cytotoxic T cells and IFN-γ-induced PD-L1+ tumor cells (TCs), which predicts high response rate to anti-PD-1/L1 therapy. Recently, CD161 and its ligand LLT1 (CLEC2D) have been identified as an emerging checkpoint for immunotherapy. Clarifying its heterogeneous clinical expression pattern and its immune landscape is a prerequisite for maximizing the response rate of CD161 blockade therapy in a specific population of oral squamous cell carcinoma (OSCC) patients. Here, we investigated the expression pattern of CD161/LLT1 and its association with major immunocytes (T cells, B cells, NK cells, and macrophages) by multiplex immunofluorescence, immunohistochemistry, and flow cytometry in 109 OSCC tissues and 102 peripheral blood samples. TCs showed higher LLT1 levels than tumor infiltrating lymphocytes (TILs), whereas CD161 was highly expressed in CD8+ T cells at the tumor front, which was decreased in paracancerous tissue. High expression of TC-derived LLT1 (LLT1TC ) conferred poor clinical outcomes, whereas higher CD161+ and LLT1+ TILs were associated with better prognosis. Meanwhile, patients with high LLT1TC showed a decreased ratio of CD8+ /Foxp3+ T cells in situ, but CD161+ TILs correlated with more peripheral CD3+ T cells. Interestingly, treatment of OSCC patients with nivolumab (anti-PD-1) could restore tumoral CD161/LLT1 signal. Furthermore, an OSCC subgroup characterized by high LLT1+ TCs and low CD161+ CD8+ T cells showed fewer peripheral T cells and a higher risk of lymph node metastasis, leading to a shorter 5-year survival time (29%). More LLT1TC at the invasive front was another risk characteristic of exhausted T cells. In conclusion, in view of this heterogeneity, the LLT1/CD161 distribution pattern should be determined before CD161-based immunotherapy.
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Affiliation(s)
- Xinyang Hu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Yuexin Dong
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Shixin Xie
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Yuxian Song
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Chenhang Yu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Yijia He
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Zhiyong Wang
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Qingang Hu
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Yanhong Ni
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
| | - Liang Ding
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical SchoolNanjing UniversityNanjingPR China
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13
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Marchesini Tovar G, Gallen C, Bergsbaken T. CD8+ Tissue-Resident Memory T Cells: Versatile Guardians of the Tissue. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:361-368. [PMID: 38227907 PMCID: PMC10794029 DOI: 10.4049/jimmunol.2300399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/07/2023] [Indexed: 01/18/2024]
Abstract
Tissue-resident memory T (Trm) cells are a subset of T cells maintained throughout life within nonlymphoid tissues without significant contribution from circulating memory T cells. CD8+ Trm cells contribute to both tissue surveillance and direct elimination of pathogens through a variety of mechanisms. Reactivation of these Trm cells during infection drives systematic changes within the tissue, including altering the state of the epithelium, activating local immune cells, and contributing to the permissiveness of the tissue for circulating immune cell entry. Trm cells can be further classified by their functional outputs, which can be either subset- or tissue-specific, and include proliferation, tissue egress, and modulation of tissue physiology. These functional outputs of Trm cells are linked to the heterogeneity and plasticity of this population, and uncovering the unique responses of different Trm cell subsets and their role in immunity will allow us to modulate Trm cell responses for optimal control of disease.
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Affiliation(s)
- Giuseppina Marchesini Tovar
- Center for Immunity and Inflammation, Department of Pathology, Immunology, and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Corey Gallen
- Center for Immunity and Inflammation, Department of Pathology, Immunology, and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Tessa Bergsbaken
- Center for Immunity and Inflammation, Department of Pathology, Immunology, and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
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14
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Paroli M, Caccavale R, Accapezzato D. Giant Cell Arteritis: Advances in Understanding Pathogenesis and Implications for Clinical Practice. Cells 2024; 13:267. [PMID: 38334659 PMCID: PMC10855045 DOI: 10.3390/cells13030267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 01/27/2024] [Accepted: 01/30/2024] [Indexed: 02/10/2024] Open
Abstract
Giant cell arteritis (GCA) is a noninfectious granulomatous vasculitis of unknown etiology affecting individuals older than 50 years. Two forms of GCA have been identified: a cranial form involving the medium-caliber temporal artery causing temporal arteritis (TA) and an extracranial form involving the large vessels, mainly the thoracic aorta and its branches. GCA generally affects individuals with a genetic predisposition, but several epigenetic (micro)environmental factors are often critical for the onset of this vasculitis. A key role in the pathogenesis of GCA is played by cells of both the innate and adaptive immune systems, which contribute to the formation of granulomas that may include giant cells, a hallmark of the disease, and arterial tertiary follicular organs. Cells of the vessel wall cells, including vascular smooth muscle cells (VSMCs) and endothelial cells, actively contribute to vascular remodeling responsible for vascular stenosis and ischemic complications. This review will discuss new insights into the molecular and cellular pathogenetic mechanisms of GCA, as well as the implications of these findings for the development of new diagnostic biomarkers and targeted drugs that could hopefully replace glucocorticoids (GCs), still the backbone of therapy for this vasculitis.
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Affiliation(s)
- Marino Paroli
- Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Polo Pontino, 04100 Latina, Italy; (R.C.); (D.A.)
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15
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Devan J, Nosi V, Spagnuolo J, Chancellor A, Beshirova A, Loureiro JP, Vacchini A, Hendrik Niess J, Calogero R, Mori L, De Libero G, Hruz P. Surface protein and functional analyses identify CD4+CD39+ TCR αβ+ and activated TCR Vδ1+ cells with distinct pro-inflammatory functions in Crohn's disease lesions. Clin Exp Immunol 2024; 215:79-93. [PMID: 37586415 PMCID: PMC10776239 DOI: 10.1093/cei/uxad098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 07/06/2023] [Accepted: 08/14/2023] [Indexed: 08/18/2023] Open
Abstract
Crohn's disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. Extensive screening studies have revealed the accumulation of immune cell subsets with unique plasticity and immunoregulatory properties in patients with CD. We performed phenotypic and functional studies on inflamed and non-inflamed bioptic tissue to investigate the presence of distinct T cells in the intestinal mucosa of CD patients. We analysed hundreds of surface molecules expressed on cells isolated from the intestinal tissue of CD patients using anti-CD45 mAbs-based barcoding. A gene ontology enrichment analysis showed that proteins that regulate the activation of T cells were the most enriched group. We, therefore, designed T-cell focused multicolour flow-cytometry panels and performed clustering analysis which revealed an accumulation of activated TEM CD4+CD39+ T cells producing IL-17 and IL-21 and increased frequency of terminally differentiated TCR Vδ1+ cells producing TNF-α and IFN-γ in inflamed tissue of CD patients. The different functional capacities of CD4+ and TCR Vδ1+ cells in CD lesions indicate their non-overlapping contribution to inflammation. The abnormally high number of terminally differentiated TCR Vδ1+ cells suggests that they are continuously activated in inflamed tissue, making them a potential target for novel therapies.
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Affiliation(s)
- Jan Devan
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Vladimir Nosi
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Julian Spagnuolo
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Andrew Chancellor
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Aisha Beshirova
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Jose Pedro Loureiro
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Alessandro Vacchini
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Jan Hendrik Niess
- Gastroenterology, Department of Biomedicine, University of Basel, Clarunis, Basel, Switzerland
- Department of Clinical Research, University of Basel, Basel, Switzerland
- University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Raffaele Calogero
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Lucia Mori
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Gennaro De Libero
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Petr Hruz
- Experimental Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
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16
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Leccese G, Chiara M, Dusetti I, Noviello D, Billard E, Bibi A, Conte G, Consolandi C, Vecchi M, Conte MP, Barnich N, Caprioli F, Facciotti F, Paroni M. AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn's disease is suppressed by rfaP and ybaT deletion. Gut Microbes 2024; 16:2380064. [PMID: 39069911 PMCID: PMC11290758 DOI: 10.1080/19490976.2024.2380064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/30/2024] Open
Abstract
Mucosal enrichment of the Adherent-Invasive E. coli (AIEC) pathotype and the expansion of pathogenic IFNγ-producing Th17 (pTh17) cells have been linked to Crohn's Disease (CD) pathogenesis. However, the molecular pathways underlying the AIEC-dependent pTh17 cell transdifferentiation in CD patients remain elusive. To this aim, we created and functionally screened a transposon AIEC mutant library of 10.058 mutants to identify the virulence determinants directly implicated in triggering IL-23 production and pTh17 cell generation. pTh17 cell transdifferentiation was assessed in functional assays by co-culturing AIEC-infected human dendritic cells (DCs) with autologous conventional Th17 (cTh17) cells isolated from blood of Healthy Donors (HD) or CD patients. AIEC triggered IL-23 hypersecretion and transdifferentiation of cTh17 into pTh17 cells selectively through the interaction with CD-derived DCs. Moreover, the chronic release of IL-23 by AIEC-colonized DCs required a continuous IL-23 neutralization to significantly reduce the AIEC-dependent pTh17 cell differentiation. The multi-step screenings of the AIEC mutant's library revealed that deletion of ybaT or rfaP efficiently hinder the IL-23 hypersecretion and hampered the AIEC-dependent skewing of protective cTh17 into pathogenic IFNγ-producing pTh17 cells. Overall, our findings indicate that ybaT (inner membrane transport protein) and rfaP (LPS-core heptose kinase) represent novel and attractive candidate targets to prevent chronic intestinal inflammation in CD.
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Affiliation(s)
- G. Leccese
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - M. Chiara
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - I. Dusetti
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - D. Noviello
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - E. Billard
- M2iSH, UMR 1071 Inserm, INRAe USC 1382, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
| | - A. Bibi
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - G. Conte
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - C. Consolandi
- Institute of Biomedical Technologies, National Research Council (ITB-CNR), Segrate, Milan, Italy
| | - M. Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - MP Conte
- Department of Public Health and Infectious Diseases, ‘Sapienza’ University of Rome, Rome, Italy
| | - N. Barnich
- M2iSH, UMR 1071 Inserm, INRAe USC 1382, CRNH, University of Clermont Auvergne, Clermont-Ferrand, France
| | - F. Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - F. Facciotti
- Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy
| | - M. Paroni
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
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17
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Lutter L, Ter Linde JJM, Brand EC, Hoytema van Konijnenburg DP, Roosenboom B, Horjus Talabur-Horje C, Oldenburg B, van Wijk F. Compartment-driven imprinting of intestinal CD4 T cells in inflammatory bowel disease and homeostasis. Clin Exp Immunol 2023; 214:235-248. [PMID: 37565620 PMCID: PMC10719222 DOI: 10.1093/cei/uxad095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 07/16/2023] [Accepted: 08/09/2023] [Indexed: 08/12/2023] Open
Abstract
The mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T-cell populations. Human CD4 T-cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remain incompletely understood. We performed flow cytometry, bulk, and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8αα, regulatory T cells (Tregs), CD69- and CD69high Trm T cells) in controls and Crohn's disease (CD) patients (paired non-inflamed and inflamed). Inflammation results in alterations of the CD4 T-cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T-cell activation, increased IFNγ responses, and an effector Treg profile. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. In summary, inflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T-cell imprinting, driven by shared regulators, between the lamina propria and the epithelium. The main consequence of intraepithelial adaptation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium.
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Affiliation(s)
- Lisanne Lutter
- Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - José J M Ter Linde
- Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Eelco C Brand
- Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - David P Hoytema van Konijnenburg
- Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Britt Roosenboom
- Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | | | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Femke van Wijk
- Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
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18
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Yu H, Xue W, Yu H, Song Y, Liu X, Qin L, Wang S, Bao H, Gu H, Chen G, Zhao D, Tu Y, Cheng J, Wang L, Ai Z, Hu D, Wang L, Peng A. Single-cell transcriptomics reveals variations in monocytes and Tregs between gout flare and remission. JCI Insight 2023; 8:e171417. [PMID: 38063198 PMCID: PMC10795830 DOI: 10.1172/jci.insight.171417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/25/2023] [Indexed: 12/18/2023] Open
Abstract
Gout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.
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Affiliation(s)
- Hanjie Yu
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Wen Xue
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Hanqing Yu
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Yaxiang Song
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Xinying Liu
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Ling Qin
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Shu Wang
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Hui Bao
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Hongchen Gu
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Guangqi Chen
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Dake Zhao
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Yang Tu
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Jiafen Cheng
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Liya Wang
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Zisheng Ai
- Department of Medical Statistics, Tongji University School of Medicine, Shanghai, China
| | - Dayong Hu
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Ling Wang
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
| | - Ai Peng
- Center for Nephrology and Clinical Metabolomics and Division of Nephrology, Shanghai Tenth People’s Hospital, and
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19
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Liu J, Zhang J, Zhao X, Pan C, Liu Y, Luo S, Miao X, Wu T, Cheng X. Identification of CXCL16 as a diagnostic biomarker for obesity and intervertebral disc degeneration based on machine learning. Sci Rep 2023; 13:21316. [PMID: 38044363 PMCID: PMC10694141 DOI: 10.1038/s41598-023-48580-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/28/2023] [Indexed: 12/05/2023] Open
Abstract
Intervertebral disc degeneration (IDD) is the primary cause of neck and back pain. Obesity has been established as a significant risk factor for IDD. The objective of this study was to explore the molecular mechanisms affecting obesity and IDD by identifying the overlapping crosstalk genes associated with both conditions. The identification of specific diagnostic biomarkers for obesity and IDD would have crucial clinical implications. We obtained gene expression profiles of GSE70362 and GSE152991 from the Gene Expression Omnibus, followed by their analysis using two machine learning algorithms, least absolute shrinkage and selection operator and support vector machine-recursive feature elimination, which enabled the identification of C-X-C motif chemokine ligand 16 (CXCL16) as a shared diagnostic biomarker for obesity and IDD. Additionally, gene set variant analysis was used to explore the potential mechanism of CXCL16 in these diseases, and CXCL16 was found to affect IDD through its effect on fatty acid metabolism. Furthermore, correlation analysis between CXCL16 and immune cells demonstrated that CXCL16 negatively regulated T helper 17 cells to promote IDD. Finally, independent external datasets (GSE124272 and GSE59034) were used to verify the diagnostic efficacy of CXCL16. In conclusion, a common diagnostic biomarker for obesity and IDD, CXCL16, was identified using a machine learning algorithm. This study provides a new perspective for exploring the possible mechanisms by which obesity impacts the development of IDD.
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Affiliation(s)
- Jiahao Liu
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
| | - Jian Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
| | - Xiaokun Zhao
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
| | - Chongzhi Pan
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
| | - Yuchi Liu
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
| | - Shengzhong Luo
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
| | - Xinxin Miao
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Tianlong Wu
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Xigao Cheng
- Department of Orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
- Institute of Orthopedics of Jiangxi Province, Nanchang, 330006, Jiangxi, China.
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, 330006, Jiangxi, China.
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Carlson SL, Mathew L, Savage M, Kok K, Lindsay JO, Munro CA, McCarthy NE. Mucosal Immunity to Gut Fungi in Health and Inflammatory Bowel Disease. J Fungi (Basel) 2023; 9:1105. [PMID: 37998910 PMCID: PMC10672531 DOI: 10.3390/jof9111105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 11/25/2023] Open
Abstract
The gut microbiome is a diverse microbial community composed of bacteria, viruses, and fungi that plays a major role in human health and disease. Dysregulation of these gut organisms in a genetically susceptible host is fundamental to the pathogenesis of inflammatory bowel disease (IBD). While bacterial dysbiosis has been a predominant focus of research for many years, there is growing recognition that fungal interactions with the host immune system are an important driver of gut inflammation. Candida albicans is likely the most studied fungus in the context of IBD, being a near universal gut commensal in humans and also a major barrier-invasive pathogen. There is emerging evidence that intra-strain variation in C. albicans virulence factors exerts a critical influence on IBD pathophysiology. In this review, we describe the immunological impacts of variations in C. lbicans colonisation, morphology, genetics, and proteomics in IBD, as well as the clinical and therapeutic implications.
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Affiliation(s)
- Sean L. Carlson
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Liya Mathew
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Michael Savage
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Klaartje Kok
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - James O. Lindsay
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Carol A. Munro
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB24 3FX, UK
| | - Neil E. McCarthy
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
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21
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Wang Q, Lu Q, Jia S, Zhao M. Gut immune microenvironment and autoimmunity. Int Immunopharmacol 2023; 124:110842. [PMID: 37643491 DOI: 10.1016/j.intimp.2023.110842] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/14/2023] [Accepted: 08/19/2023] [Indexed: 08/31/2023]
Abstract
A variety of immune cells or tissues are present in the gut to form the gut immune microenvironment by interacting with gut microbiota, and to maintain the gut immune homeostasis. Accumulating evidence indicated that gut microbiota dysbiosis might break the homeostasis of the gut immune microenvironment, which was associated with many health problems including autoimmune diseases. Moreover, disturbance of the gut immune microenvironment can also induce extra-intestinal autoimmune disorders through the migration of intestinal pro-inflammatory effector cells from the intestine to peripheral inflamed sites. This review discussed the composition of the gut immune microenvironment and its association with autoimmunity. These findings are expected to provide new insights into the pathogenesis of various autoimmune disorders, as well as novel strategies for the prevention and treatment against related diseases.
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Affiliation(s)
- Qiaolin Wang
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Qianjin Lu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China
| | - Sujie Jia
- Department of Pharmacy, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China.
| | - Ming Zhao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing 210042, China.
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22
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Liu X, Wang X, Zhang P, Fang Y, Liu Y, Ding Y, Zhang W. Intestinal homeostasis in the gut-lung-kidney axis: a prospective therapeutic target in immune-related chronic kidney diseases. Front Immunol 2023; 14:1266792. [PMID: 38022571 PMCID: PMC10646503 DOI: 10.3389/fimmu.2023.1266792] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
In recent years, the role of intestinal homeostasis in health has received increasing interest, significantly improving our understanding of the complex pathophysiological interactions of the gut with other organs. Microbiota dysbiosis, impaired intestinal barrier, and aberrant intestinal immunity appear to contribute to the pathogenesis of immune-related chronic kidney diseases (CKD). Meanwhile, the relationship between the pathological changes in the respiratory tract (e.g., infection, fibrosis, granuloma) and immune-related CKD cannot be ignored. The present review aimed to elucidate the new underlying mechanism of immune-related CKD. The lungs may affect kidney function through intestinal mediation. Communication is believed to exist between the gut and lung microbiota across long physiological distances. Following the inhalation of various pathogenic factors (e.g., particulate matter 2.5 mum or less in diameter, pathogen) in the air through the mouth and nose, considering the anatomical connection between the nasopharynx and lungs, gut microbiome regulates oxidative stress and inflammatory states in the lungs and kidneys. Meanwhile, the intestine participates in the differentiation of T cells and promotes the migration of various immune cells to specific organs. This better explain the occurrence and progression of CKD caused by upper respiratory tract precursor infection and suggests the relationship between the lungs and kidney complications in some autoimmune diseases (e.g., anti-neutrophil cytoplasm antibodies -associated vasculitis, systemic lupus erythematosus). CKD can also affect the progression of lung diseases (e.g., acute respiratory distress syndrome and chronic obstructive pulmonary disease). We conclude that damage to the gut barrier appears to contribute to the development of immune-related CKD through gut-lung-kidney interplay, leading us to establish the gut-lung-kidney axis hypothesis. Further, we discuss possible therapeutic interventions and targets. For example, using prebiotics, probiotics, and laxatives (e.g., Rhubarb officinale) to regulate the gut ecology to alleviate oxidative stress, as well as improve the local immune system of the intestine and immune communication with the lungs and kidneys.
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Affiliation(s)
- Xinyin Liu
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- Department of Traditional Chinese Medicine, Jiande First People’s Hospital, Jiande, Hangzhou, China
| | - Xiaoran Wang
- Department of Nephrology, The First People’s Hospital of Hangzhou Lin’an District, Hangzhou, China
| | - Peipei Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Yiwen Fang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yanyan Liu
- Department of Geriatric, Zhejiang Aged Care Hospital, Hangzhou, China
| | - Yueyue Ding
- Department of Geriatric, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Wen Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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23
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Gao Y, Wang Y, Chauss D, Villarino AV, Link VM, Nagashima H, Spinner CA, Koparde VN, Bouladoux N, Abers MS, Break TJ, Chopp LB, Park JH, Zhu J, Wiest DL, Leonard WJ, Lionakis MS, O'Shea JJ, Afzali B, Belkaid Y, Lazarevic V. Transcription factor EGR2 controls homing and pathogenicity of T H17 cells in the central nervous system. Nat Immunol 2023; 24:1331-1344. [PMID: 37443284 PMCID: PMC10500342 DOI: 10.1038/s41590-023-01553-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 06/08/2023] [Indexed: 07/15/2023]
Abstract
CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.
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Affiliation(s)
- Yuanyuan Gao
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yan Wang
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Daniel Chauss
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Alejandro V Villarino
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Verena M Link
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- NIH Center for Human Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hiroyuki Nagashima
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Camille A Spinner
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Vishal N Koparde
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA
| | - Nicolas Bouladoux
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Michael S Abers
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Timothy J Break
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Laura B Chopp
- Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jung-Hyun Park
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jinfang Zhu
- Molecular and Cellular Immunoregulation Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David L Wiest
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Warren J Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michail S Lionakis
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - John J O'Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yasmine Belkaid
- Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Vanja Lazarevic
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Dold L, Frank L, Lutz P, Kaczmarek DJ, Krämer B, Nattermann J, Weismüller TJ, Branchi V, Toma M, Gonzalez-Carmona M, Strassburg CP, Spengler U, Langhans B. IL-6-Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis. Clin Transl Gastroenterol 2023; 14:e00603. [PMID: 37256725 PMCID: PMC10461951 DOI: 10.14309/ctg.0000000000000603] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 05/04/2023] [Indexed: 06/02/2023] Open
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6-dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4 + T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3-positive CD4 + T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3-positive cells were enriched in the peribiliary liver stroma and represented CD4 + T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.
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Affiliation(s)
- Leona Dold
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
- German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany;
| | - Leonie Frank
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
| | - Philipp Lutz
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
| | | | - Benjamin Krämer
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
- German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany;
| | - Tobias J. Weismüller
- Department of Internal Medicine - Gastroenterology and Oncology, Vivantes Humboldt Hospital, Berlin, Germany;
| | - Vittorio Branchi
- Department of General, Abdominal, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany;
| | - Marieta Toma
- Institute of Pathology, University Hospital Bonn, Bonn, Germany.
| | | | | | - Ulrich Spengler
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
| | - Bettina Langhans
- Department of Internal Medicine I, University Hospital of Bonn, Bonn, Germany;
- German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany;
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25
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Kobayashi T, Iijima K, Matsumoto K, Lama JK, Kita H. Lung-resident CD69 +ST2 + T H2 cells mediate long-term type 2 memory to inhaled antigen in mice. J Allergy Clin Immunol 2023; 152:167-181.e6. [PMID: 36720287 PMCID: PMC10330297 DOI: 10.1016/j.jaci.2023.01.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 01/30/2023]
Abstract
BACKGROUND Chronic airway diseases such as asthma are characterized by persistent type 2 immunity in the airways. We know little about the mechanisms that explain why type 2 inflammation continues in these diseases. OBJECTIVE We used mouse models to investigate the mechanisms involved in long-lasting immune memory. METHODS Naive mice were exposed intranasally to ovalbumin (OVA) antigen with Alternaria extract as an adjuvant. Type 2 memory was analyzed by parabiosis model, flow cytometry with in vivo antibody labeling, and intranasal OVA recall challenge. Gene-deficient mice were used to analyze the mechanisms. RESULTS In the parabiosis model, mice previously exposed intranasally to OVA with Alternaria showed more robust antigen-specific immune responses and airway inflammation than mice with circulating OVA-specific T cells. After a single airway exposure to OVA with Alternaria, CD69+ST2+ TH2-type T cells, which highly express type 2 cytokine messenger RNA and lack CD62L expression, appeared in lung tissue within 5 days and persisted for at least 84 days. When exposed again to OVA in vivo, these cells produced type 2 cytokines quickly without involving circulating T cells. Development of tissue-resident CD69+ST2+ TH2 cells and long-term memory to an inhaled antigen were abrogated in mice deficient in ST2 or IL-33, but not TSLP receptor. CONCLUSION CD69+ST2+ TH2 memory cells develop quickly in lung tissue after initial allergen exposure and persist for a prolonged period. The ST2/IL-33 pathway may play a role in the development of immune memory in lung to certain allergens.
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Affiliation(s)
- Takao Kobayashi
- Division of Allergic Diseases, Asthma and Clinical Immunology, and Department of Medicine, Mayo Clinic, Scottsdale, Ariz
| | - Koji Iijima
- Division of Allergic Diseases, Asthma and Clinical Immunology, and Department of Medicine, Mayo Clinic, Scottsdale, Ariz
| | - Koji Matsumoto
- Division of Allergic Diseases, Asthma and Clinical Immunology, and Department of Medicine, Mayo Clinic, Scottsdale, Ariz
| | - Jyoti K Lama
- Immunology Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester and Scottsdale, Rochester, Minn
| | - Hirohito Kita
- Division of Allergic Diseases, Asthma and Clinical Immunology, and Department of Medicine, Mayo Clinic, Scottsdale, Ariz; Department of Immunology, Mayo Clinic, Rochester, and Mayo Clinic, Scottsdale, Ariz.
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Wang Y, Fang S, Zhou H. Pathogenic role of Th17 cells in autoimmune thyroid disease and their underlying mechanisms. Best Pract Res Clin Endocrinol Metab 2023; 37:101743. [PMID: 36841747 DOI: 10.1016/j.beem.2023.101743] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Autoimmune thyroid disease, encompassing Graves' disease and Hashimoto's thyroiditis, has a very complex etiology. Pathogenesis of the disease involves both genetic susceptibility and environmental triggers. Traditionally, imbalance of T helper cell 1 and 2 was thought to result in the immune disorders in Graves' disease and Hashimoto's thyroiditis. However, increasing evidence recently revealed the important role of T helper 17 cell and its relative cellular and secretory components in the pathogenesis and progression of autoimmune thyroid disease. This review is aimed to summarize the published studies on the involvement of T helper 17 cell in autoimmune thyroid disease and discuss the underlying regulatory mechanisms, which could possibly serve as the foundation of discovering new therapeutic targets.
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Affiliation(s)
- Yi Wang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China; Chinese Consortium for Thyroid Eye Disease (CCTED), China; Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
| | - Sijie Fang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China; Chinese Consortium for Thyroid Eye Disease (CCTED), China; Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
| | - Huifang Zhou
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China; Chinese Consortium for Thyroid Eye Disease (CCTED), China.
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Gu L, Jiang J, Liu Z, Liu Q, Liao J, Zeng Q, Chen C, Liu Z. Intestinal recruitment of CCR6-expressing Th17 cells by suppressing miR-681 alleviates endotoxemia-induced intestinal injury and reduces mortality. Inflamm Res 2023; 72:715-729. [PMID: 36749385 DOI: 10.1007/s00011-023-01697-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/07/2022] [Accepted: 01/22/2023] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Sepsis or endotoxemia can induce intestinal dysfunction in the epithelial and immune barrier. Th17 cells, a distinct subset of CD4+ T-helper cells, act as "border patrol" in the intestine under pathological condition and in the previous studies, Th17 cells exhibited an ambiguous function in intestinal inflammation. Our study will explore a specific role of Th17 cells and its relevant mechanism in endotoxemia-induced intestinal injury. MATERIALS AND METHODS Lipopolysaccharide was used to establish mouse model of endotoxemia. miR-681 was analyzed by RT-PCR and northern blot analysis and its regulation by HIF-1α was determined by chromatin immunoprecipitation and luciferase reporter assay. Intestinal Th17 cells isolated from endotoxemic mice were quantitatively evaluated by flow cytometry and its recruitment to the intestine controlled by miR-681/CCR6 pathway was assessed by using anti-miRNA treatment and CCR6 knockout mice. Intestinal histopathology, villus length, intestinal inflammation, intestinal permeability, bacterial translocation and survival were investigated, by histology and TUNEL analysis, ELISA, measurement of diamine oxidase, bacterial culture, with or without anti-miR-681 treatment in endotoxemic wild-type and (or) CCR6 knockout mice. RESULTS In this study, we found that miR-681 was significantly promoted in intestinal Th17 cells during endotoxemia, which was dependent on hypoxia-inducible factor-1α (HIF-1α). Interestingly, miR-681 could directly suppress CCR6, which was a critical modulator for Th17 cell recruitment to the intestines. In vivo, anti-miR-681 enhanced survival, increased number of intestinal Th17 cells, reduced crypt and villi apoptosis, decreased intestinal inflammation and bacterial translocation, resulting in protection against endotoxemia-induced intestinal injury in mice. However, CCR6 deficiency could neutralize the beneficial effect of anti-miR-681 on the intestine during endotoxemia, suggesting that the increment of intestinal Th17 cells caused by anti-miR-681 relies on CCR6 expression. CONCLUSION The results of the study indicate that control of intestinal Th17 cells by regulating novel miR-681/CCR6 signaling attenuates endotoxemia-induced intestinal injury.
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Affiliation(s)
- Liwen Gu
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No.600, Tianhe Road, Guangzhou, 510360, China
| | - Zhigang Liu
- Department of Head and Neck Oncology, The cancer center of The Fifth Affiliated Hospital of Sun Yat-Sen University, Phase 1 Clinical Trial Ward, Zhuhai, 519001, China.,Cancer Cente, Affiliated Dongguan Hospital, Southern Medical University, No.3, Wandao Road, Wanjiang district, Guangzhou, 523058, China
| | - Qiangqiang Liu
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Jinli Liao
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Qingli Zeng
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Chuanxi Chen
- Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China.
| | - Zhihao Liu
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-Sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China.
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Identification of a unique subset of tissue-resident memory CD4 + T cells in Crohn's disease. Proc Natl Acad Sci U S A 2023; 120:e2204269120. [PMID: 36574662 PMCID: PMC9910620 DOI: 10.1073/pnas.2204269120] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4+ tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4+ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4+ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4+ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4+ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.
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Schreibing F, Hannani MT, Kim H, Nagai JS, Ticconi F, Fewings E, Bleckwehl T, Begemann M, Torow N, Kuppe C, Kurth I, Kranz J, Frank D, Anslinger TM, Ziegler P, Kraus T, Enczmann J, Balz V, Windhofer F, Balfanz P, Kurts C, Marx G, Marx N, Dreher M, Schneider RK, Saez-Rodriguez J, Costa I, Hayat S, Kramann R. Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell immunoprofiling. Front Immunol 2022; 13:1066176. [PMID: 36591270 PMCID: PMC9800604 DOI: 10.3389/fimmu.2022.1066176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/14/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction SARS-CoV-2 infection results in varying disease severity, ranging from asymptomatic infection to severe illness. A detailed understanding of the immune response to SARS-CoV-2 is critical to unravel the causative factors underlying differences in disease severity and to develop optimal vaccines against new SARS-CoV-2 variants. Methods We combined single-cell RNA and T cell receptor sequencing with CITE-seq antibodies to characterize the CD8+ T cell response to SARS-CoV-2 infection at high resolution and compared responses between mild and severe COVID-19. Results We observed increased CD8+ T cell exhaustion in severe SARS-CoV-2 infection and identified a population of NK-like, terminally differentiated CD8+ effector T cells characterized by expression of FCGR3A (encoding CD16). Further characterization of NK-like CD8+ T cells revealed heterogeneity among CD16+ NK-like CD8+ T cells and profound differences in cytotoxicity, exhaustion, and NK-like differentiation between mild and severe disease conditions. Discussion We propose a model in which differences in the surrounding inflammatory milieu lead to crucial differences in NK-like differentiation of CD8+ effector T cells, ultimately resulting in the appearance of NK-like CD8+ T cell populations of different functionality and pathogenicity. Our in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection provides a basis for further investigation of the importance of NK-like CD8+ T cells in COVID-19 severity.
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Affiliation(s)
- Felix Schreibing
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Monica T. Hannani
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Hyojin Kim
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - James S. Nagai
- Institute for Computational Genomics, Medical Faculty, RWTH Aachen University, Aachen, Germany,Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Fabio Ticconi
- Institute for Computational Genomics, Medical Faculty, RWTH Aachen University, Aachen, Germany,Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleanor Fewings
- Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Tore Bleckwehl
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Matthias Begemann
- Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Natalia Torow
- Institute of Medical Microbiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Christoph Kuppe
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Ingo Kurth
- Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Jennifer Kranz
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Urology and Pediatric Urology, RWTH Aachen University, Aachen, Germany,Department of Urology and Kidney Transplantation, Martin Luther University (Saale), Halle, Germany
| | - Dario Frank
- Department of Medicine, St Antonius Hospital, Eschweiler, Germany
| | - Teresa M. Anslinger
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Patrick Ziegler
- Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Thomas Kraus
- Institute for Occupational, Social and Environmental Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Jürgen Enczmann
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Vera Balz
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Frank Windhofer
- Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Paul Balfanz
- Department of Cardiology, Angiology and Intensive Care Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Christian Kurts
- Institute of Molecular Medicine and Experimental Immunology, Medical Faculty, University of Bonn, Bonn, Germany
| | - Gernot Marx
- Department of Intensive and Intermediate Care, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Nikolaus Marx
- Department of Cardiology, Angiology and Intensive Care Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Michael Dreher
- Department of Pneumology and Intensive Care Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Rebekka K. Schneider
- Institute of Cell and Tumor Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Developmental Biology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Julio Saez-Rodriguez
- Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine, Heidelberg University Hospital, Heidelberg, Germany,Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Ivan Costa
- Institute for Computational Genomics, Medical Faculty, RWTH Aachen University, Aachen, Germany,Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Sikander Hayat
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Rafael Kramann
- Institute of Experimental Medicine and Systems Biology, Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Renal and Hypertensive Disorders, Rheumatological and Immunological Diseases (Medical Clinic II), Medical Faculty, RWTH Aachen University, Aachen, Germany,Department of Internal Medicine, Erasmus Medical Center (MC), Rotterdam, Netherlands,*Correspondence: Rafael Kramann,
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Hackstein CP, Costigan D, Drexhage L, Pearson C, Bullers S, Ilott N, Akther HD, Gu Y, FitzPatrick MEB, Harrison OJ, Garner LC, Mann EH, Pandey S, Friedrich M, Provine NM, Uhlig HH, Marchi E, Powrie F, Klenerman P, Thornton EE. A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice. Nat Commun 2022; 13:7472. [PMID: 36463279 PMCID: PMC9719512 DOI: 10.1038/s41467-022-35126-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 11/20/2022] [Indexed: 12/05/2022] Open
Abstract
Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.
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Affiliation(s)
- Carl-Philipp Hackstein
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Dana Costigan
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Linnea Drexhage
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Claire Pearson
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Samuel Bullers
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Nicholas Ilott
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Hossain Delowar Akther
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Yisu Gu
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Michael E B FitzPatrick
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Oliver J Harrison
- Center for Fundamental Immunology, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101, USA
- Department of Immunology, University of Washington, 750 Republican St, Seattle, WA, 98108, USA
| | - Lucy C Garner
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Elizabeth H Mann
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Sumeet Pandey
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Matthias Friedrich
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Nicholas M Provine
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit, and Biomedical Research Centre, and Department of Paediatrics, University of Oxford, Oxford, OX39DU, UK
| | - Emanuele Marchi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Emily E Thornton
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.
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31
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Notarbartolo S, Abrignani S. Human T lymphocytes at tumor sites. Semin Immunopathol 2022; 44:883-901. [PMID: 36385379 PMCID: PMC9668216 DOI: 10.1007/s00281-022-00970-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/14/2022] [Indexed: 12/15/2022]
Abstract
CD4+ and CD8+ T lymphocytes mediate most of the adaptive immune response against tumors. Naïve T lymphocytes specific for tumor antigens are primed in lymph nodes by dendritic cells. Upon activation, antigen-specific T cells proliferate and differentiate into effector cells that migrate out of peripheral blood into tumor sites in an attempt to eliminate cancer cells. After accomplishing their function, most effector T cells die in the tissue, while a small fraction of antigen-specific T cells persist as long-lived memory cells, circulating between peripheral blood and lymphoid tissues, to generate enhanced immune responses when re-encountering the same antigen. A subset of memory T cells, called resident memory T (TRM) cells, stably resides in non-lymphoid peripheral tissues and may provide rapid immunity independently of T cells recruited from blood. Being adapted to the tissue microenvironment, TRM cells are potentially endowed with the best features to protect against the reemergence of cancer cells. However, when tumors give clinical manifestation, it means that tumor cells have evaded immune surveillance, including that of TRM cells. Here, we review the current knowledge as to how TRM cells are generated during an immune response and then maintained in non-lymphoid tissues. We then focus on what is known about the role of CD4+ and CD8+ TRM cells in antitumor immunity and their possible contribution to the efficacy of immunotherapy. Finally, we highlight some open questions in the field and discuss how new technologies may help in addressing them.
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Affiliation(s)
- Samuele Notarbartolo
- INGM, Istituto Nazionale Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.
| | - Sergio Abrignani
- INGM, Istituto Nazionale Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.
- Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, Milan, Italy.
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32
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Globig AM, Mayer LS, Heeg M, Andrieux G, Ku M, Otto-Mora P, Hipp AV, Zoldan K, Pattekar A, Rana N, Schell C, Boerries M, Hofmann M, Neumann-Haefelin C, Kuellmer A, Schmidt A, Boettler T, Tomov V, Thimme R, Hasselblatt P, Bengsch B. Exhaustion of CD39-Expressing CD8 + T Cells in Crohn's Disease Is Linked to Clinical Outcome. Gastroenterology 2022; 163:965-981.e31. [PMID: 35738329 DOI: 10.1053/j.gastro.2022.06.045] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 06/07/2022] [Accepted: 06/14/2022] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Exhaustion of CD8 T cells has been suggested to inform different clinical outcomes in Crohn's disease, but detailed analyses are lacking. This study aimed to identify the role of exhaustion on a single-cell level and identify relevant CD8 T cell populations in Crohn's disease. METHODS Blood and intestinal tissue from 58 patients with Crohn's disease (active disease or remission) were assessed for CD8 T cell expression of exhaustion markers and their cytokine profile by highly multiplexed flow and mass cytometry. Key disease-associated subsets were sorted and analyzed by RNA sequencing. CD39 inhibition assays were performed in vitro. RESULTS Activated CD39+ and CD39+PD-1+ CD8 T cell subsets expressing multiple exhaustion markers were enriched at low frequency in active Crohn's disease. Their cytokine production capacity was inversely linked to the Harvey-Bradshaw Index. Subset-level protein and transcriptome profiling revealed co-existence of effector and exhaustion programs in CD39+ and CD39+ PD-1+CD8 T cells, with CD39+ cells likely originating from the intestine. CD39 enzymatic activity controlled T cell cytokine production. Importantly, transcriptional exhaustion signatures were enriched in remission in CD39-expressing subsets with up-regulation of TOX. Subset-level transcriptomics revealed a CD39-related gene module that is associated with the clinical course. CONCLUSIONS These data showed a role for the exhaustion of peripheral CD39-expressing CD8 T cell subsets in Crohn's disease. Their low frequency illustrated the utility of single-cell cytometry methods for identification of relevant immune populations. Importantly, the link of their exhaustion status to the clinical activity and their specific gene signatures have implications for exhaustion-based personalized medicine approaches.
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Affiliation(s)
- Anna-Maria Globig
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Lena Sophie Mayer
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Maximilian Heeg
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg, German Cancer Research Center, Heidelberg, Germany
| | - Manching Ku
- Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Patricia Otto-Mora
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Anna Veronika Hipp
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Katharina Zoldan
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Ajinkya Pattekar
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Nisha Rana
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Christoph Schell
- Institute for Surgical Pathology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg, German Cancer Research Center, Heidelberg, Germany
| | - Maike Hofmann
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Armin Kuellmer
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Arthur Schmidt
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Tobias Boettler
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Vesselin Tomov
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Robert Thimme
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Peter Hasselblatt
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Bertram Bengsch
- Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg, German Cancer Research Center, Heidelberg, Germany; Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany.
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High-dimensional profiling reveals Tc17 cell enrichment in active Crohn's disease and identifies a potentially targetable signature. Nat Commun 2022; 13:3688. [PMID: 35760777 PMCID: PMC9237103 DOI: 10.1038/s41467-022-31229-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 05/25/2022] [Indexed: 11/20/2022] Open
Abstract
The immune-pathology in Crohn’s disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn’s disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn’s disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions. The T cell compartment in patients with Crohn's disease is dysregulated. Here the authors use cytometric profiling to reveal an enrichment of distinct Tc17 cells during active Crohn's disease and may suggest CD6 as a potential target for therapeutic studies.
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Ogundepo S, Chiamaka AM, Olatinwo M, Adepoju D, Aladesanmi MT, Celestine UO, Ali KC, Umezinwa OJ, Olasore J, Alausa A. The role of diosgenin in crohn’s disease. CLINICAL PHYTOSCIENCE 2022. [DOI: 10.1186/s40816-022-00338-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractInflammatory bowel disease (IBD) is a chronic idiopathic inflammation that can grossly affect the entire gastrointestinal tract (GIT) from the mouth to the anus. Crohn’s disease is the most known type of IBD and has been the focus of attention due to its increase in prevalence worldwide. Although the etiology is yet to be elucidated, recent studies have pointed out Crohn’s disease to arise from a complex interaction between environmental influences, genetic predisposition, and altered gut microbiota, resulting in dysregulated adaptive and innate responses. The presenting hallmarks of Crohn’s disease may include weight loss, nausea, vomiting, abdominal pain, diarrhea, fever, or chills. Treatment is usually done with many approved immunosuppressive drugs and surgery. However, a promising avenue from natural compounds is a safer therapy due to its safe natural active ingredients and the strong activity it shows in the treatment and management of diseases. Diosgenin, “a major biologically active natural steroidal sapogenin found in Chinese yam,” has been widely reported as a therapeutic agent in the treatment of various classes of disorders such as hyperlipidemia, inflammation, diabetes, cancer, infection, and immunoregulation. In this review, an analysis of literature data on diosgenin employed as a therapeutic agent for the treatment of Crohn’s disease is approached, to strengthen the scientific database and curtail the dreadful impact of Crohn’s disease.
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Braud VM, Meghraoui-Kheddar A, Elaldi R, Petti L, Germain C, Anjuère F. LLT1-CD161 Interaction in Cancer: Promises and Challenges. Front Immunol 2022; 13:847576. [PMID: 35185935 PMCID: PMC8854185 DOI: 10.3389/fimmu.2022.847576] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 01/20/2022] [Indexed: 12/19/2022] Open
Abstract
The success of immune checkpoint therapy in cancer has changed our way of thinking, promoting the design of future cancer treatments that places the immune system at the center stage. The knowledge gained on immune regulation and tolerance helped the identification of promising new clinical immune targets. Among them, the lectin-like transcript 1 (LLT1) is the ligand of CD161 (NKR-P1A) receptor expressed on natural killer cells and T cells. LLT1/CD161 interaction modulates immune responses but the exact nature of the signals delivered is still partially resolved. Investigation on the role of LLT1/CD161 interaction has been hampered by the lack of functional homologues in animal models. Also, some studies have been misled by the use of non-specific reagents. Recent studies and meta-analyses of single cell data are bringing new insights into the function of LLT1 and CD161 in human pathology and notably in cancer. The advances made on the characterization of the tumor microenvironment prompt us to integrate LLT1/CD161 interaction into the equation. This review recapitulates the key findings on the expression profile of LLT1 and CD161, their regulation, the role of their interaction in cancer development, and the relevance of targeting LLT1/CD161 interaction.
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Affiliation(s)
- Veronique M. Braud
- Université Côte d’Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
- *Correspondence: Veronique M. Braud,
| | - Aïda Meghraoui-Kheddar
- Université Côte d’Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
| | - Roxane Elaldi
- Université Côte d’Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
| | - Luciana Petti
- Université Côte d’Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
| | | | - Fabienne Anjuère
- Université Côte d’Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France
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Pimentel-Muiños FX. Autophagy in the gastrointestinal system and cross talk with microbiota. AUTOPHAGY IN HEALTH AND DISEASE 2022:321-333. [DOI: 10.1016/b978-0-12-822003-0.00016-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Artemniak-Wojtowicz D, Kucharska AM, Stelmaszczyk-Emmel A, Majcher A, Pyrżak B. Changes of Peripheral Th17 Cells Subset in Overweight and Obese Children After Body Weight Reduction. Front Endocrinol (Lausanne) 2022; 13:917402. [PMID: 35873001 PMCID: PMC9299423 DOI: 10.3389/fendo.2022.917402] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Obesity has been a growing problem in young patients leading to serious metabolic complications. There are many studies supporting the idea, that obesity should be considered as a chronic inflammation closely associated with immune system alterations. Th17 subpopulation is strongly involved in this process. The aim of our study was to evaluate circulating Th17 cells in overweight and obese children and explore the relationships between Th17 subset and metabolic parameters. METHODS We evaluated peripheral Th17 cells in fresh peripheral blood samples from 27 overweight and obese and 15 normal-weight children. Th17 cells were identified by flow cytometry using monoclonal antibody and intracellular IL-17A staining. Th17 cells were defined as CD3+CD4+CD196+IL-17Aic+. The analysis involved anthropometric and metabolic parameters measured at baseline and three months after the change of lifestyle and diet. We evaluated the relationship between metabolic parameters and Th17 cells. RESULTS In overweight and obese children we found significantly higher Th17 cells percentage compared to normal weight controls (median 0.097% (0.044 - 0.289) vs 0.041% (0.023 - 0.099), p = 0.048). The percentage of Th17 cells decreased statistically significantly in children who reduced weight after the intervention (0.210% (0.143 - 0.315) vs 0.039% (0.028 - 0.106), p = 0.004). In this group we also noticed statistically significant reduction of TC and LDL-C concentration (p = 0.01, p = 0.04, respectively). CONCLUSIONS Obesity in children is associated with increased percentage of peripheral Th17 cells. Weight reduction leads to significant decrease of circulating Th17 cells and improvement of lipid parameters. This significant reduction of proinflammatory Th17 cells is a promising finding suggesting that obesity-induced inflammation in children could be relatively easily reversible.
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Affiliation(s)
- Dorota Artemniak-Wojtowicz
- Department of Pediatrics and Endocrinology, Medical University of Warsaw, Warsaw, Poland
- *Correspondence: Dorota Artemniak-Wojtowicz, ; Anna M. Kucharska,
| | - Anna M. Kucharska
- Department of Pediatrics and Endocrinology, Medical University of Warsaw, Warsaw, Poland
- *Correspondence: Dorota Artemniak-Wojtowicz, ; Anna M. Kucharska,
| | - Anna Stelmaszczyk-Emmel
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland
| | - Anna Majcher
- Department of Pediatrics and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Beata Pyrżak
- Department of Pediatrics and Endocrinology, Medical University of Warsaw, Warsaw, Poland
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The Role of Interleukins in the Pathogenesis of Dermatological Immune-Mediated Diseases. Adv Ther 2022; 39:4474-4508. [PMID: 35997892 PMCID: PMC9395905 DOI: 10.1007/s12325-022-02241-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/22/2022] [Indexed: 01/30/2023]
Abstract
Autoimmune inflammatory diseases are primarily characterized by deregulated expression of cytokines, which drive pathogenesis of these diseases. A number of approved and experimental therapies utilize monoclonal antibodies against cytokine proteins. Cytokines can be classified into different families including the interleukins, which are secreted and act on leukocytes, the tumor necrosis factor (TNF) family, as well as chemokine proteins. In this review article, we focus on the interleukin family of cytokines, of which 39 members have been identified to this date. We outline the role of each of these interleukins in the immune system, and various dermatological inflammatory diseases with a focused discussion on the pathogenesis of psoriasis and atopic dermatitis. In addition, we describe the roles of various interleukins in psychiatric, cardiovascular, and gastrointestinal comorbidities. Finally, we review clinical efficacy and safety data from emerging late-phase anti-interleukin therapies under development for psoriasis and atopic dermatitis. Collectively, additional fundamental and clinical research remains necessary to fully elucidate the roles of various interleukin proteins in the pathogenesis of inflammatory dermatologic diseases, and treatment outcomes in patients.
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39
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Cossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, del Zotto G, Delacher M, Di Rosa F, Di Santo J, Diefenbach A, Dong J, Dörner T, Dress RJ, Dutertre CA, Eckle SBG, Eede P, Evrard M, Falk CS, Feuerer M, Fillatreau S, Fiz-Lopez A, Follo M, Foulds GA, Fröbel J, Gagliani N, Galletti G, Gangaev A, Garbi N, Garrote JA, Geginat J, Gherardin NA, Gibellini L, Ginhoux F, Godfrey DI, Gruarin P, Haftmann C, Hansmann L, Harpur CM, Hayday AC, Heine G, Hernández DC, Herrmann M, Hoelsken O, Huang Q, Huber S, Huber JE, Huehn J, Hundemer M, Hwang WYK, Iannacone M, Ivison SM, Jäck HM, Jani PK, Keller B, Kessler N, Ketelaars S, Knop L, Knopf J, Koay HF, Kobow K, Kriegsmann K, Kristyanto H, Krueger A, Kuehne JF, Kunze-Schumacher H, Kvistborg P, Kwok I, Latorre D, et alCossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, del Zotto G, Delacher M, Di Rosa F, Di Santo J, Diefenbach A, Dong J, Dörner T, Dress RJ, Dutertre CA, Eckle SBG, Eede P, Evrard M, Falk CS, Feuerer M, Fillatreau S, Fiz-Lopez A, Follo M, Foulds GA, Fröbel J, Gagliani N, Galletti G, Gangaev A, Garbi N, Garrote JA, Geginat J, Gherardin NA, Gibellini L, Ginhoux F, Godfrey DI, Gruarin P, Haftmann C, Hansmann L, Harpur CM, Hayday AC, Heine G, Hernández DC, Herrmann M, Hoelsken O, Huang Q, Huber S, Huber JE, Huehn J, Hundemer M, Hwang WYK, Iannacone M, Ivison SM, Jäck HM, Jani PK, Keller B, Kessler N, Ketelaars S, Knop L, Knopf J, Koay HF, Kobow K, Kriegsmann K, Kristyanto H, Krueger A, Kuehne JF, Kunze-Schumacher H, Kvistborg P, Kwok I, Latorre D, Lenz D, Levings MK, Lino AC, Liotta F, Long HM, Lugli E, MacDonald KN, Maggi L, Maini MK, Mair F, Manta C, Manz RA, Mashreghi MF, Mazzoni A, McCluskey J, Mei HE, Melchers F, Melzer S, Mielenz D, Monin L, Moretta L, Multhoff G, Muñoz LE, Muñoz-Ruiz M, Muscate F, Natalini A, Neumann K, Ng LG, Niedobitek A, Niemz J, Almeida LN, Notarbartolo S, Ostendorf L, Pallett LJ, Patel AA, Percin GI, Peruzzi G, Pinti M, Pockley AG, Pracht K, Prinz I, Pujol-Autonell I, Pulvirenti N, Quatrini L, Quinn KM, Radbruch H, Rhys H, Rodrigo MB, Romagnani C, Saggau C, Sakaguchi S, Sallusto F, Sanderink L, Sandrock I, Schauer C, Scheffold A, Scherer HU, Schiemann M, Schildberg FA, Schober K, Schoen J, Schuh W, Schüler T, Schulz AR, Schulz S, Schulze J, Simonetti S, Singh J, Sitnik KM, Stark R, Starossom S, Stehle C, Szelinski F, Tan L, Tarnok A, Tornack J, Tree TIM, van Beek JJP, van de Veen W, van Gisbergen K, Vasco C, Verheyden NA, von Borstel A, Ward-Hartstonge KA, Warnatz K, Waskow C, Wiedemann A, Wilharm A, Wing J, Wirz O, Wittner J, Yang JHM, Yang J. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition). Eur J Immunol 2021; 51:2708-3145. [PMID: 34910301 PMCID: PMC11115438 DOI: 10.1002/eji.202170126] [Show More Authors] [Citation(s) in RCA: 274] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.
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Affiliation(s)
- Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Hyun-Dong Chang
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Institute for Biotechnology, Technische Universität, Berlin, Germany
| | - Andreas Radbruch
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sergio Abrignani
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Richard Addo
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Immanuel Andrä
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Francesco Andreata
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Annunziato
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Eduardo Arranz
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
| | - Petra Bacher
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology Christian-Albrechts Universität zu Kiel, Kiel, Germany
| | - Sudipto Bari
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Vincenzo Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
- Center for Life Nano & Neuro Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Rome, Italy
- Istituto Pasteur - Fondazione Cenci Bolognetti, Rome, Italy
| | | | - Dirk Baumjohann
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Cristian G. Beccaria
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - David Bernardo
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Dominic A. Boardman
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Jessica Borger
- Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
| | - Chotima Böttcher
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Leonie Brockmann
- Department of Microbiology & Immunology, Columbia University, New York City, USA
| | - Marie Burns
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Dirk H. Busch
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Garth Cameron
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Ilenia Cammarata
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Antonino Cassotta
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Yinshui Chang
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Fernando Gabriel Chirdo
- Instituto de Estudios Inmunológicos y Fisiopatológicos - IIFP (UNLP-CONICET), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Eleni Christakou
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Luka Čičin-Šain
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Laura Cook
- BC Children’s Hospital Research Institute, Vancouver, Canada
- Department of Medicine, The University of British Columbia, Vancouver, Canada
| | - Alexandra J. Corbett
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Rebecca Cornelis
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Lorenzo Cosmi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Martin S. Davey
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Gabriele De Simone
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Michael Delacher
- Institute for Immunology, University Medical Center Mainz, Mainz, Germany
- Research Centre for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - James Di Santo
- Innate Immunity Unit, Department of Immunology, Institut Pasteur, Paris, France
- Inserm U1223, Paris, France
| | - Andreas Diefenbach
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Mucosal and Developmental Immunology, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Jun Dong
- Cell Biology, German Rheumatism Research Center Berlin (DRFZ), An Institute of the Leibniz Association, Berlin, Germany
| | - Thomas Dörner
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Regine J. Dress
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Charles-Antoine Dutertre
- Institut National de la Sante Et de la Recherce Medicale (INSERM) U1015, Equipe Labellisee-Ligue Nationale contre le Cancer, Villejuif, France
| | - Sidonia B. G. Eckle
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Pascale Eede
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Maximilien Evrard
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Markus Feuerer
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Regensburg, Germany
| | - Simon Fillatreau
- Institut Necker Enfants Malades, INSERM U1151-CNRS, UMR8253, Paris, France
- Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France
- AP-HP, Hôpital Necker Enfants Malades, Paris, France
| | - Aida Fiz-Lopez
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
| | - Marie Follo
- Department of Medicine I, Lighthouse Core Facility, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Gemma A. Foulds
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Julia Fröbel
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Nicola Gagliani
- Department of Medicine, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
| | - Giovanni Galletti
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Anastasia Gangaev
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Natalio Garbi
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - José Antonio Garrote
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
- Laboratory of Molecular Genetics, Servicio de Análisis Clínicos, Hospital Universitario Río Hortega, Gerencia Regional de Salud de Castilla y León (SACYL), Valladolid, Spain
| | - Jens Geginat
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Nicholas A. Gherardin
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Dale I. Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Paola Gruarin
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Claudia Haftmann
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Leo Hansmann
- Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin (CVK), Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, Germany
| | - Christopher M. Harpur
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
| | - Adrian C. Hayday
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Guido Heine
- Division of Allergy, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Daniela Carolina Hernández
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Martin Herrmann
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Oliver Hoelsken
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Mucosal and Developmental Immunology, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Qing Huang
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Samuel Huber
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna E. Huber
- Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany
| | - Jochen Huehn
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Michael Hundemer
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - William Y. K. Hwang
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
- Department of Hematology, Singapore General Hospital, Singapore, Singapore
- Executive Offices, National Cancer Centre Singapore, Singapore
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sabine M. Ivison
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Peter K. Jani
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Baerbel Keller
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nina Kessler
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - Steven Ketelaars
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Laura Knop
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Jasmin Knopf
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Hui-Fern Koay
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Katja Kobow
- Department of Neuropathology, Universitätsklinikum Erlangen, Germany
| | - Katharina Kriegsmann
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - H. Kristyanto
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Andreas Krueger
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Jenny F. Kuehne
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Heike Kunze-Schumacher
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Pia Kvistborg
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
| | | | - Daniel Lenz
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Megan K. Levings
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
| | - Andreia C. Lino
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Francesco Liotta
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Heather M. Long
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Enrico Lugli
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Katherine N. MacDonald
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
- Michael Smith Laboratories, The University of British Columbia, Vancouver, Canada
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Mala K. Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Florian Mair
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Calin Manta
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - Rudolf Armin Manz
- Institute for Systemic Inflammation Research, University of Luebeck, Luebeck, Germany
| | | | - Alessio Mazzoni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - James McCluskey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Henrik E. Mei
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Fritz Melchers
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Susanne Melzer
- Clinical Trial Center Leipzig, Leipzig University, Härtelstr.16, −18, Leipzig, 04107, Germany
| | - Dirk Mielenz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Leticia Monin
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Gabriele Multhoff
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
- Department of Radiation Oncology, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
| | - Luis Enrique Muñoz
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Miguel Muñoz-Ruiz
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Franziska Muscate
- Department of Medicine, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ambra Natalini
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lai Guan Ng
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Department of Microbiology & Immunology, Immunology Programme, Life Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | | | - Jana Niemz
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Samuele Notarbartolo
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Lennard Ostendorf
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Laura J. Pallett
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Amit A. Patel
- Institut National de la Sante Et de la Recherce Medicale (INSERM) U1015, Equipe Labellisee-Ligue Nationale contre le Cancer, Villejuif, France
| | - Gulce Itir Percin
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Giovanna Peruzzi
- Center for Life Nano & Neuro Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - A. Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Katharina Pracht
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Irma Pujol-Autonell
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
- Peter Gorer Department of Immunobiology, King’s College London, London, UK
| | - Nadia Pulvirenti
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Linda Quatrini
- Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Kylie M. Quinn
- School of Biomedical and Health Sciences, RMIT University, Bundorra, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Helena Radbruch
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Hefin Rhys
- Flow Cytometry Science Technology Platform, The Francis Crick Institute, London, UK
| | - Maria B. Rodrigo
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - Chiara Romagnani
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Carina Saggau
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | | | - Federica Sallusto
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland
| | - Lieke Sanderink
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Regensburg, Germany
| | - Inga Sandrock
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Christine Schauer
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Alexander Scheffold
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | - Hans U. Scherer
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Matthias Schiemann
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Frank A. Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Kilian Schober
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Germany
| | - Janina Schoen
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wolfgang Schuh
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Schüler
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Axel R. Schulz
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sebastian Schulz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Julia Schulze
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sonia Simonetti
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
| | - Jeeshan Singh
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katarzyna M. Sitnik
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Regina Stark
- Charité Universitätsmedizin Berlin – BIH Center for Regenerative Therapies, Berlin, Germany
- Sanquin Research – Adaptive Immunity, Amsterdam, The Netherlands
| | - Sarah Starossom
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christina Stehle
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Franziska Szelinski
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Leonard Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Department of Microbiology & Immunology, Immunology Programme, Life Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Attila Tarnok
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany
- Department of Precision Instrument, Tsinghua University, Beijing, China
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
| | - Julia Tornack
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Timothy I. M. Tree
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Jasper J. P. van Beek
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | | | - Chiara Vasco
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Nikita A. Verheyden
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Anouk von Borstel
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Kirsten A. Ward-Hartstonge
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Klaus Warnatz
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Claudia Waskow
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich-Schiller-University Jena, Jena, Germany
- Department of Medicine III, Technical University Dresden, Dresden, Germany
| | - Annika Wiedemann
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anneke Wilharm
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - James Wing
- Immunology Frontier Research Center, Osaka University, Japan
| | - Oliver Wirz
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jens Wittner
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Jennie H. M. Yang
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Juhao Yang
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Flores RA, Cammayo PLT, Nguyen BT, Fernandez-Colorado CP, Kim S, Kim WH, Min W. Duck Interleukin-22: Identification and Expression Analysis in Riemerella anatipestifer Infection. J Immunol Res 2021; 2021:3862492. [PMID: 34805416 PMCID: PMC8601822 DOI: 10.1155/2021/3862492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/07/2021] [Indexed: 01/05/2023] Open
Abstract
Riemerella anatipestifer is one of the most devastating pathogens affecting the global duck farms. Infection is involved in secretion of proinflammatory cytokines, including interleukin- (IL-) 17A. During the immune response to infection, IL-22 and IL-17A are often produced concurrently and at high levels in inflamed tissues. Little is known about duck IL-22 (duIL-22) during R. anatipestifer infection. We describe the characterization of duIL-22 and its mRNA expression analysis in splenic lymphocytes and macrophages treated with heat-killed R. anatipestifer and in the spleens and livers of R. anatipestifer-infected ducks. Full-length cDNA of duIL-22 encoded 197 amino acids. The deduced amino acid sequence of duIL-22 shared a 30.4-40.5% similarity with piscine counterparts, 57.4-60.1% with mammalian homologs, and 93.4% similarity to the chicken. Duck IL-22 mRNA expression level was relatively high in the skin of normal ducks. It was increased in mitogen-stimulated splenic lymphocytes and in killed R. anatipestifer-activated splenic lymphocytes and macrophages. Compared with healthy ducks, IL-22 transcript expression was significantly upregulated in the livers and spleens on days 1 and 4 postinfection, but not on day 7. IL-17A was significantly increased in the spleens only on day 4 postinfection and in the livers at all time points. When splenic lymphocytes were stimulated with heat-killed R. anatipestifer, CD4+ cells predominantly produced IL-22 while IL-17A was expressed both by CD4+ and CD4- cells. These results suggested that IL-22 and IL-17A are likely expressed in different cell types during R. anatipestifer infection.
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Affiliation(s)
- Rochelle A. Flores
- College of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Paula Leona T. Cammayo
- College of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Binh T. Nguyen
- College of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Cherry P. Fernandez-Colorado
- Department of Veterinary Paraclinical Sciences, College of Veterinary Medicine, University of the Philippines Los Baños College, Laguna 4031, Philippines
| | - Suk Kim
- College of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Woo H. Kim
- College of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Wongi Min
- College of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
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41
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Eliasse Y, Leveque E, Garidou L, Battut L, McKenzie B, Nocera T, Redoules D, Espinosa E. IL-17 + Mast Cell/T Helper Cell Axis in the Early Stages of Acne. Front Immunol 2021; 12:740540. [PMID: 34650562 PMCID: PMC8506309 DOI: 10.3389/fimmu.2021.740540] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/02/2021] [Indexed: 12/19/2022] Open
Abstract
Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.
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Affiliation(s)
- Yoan Eliasse
- Inserm, U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.,Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Edouard Leveque
- Inserm, U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.,Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Lucile Garidou
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse, France
| | - Louise Battut
- Inserm, U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.,Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Brienne McKenzie
- Inserm, U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.,Université de Toulouse, Université Paul Sabatier, Toulouse, France
| | - Thérèse Nocera
- Clinical Evaluation Center, Pierre Fabre Dermo-Cosmétique, Toulouse, France.,Dermatology Department, University Hospital Larrey, Toulouse, France
| | - Daniel Redoules
- Department of Pharmacology, Pierre Fabre Dermo-Cosmétique, Toulouse, France
| | - Eric Espinosa
- Inserm, U1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Toulouse, France.,Université de Toulouse, Université Paul Sabatier, Toulouse, France
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42
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Shenoy AT, Lyon De Ana C, Arafa EI, Salwig I, Barker KA, Korkmaz FT, Ramanujan A, Etesami NS, Soucy AM, Martin IMC, Tilton BR, Hinds A, Goltry WN, Kathuria H, Braun T, Jones MR, Quinton LJ, Belkina AC, Mizgerd JP. Antigen presentation by lung epithelial cells directs CD4 + T RM cell function and regulates barrier immunity. Nat Commun 2021; 12:5834. [PMID: 34611166 PMCID: PMC8492657 DOI: 10.1038/s41467-021-26045-w] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 08/31/2021] [Indexed: 12/17/2022] Open
Abstract
Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity.
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Affiliation(s)
- Anukul T Shenoy
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Carolina Lyon De Ana
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Emad I Arafa
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Isabelle Salwig
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
| | - Kimberly A Barker
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Filiz T Korkmaz
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Aditya Ramanujan
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Neelou S Etesami
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Alicia M Soucy
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Ian M C Martin
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Brian R Tilton
- Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Anne Hinds
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Wesley N Goltry
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Hasmeena Kathuria
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Thomas Braun
- Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
| | - Matthew R Jones
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Lee J Quinton
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Anna C Belkina
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA
- Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, 02118, USA
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Joseph P Mizgerd
- Pulmonary Center, Boston University School of Medicine, Boston, MA, 02118, USA.
- Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA.
- Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, 02118, USA.
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43
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Wah-Suárez MI, Vázquez MAM, Bosques-Padilla FJ. Inflammatory bowel disease: The role of commensal microbiome in immune regulation. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:626-636. [PMID: 34543718 DOI: 10.1016/j.gastrohep.2021.08.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/29/2021] [Indexed: 11/29/2022]
Abstract
The incidence of inflammatory bowel disease (IBD) is increasing. Microbiome is one of the most important factors in its development and affects the different clinical outcomes of IBD patients depending on its composition and different alterations. We conducted a systematic review to discuss the association between microbiome and IBD in terms of immune regulation, and therapies that can modify microbiota. A comprehensive systematic literature search was performed through April 2020 in PubMed, Web of Science, the Cochrane Library, and clinicaltrials.gov. Inclusion criteria required IBD immune regulation and alternate therapeutics for IBD. This analysis helps explain the multifactorial origin of microbiome diversity including normal immune regulation, immune pathophysiology of IBD, and shows the evidence of several therapeutic targets to change microbiome in patients with IBD, such as prebiotics, probiotics, antibiotics, fecal microbiota transplant, and others.
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44
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Zanza C, Romenskaya T, Thangathurai D, Ojetti V, Saviano A, Abenavoli L, Robba C, Cammarota G, Franceschi F, Piccioni A, Longhitano Y. Microbiome in Critical illness: An Unconventional and Unknown Ally. Curr Med Chem 2021; 29:3179-3188. [PMID: 34525908 DOI: 10.2174/0929867328666210915115056] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/10/2021] [Accepted: 08/15/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The digestive tract represents an interface between the external environment and the body where the interaction of a complex polymicrobial ecology has an important influence on health and disease. The physiological mechanisms that are altered during the hospitalization and in the intensive care unit (ICU) contribute to the pathobiota's growth. Intestinal dysbiosis occurs within hours of being admitted to ICU. This may be due to different factors, such as alterations of normal intestinal transit, administration of variuos medications or alterations in the intestinal wall which causes a cascade of events that will lead to the increase of nitrates and decrease of oxygen concentration, liberation of free radicals. OBJECTIVE This work aims to report the latest updates on the microbiota's contribution to developing sepsis in patients in the ICU department. In this short review were reviewed the latest scientific findings on the mechanisms of intestinal immune defenses performed both locally and systemically. In addition, we considered it necessary to review the literature to report the current best treatment strategies to prevent the infection spread which can bring systemic infections in patients admitted to ICU. MATERIAL AND METHODS This review has been written to answer at three main questions: what are the main intestinal flora's defense mechanisms that help us to prevent the risk of developing systemic diseases on a day-to-day basis? What are the main dysbiosis' systemic abnormalities? What are the modern strategies that are used in the ICU patients to prevent the infection spread? Using the combination of following keywords: microbiota and ICU, ICU and gut, microbiota and critical illness, microbiota and critical care, microbiota and sepsis, microbiota and infection, gastrointestinal immunity,in the Cochrane Controlled Trials Register, the Cochrane Library, medline and pubmed, google scholar, ovid/wiley. Finally, we reviewed and selected 72 articles. We also consulted the site ClinicalTrials.com to find out studies that are recently conducted or ongoing. RESULTS The critical illness can alter intestinal bacterial flora leading to homeostasis disequilibrium. Despite numerous mechanisms, such as epithelial cells with calciform cells that together build a mechanical barrier for pathogenic bacteria, the presence of mucous associated lymphoid tissue (MALT) which stimulates an immune response through the production of interferon-gamma (IFN-y) and THN-a or by stimulating lymphocytes T helper-2 produces anti-inflammatory cytokines. But these defenses can be altered following a hospitalization in ICU and lead to serious complications such as acute respiratory distress syndrome (ARDS), health care associated pneumonia (HAP) and ventilator associated pneumonia (VAP), Systemic infection and multiple organ failure (MOF), but also in the development of coronary artery disease (CAD). In addition, the microbiota has a significant impact on the development of intestinal complications and the severity of the SARS-COVID-19 patients. CONCLUSION The microbiota is recognized as one of the important factors that can worsen the clinical conditions of patients who are already very frailty in intensive care unit. At the same time, the microbiota also plays a crucial role in the prevention of ICU associated complications. By using the resources, we have available, such as probiotics, symbiotics or fecal microbiota transplantation (FMT), we can preserve the integrity of the microbiota and the GUT, which will later help maintain homeostasis in ICU patients.
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Affiliation(s)
- Christian Zanza
- Department of Emergency Medicine Division, Policlinico Gemelli/IRCCS- University of Catholic of Sacred Heart, Rome. Italy
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care Medicine - AON St. Antonio and Biagio and Cesare Arrigo Hospital, Alessandria. Italy
| | - Duraiyah Thangathurai
- Department of Anesthesiology - Keck Medical School of University of Southern California, Los Angeles. United States
| | - Veronica Ojetti
- Department of Emergency Medicine Division, Policlinico Gemelli/IRCCS- University of Catholic of Sacred Heart, Rome. Italy
| | - Angela Saviano
- Department of Emergency Medicine Division, Policlinico Gemelli/IRCCS- University of Catholic of Sacred Heart, Rome. Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, University "Magna Graecia", Catanzaro. Italy
| | - Chiara Robba
- Department of Surgical Sciences and Diagnostic Integrated, University of Genoa. Italy
| | - Gianmaria Cammarota
- Department of Medicine and Surgery, Section of Anaesthesia, Analgesia, and Intensive Care, University of Perugia, Perugia. Italy
| | - Francesco Franceschi
- Department of Emergency Medicine Division, Policlinico Gemelli/IRCCS- University of Catholic of Sacred Heart, Rome. Italy
| | - Andrea Piccioni
- Department of Emergency Medicine Division, Policlinico Gemelli/IRCCS- University of Catholic of Sacred Heart, Rome. Italy
| | - Yaroslava Longhitano
- Foundation of "Ospedale Alba-Bra" and Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, Verduno. Italy
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45
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Wyrożemski Ł, Qiao SW. Immunobiology and conflicting roles of the human CD161 receptor in T cells. Scand J Immunol 2021; 94:e13090. [PMID: 35611672 DOI: 10.1111/sji.13090] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/29/2021] [Accepted: 06/21/2021] [Indexed: 12/22/2022]
Abstract
Human C-type lectin-like CD161 is a type-II transmembrane protein expressed on the surface of various lymphocytes across innate and adaptive immune systems. CD161+ T cells displayed enhanced ability to produce cytokines and were shown to be enriched in the gut. Independently of function, CD161 was used as marker of innate-like T cells and marker of IL-17-producing cells. The function of CD161 is still not fully understood. In T cells, CD161 was proposed to act as co-signalling receptor that influence T-cell receptor-dependent responses. However, conflicting studies were published demonstrating lack of agreement over the role of CD161 during T-cell activation. In this review, we outline phenotypical and functional consequences of CD161 expression in T cells. We provide critical discussion over the most pressing issues including in depth evaluation of the literature concerning CD161 putative co-signalling properties.
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Affiliation(s)
- Łukasz Wyrożemski
- K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway.,Department of Immunology, University of Oslo, Oslo, Norway
| | - Shuo-Wang Qiao
- K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway.,Department of Immunology, University of Oslo, Oslo, Norway.,Department of Immunology, Oslo University Hospital, Oslo, Norway
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46
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Bhattarai A, Kowalczyk W, Tran TN. A literature review on large intestinal hyperelastic constitutive modeling. Clin Biomech (Bristol, Avon) 2021; 88:105445. [PMID: 34416632 DOI: 10.1016/j.clinbiomech.2021.105445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/29/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023]
Abstract
Impacts, traumas and strokes are spontaneously life-threatening, but chronic symptoms strangle patient every day. Colorectal tissue mechanics in such chronic situations not only regulates the physio-psychological well-being of the patient, but also confirms the level of comfort and post-operative clinical outcomes. Numerous uniaxial and multiaxial tensile experiments on healthy and affected samples have evidenced significant differences in tissue mechanical behavior and strong colorectal anisotropy across each layer in thickness direction and along the length. Furthermore, this study reviewed various forms of passive constitutive models for the highly fibrous colorectal tissue ranging from the simplest linearly elastic and the conventional isotropic hyperelastic to the most sophisticated second harmonic generation image based anisotropic mathematical formulation. Under large deformation, the isotropic description of tissue mechanics is unequivocally ineffective which demands a microstructural based tissue definition. Therefore, the information collected in this review paper would present the current state-of-the-art in colorectal biomechanics and profoundly serve as updated computational resources to develop a sophisticated characterization of colorectal tissues.
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Affiliation(s)
- Aroj Bhattarai
- Department of Orthopaedic Surgery, University of Saarland, Germany
| | | | - Thanh Ngoc Tran
- Department of Orthopaedic Surgery, University of Saarland, Germany.
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47
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Aschenbrenner D, Quaranta M, Banerjee S, Ilott N, Jansen J, Steere B, Chen YH, Ho S, Cox K, Arancibia-Cárcamo CV, Coles M, Gaffney E, Travis SP, Denson L, Kugathasan S, Schmitz J, Powrie F, Sansom SN, Uhlig HH. Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance. Gut 2021; 70:1023-1036. [PMID: 33037057 PMCID: PMC8108288 DOI: 10.1136/gutjnl-2020-321731] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/16/2020] [Accepted: 08/28/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.
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Affiliation(s)
- Dominik Aschenbrenner
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
| | - Maria Quaranta
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Milan, Italy
| | - Soumya Banerjee
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
- Department of Psychology, University of Cambridge, Cambridge, Cambridgeshire, UK
| | - Nicholas Ilott
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, Oxfordshire, UK
| | - Joanneke Jansen
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
- Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, Oxfordshire, UK
| | - Boyd Steere
- Immunology Translational Sciences, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Yin-Huai Chen
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
| | - Stephen Ho
- Immunology Translational Sciences, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Karen Cox
- Immunology Translational Sciences, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Carolina V Arancibia-Cárcamo
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
| | - Mark Coles
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, Oxfordshire, UK
| | - Eamonn Gaffney
- Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, Oxfordshire, UK
| | - Simon Pl Travis
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
| | - Lee Denson
- Pediatric Gastroenterology, Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio, USA
| | - Subra Kugathasan
- Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Jochen Schmitz
- Immunology Translational Sciences, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, Oxfordshire, UK
| | - Stephen N Sansom
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, Oxfordshire, UK
| | - Holm H Uhlig
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK
- Department of Paediatrics, University of Oxford, Oxford, Oxfordshire, UK
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48
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Camiolo MJ, Zhou X, Oriss TB, Yan Q, Gorry M, Horne W, Trudeau JB, Scholl K, Chen W, Kolls JK, Ray P, Weisel FJ, Weisel NM, Aghaeepour N, Nadeau K, Wenzel SE, Ray A. High-dimensional profiling clusters asthma severity by lymphoid and non-lymphoid status. Cell Rep 2021; 35:108974. [PMID: 33852838 PMCID: PMC8133874 DOI: 10.1016/j.celrep.2021.108974] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 02/26/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022] Open
Abstract
Clinical definitions of asthma fail to capture the heterogeneity of immune dysfunction in severe, treatment-refractory disease. Applying mass cytometry and machine learning to bronchoalveolar lavage (BAL) cells, we find that corticosteroid-resistant asthma patients cluster largely into two groups: one enriched in interleukin (IL)-4+ innate immune cells and another dominated by interferon (IFN)-γ+ T cells, including tissue-resident memory cells. In contrast, BAL cells of a healthier population are enriched in IL-10+ macrophages. To better understand cellular mediators of severe asthma, we developed the Immune Cell Linkage through Exploratory Matrices (ICLite) algorithm to perform deconvolution of bulk RNA sequencing of mixed-cell populations. Signatures of mitosis and IL-7 signaling in CD206-FcεRI+CD127+IL-4+ innate cells in one patient group, contrasting with adaptive immune response in T cells in the other, are preserved across technologies. Transcriptional signatures uncovered by ICLite identify T-cell-high and T-cell-poor severe asthma patients in an independent cohort, suggesting broad applicability of our findings.
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Affiliation(s)
- Matthew J Camiolo
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Xiaoying Zhou
- Sean N Parker Center for Allergy Research and Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA, USA
| | - Timothy B Oriss
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Qi Yan
- Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael Gorry
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - William Horne
- Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - John B Trudeau
- Department of Environmental Medicine and Occupational Health, Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kathryn Scholl
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Wei Chen
- Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jay K Kolls
- Department of Medicine and Center for Translational Research in Infection and Inflammation Tulane School of Medicine, New Orleans, LA, USA
| | - Prabir Ray
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Florian J Weisel
- Departments of Anesthesiology, Pain, and Peri-operative Medicine and Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Nadine M Weisel
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Nima Aghaeepour
- Departments of Anesthesiology, Pain, and Peri-operative Medicine and Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Kari Nadeau
- Sean N Parker Center for Allergy Research and Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA, USA
| | - Sally E Wenzel
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Environmental Medicine and Occupational Health, Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Anuradha Ray
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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49
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Bertschi NL, Bazzini C, Schlapbach C. The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum Update 2021. Int Arch Allergy Immunol 2021; 182:365-380. [PMID: 33845475 DOI: 10.1159/000515144] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/09/2021] [Indexed: 11/19/2022] Open
Abstract
T helper (TH) cells have evolved into distinct subsets that mediate specific immune responses to protect the host against a myriad of infectious and noninfectious challenges. However, if dysregulated, TH-cell subsets can cause inflammatory disease. Emerging evidence now suggests that human allergic disease is caused by a distinct subpopulation of pathogenic TH2 cells. Pathogenic TH2 cells from different type-2-driven diseases share a core phenotype and show overlapping functional attributes. The unique differentiation requirements, activating signals, and metabolic characteristics of pathogenic TH2 cells are just being discovered. A better knowledge of this particular TH2 cell population will enable the specific targeting of disease-driving pathways in allergy. In this review, we introduce a rational for classifying TH cells into distinct subsets, discuss the current knowledge on pathogenic TH2 cells, and summarize their involvement in allergic diseases.
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Affiliation(s)
- Nicole L Bertschi
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Cecilia Bazzini
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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50
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Bartolomé-Casado R, Landsverk OJB, Chauhan SK, Sætre F, Hagen KT, Yaqub S, Øyen O, Horneland R, Aandahl EM, Aabakken L, Bækkevold ES, Jahnsen FL. CD4 + T cells persist for years in the human small intestine and display a T H1 cytokine profile. Mucosal Immunol 2021; 14:402-410. [PMID: 32572129 DOI: 10.1038/s41385-020-0315-5] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/30/2020] [Accepted: 06/03/2020] [Indexed: 02/04/2023]
Abstract
Studies in mice and humans have shown that CD8+ T cell immunosurveillance in non-lymphoid tissues is dominated by resident populations. Whether CD4+ T cells use the same strategies to survey peripheral tissues is less clear. Here, examining the turnover of CD4+ T cells in transplanted duodenum in humans, we demonstrate that the majority of CD4+ T cells were still donor-derived one year after transplantation. In contrast to memory CD4+ T cells in peripheral blood, intestinal CD4+ TRM cells expressed CD69 and CD161, but only a minor fraction expressed CD103. Functionally, intestinal CD4+ TRM cells were very potent cytokine producers; the vast majority being polyfunctional TH1 cells, whereas a minor fraction produced IL-17. Interestingly, a fraction of intestinal CD4+ T cells produced granzyme-B and perforin after activation. Together, we show that the intestinal CD4+ T-cell compartment is dominated by resident populations that survive for more than 1 year. This finding is of high relevance for the development of oral vaccines and therapies for diseases in the gut.
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Affiliation(s)
| | - Ole J B Landsverk
- Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Sudhir Kumar Chauhan
- Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway.,Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Frank Sætre
- Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | | | - Sheraz Yaqub
- Department of Gastrointestinal Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Ole Øyen
- Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Rune Horneland
- Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Einar Martin Aandahl
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Lars Aabakken
- Department of Gastroenterology, Oslo University Hospital - Rikshospitalet, Oslo, Norway
| | - Espen S Bækkevold
- Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Frode L Jahnsen
- Department of Pathology, Oslo University Hospital and University of Oslo, Oslo, Norway.
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