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1
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Merolle M, Striepen B, Hunter CA. Parasite and host immune factors that impact the development of a mucosal vaccine for Cryptosporidium. Mucosal Immunol 2025:S1933-0219(25)00049-2. [PMID: 40379259 DOI: 10.1016/j.mucimm.2025.05.002] [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: 12/23/2024] [Revised: 03/28/2025] [Accepted: 05/07/2025] [Indexed: 05/19/2025]
Abstract
The parasite Cryptosporidium is a leading cause of diarrhea and death in malnourished children and immunocompromised individuals and an important enteric pathogen of livestock. A mucosal vaccine to mitigate clinical disease and decrease transmission would address the public health impact of this organism, but current options are limited. The development of a rational strategy for vaccination requires an appreciation of the parasite life cycle, how Cryptosporidium interacts with its host cell (the enterocyte), and the immune mechanisms that act locally to control this organism. Here we review current knowledge of the adaptive immune mechanisms that mediate resistance to Cryptosporidium, their relevance to vaccine design, and how recent advances in parasite genetics inform vaccine development.
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Affiliation(s)
- Maria Merolle
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 380 South University Avenue, Philadelphia, PA 19104, United States
| | - Boris Striepen
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 380 South University Avenue, Philadelphia, PA 19104, United States
| | - Christopher A Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 380 South University Avenue, Philadelphia, PA 19104, United States.
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2
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Tso P, Bernier-Latmani J, Petrova TV, Liu M. Transport functions of intestinal lymphatic vessels. Nat Rev Gastroenterol Hepatol 2025; 22:127-145. [PMID: 39496888 DOI: 10.1038/s41575-024-00996-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2024] [Indexed: 11/06/2024]
Abstract
Lymphatic vessels are crucial for fluid absorption and the transport of peripheral immune cells to lymph nodes. However, in the small intestine, the lymphatic fluid is rich in diet-derived lipids incorporated into chylomicrons and gut-specific immune cells. Thus, intestinal lymphatic vessels have evolved to handle these unique cargoes and are critical for systemic dietary lipid delivery and metabolism. This Review covers mechanisms of lipid absorption from epithelial cells to the lymphatics as well as unique features of the gut microenvironment that affect these functions. Moreover, we discuss details of the intestinal lymphatics in gut immune cell trafficking and insights into the role of inter-organ communication. Lastly, we highlight the particularities of fat absorption that can be harnessed for efficient lipid-soluble drug distribution for novel therapies, including the ability of chylomicron-associated drugs to bypass first-pass liver metabolism for systemic delivery. In all, this Review will help to promote an understanding of intestinal lymphatic-systemic interactions to guide future research directions.
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Affiliation(s)
- Patrick Tso
- Department of Pathology & Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.
| | - Jeremiah Bernier-Latmani
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Tatiana V Petrova
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
- Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Lausanne, Switzerland
| | - Min Liu
- Department of Pathology & Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA
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3
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Saunders MN, Rad LM, Williams LA, Landers JJ, Urie RR, Hocevar SE, Quiros M, Chiang M, Angadi AR, Janczak KW, Bealer EJ, Crumley K, Benson OE, Griffin KV, Ross BC, Parkos CA, Nusrat A, Miller SD, Podojil JR, O'Konek JJ, Shea LD. Allergen-Encapsulating Nanoparticles Reprogram Pathogenic Allergen-Specific Th2 Cells to Suppress Food Allergy. Adv Healthc Mater 2025; 14:e2400237. [PMID: 38691819 PMCID: PMC11527797 DOI: 10.1002/adhm.202400237] [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: 01/20/2024] [Revised: 04/10/2024] [Indexed: 05/03/2024]
Abstract
Food allergy is a prevalent, potentially deadly disease caused by inadvertent sensitization to benign food antigens. Pathogenic Th2 cells are a major driver for disease, and allergen-specific immunotherapies (AIT) aim to increase the allergen threshold required to elicit severe allergic symptoms. However, the majority of AIT approaches require lengthy treatments and convey transient disease suppression, likely due to insufficient targeting of pathogenic Th2 responses. Here, the ability of allergen-encapsulating nanoparticles to directly suppress pathogenic Th2 responses and reactivity is investigated in a mouse model of food allergy. NPs associate with pro-tolerogenic antigen presenting cells, provoking accumulation of antigen-specific, functionally suppressive regulatory T cells in the small intestine lamina propria. Two intravenous doses of allergen encapsulated in poly(lactide-co-glycolide) nanoparticles (NPs) significantly reduces oral food challenge (OFC)-induced anaphylaxis. Importantly, NP treatment alters the fates of pathogenic allergen-specific Th2 cells, reprogramming these cells toward CD25+FoxP3+ regulatory and CD73+FR4+ anergic phenotypes. NP-mediated reductions in the frequency of effector cells in the gut and mast cell degranulation following OFC are also demonstrated. These studies reveal mechanisms by which an allergen-encapsulating NP therapy and, more broadly, allergen-specific immunotherapies, can rapidly attenuate allergic responses by targeting pathogenic Th2 cells.
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Affiliation(s)
- Michael N. Saunders
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Laila M. Rad
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Laura A. Williams
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Jeffrey J. Landers
- Mary H. Weiser Food Allergy CenterUniversity of MichiganAnn ArborMI48109USA
| | - Russell R. Urie
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Sarah E. Hocevar
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Neuroscience Graduate ProgramUniversity of MichiganAnn ArborMI48109USA
| | - Miguel Quiros
- Department of PathologyUniversity of MichiganAnn ArborMI48109USA
| | - Ming‐Yi Chiang
- Department of Microbiology‐ImmunologyNorthwestern UniversityChicagoIL60611USA
| | - Amogh R. Angadi
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | | | - Elizabeth J. Bealer
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Kelly Crumley
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Olivia E. Benson
- Mary H. Weiser Food Allergy CenterUniversity of MichiganAnn ArborMI48109USA
| | - Kate V. Griffin
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Brian C. Ross
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | | | - Asma Nusrat
- Department of PathologyUniversity of MichiganAnn ArborMI48109USA
| | - Stephen D. Miller
- Department of Microbiology‐ImmunologyNorthwestern UniversityChicagoIL60611USA
- Center for Human ImmunobiologyNorthwestern UniversityChicagoIL60611USA
- Interdepartmental Immunobiology CenterFeinberg School of MedicineNorthwestern UniversityChicagoIL60611USA
| | - Joseph R. Podojil
- Department of Microbiology‐ImmunologyNorthwestern UniversityChicagoIL60611USA
- Center for Human ImmunobiologyNorthwestern UniversityChicagoIL60611USA
- Cour Pharmaceuticals Development CompanyNorthbrookIL60077USA
| | - Jessica J. O'Konek
- Mary H. Weiser Food Allergy CenterUniversity of MichiganAnn ArborMI48109USA
| | - Lonnie D. Shea
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Department of Chemical EngineeringUniversity of MichiganAnn ArborMI48109USA
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4
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Xu BL, Wang YY, Chu XL, Dong CM. Research progress and immunological insights of shrimp allergens. FISH & SHELLFISH IMMUNOLOGY 2025; 156:110051. [PMID: 39608732 DOI: 10.1016/j.fsi.2024.110051] [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: 07/16/2024] [Revised: 11/09/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
Allergic diseases have become a major health issue in the 21st century. The FAO has pinpointed the eight most prevalent allergens worldwide, with shrimp allergy attracting global concern due to its escalating incidence. This review delves into the current knowledge of shrimp allergen types and traits, immune response mechanisms, advancements in cross-reactivity research, and breakthroughs in diagnostic and therapeutic methods. It highlights the variety of shrimp allergens, such as tropomyosin and arginine kinase, and concentrates on IgE-mediated immediate hypersensitivity reactions, involving mast cells and basophils, alongside the role of T cells and cytokines in non-IgE-mediated delayed hypersensitivity reactions. The exploration of cross-reactivity underscores the connection between shrimp allergy and allergies to other animals. Utilizing bioinformatics tools, including homology analysis, epitope prediction, and molecular modeling, has enhanced our comprehension of allergen molecular features. In treatment and diagnosis, innovative approaches like immunotherapy and gene editing technology hold potential to decrease allergic sensitivity, while emerging reduction techniques like heat treatment and enzymatic hydrolysis offer new strategies for the prevention and management of food allergies. The evolution of allergen detection and purification technologies has spurred innovation in testing methodologies, encompassing traditional in vivo tests like SPT and DBPCFC, in addition to a range of other techniques such as immunoassays, biochip technology, PCR, and histamine release experiments, propelling the instantaneous and accurate identification of allergens. These scientific breakthroughs not only expand our understanding of shrimp allergen biology but also lay the foundation for developing more effective allergy prevention and control strategies.
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Affiliation(s)
- Bao-Liang Xu
- College of Marine and Environmental Sciences, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Yuan-Yuan Wang
- College of Marine and Environmental Sciences, Tianjin University of Science and Technology, Tianjin, 300457, China
| | - Xin-Lei Chu
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China.
| | - Chun-Ming Dong
- College of Marine and Environmental Sciences, Tianjin University of Science and Technology, Tianjin, 300457, China.
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5
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Yin H, Feng Y, Wang Y, Jiang Q, Zhang J, Zhao J, Chen Y, Wang Y, Peng R, Wang Y, Zhao T, Zheng C, Xu L, Gao X, Gao H, Li J, Wang Z, Zhang L. Genome-Wide Scans for Selection Signatures in Ningxia Angus Cattle Reveal Genetic Variants Associated with Economic and Adaptive Traits. Animals (Basel) 2024; 15:58. [PMID: 39795001 PMCID: PMC11718920 DOI: 10.3390/ani15010058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
The genetic improvement of beef cattle breeds is crucial for the advancement of the beef cattle industry. Whole-genome resequencing technology has been widely applied in genetic breeding as well as research on selection signatures in beef cattle. In this study, 20× whole-genome resequencing was performed on 282 Angus cattle from the Ningxia region, and a high-quality dataset encompassing extensive genomic variations across the entire genome was constructed. The iHS test identified 495 selection signal regions, which included pregnancy-associated glycoprotein (PAG) family genes and immune-related genes such as UL16-binding protein 21 (ULBP21), CD1b molecule (CD1B), and tumor necrosis factor ligand superfamily member 11 (TNFSF11). A quantitative trait locus (QTL) enrichment analysis revealed that several economic traits, including longissimus muscle area, marbling score, carcass weight, average daily gain, and milk yield, were significantly enriched in cattle with these selection signatures. Although the enrichment of QTLs for health traits was low, immune-related genes may indirectly contribute to improvements in production performance. These findings show the genetic basis of economic and adaptive traits in Ningxia Angus cattle, providing a theoretical foundation and guidance for further genetic improvement and breeding strategies.
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Affiliation(s)
- Haiqi Yin
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Yuan Feng
- Ningxia Autonomous Region Animal Husbandry Workstation, Yinchuan 750004, China; (Y.F.); (Y.W.); (Q.J.); (J.Z.)
| | - Yu Wang
- Ningxia Autonomous Region Animal Husbandry Workstation, Yinchuan 750004, China; (Y.F.); (Y.W.); (Q.J.); (J.Z.)
| | - Qiufei Jiang
- Ningxia Autonomous Region Animal Husbandry Workstation, Yinchuan 750004, China; (Y.F.); (Y.W.); (Q.J.); (J.Z.)
| | - Juan Zhang
- School of Animal Science and Technology, Ningxia University, Yinchuan 750021, China;
| | - Jie Zhao
- Ningxia Autonomous Region Animal Husbandry Workstation, Yinchuan 750004, China; (Y.F.); (Y.W.); (Q.J.); (J.Z.)
| | - Yafei Chen
- Yinchuan Animal Husbandry Technology Extension Service Center, Yinchuan 750021, China;
| | - Yaxuan Wang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Ruiqi Peng
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Yahui Wang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Tong Zhao
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Caihong Zheng
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Lingyang Xu
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Xue Gao
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Huijiang Gao
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Junya Li
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Zezhao Wang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
| | - Lupei Zhang
- State Key Laboratory of Animal Biotech Breeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (H.Y.); (Y.W.); (R.P.); (Y.W.); (T.Z.); (C.Z.); (L.X.); (X.G.); (H.G.); (J.L.)
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6
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Vitali R, Novelli F, Palone F, Cucchiara S, Stronati L, Pioli C. PARP1 inactivation increases regulatory T / Th17 cell proportion in intestinal inflammation. Role of HMGB1. Immunol Lett 2024; 270:106912. [PMID: 39237041 DOI: 10.1016/j.imlet.2024.106912] [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: 12/29/2023] [Revised: 08/12/2024] [Accepted: 09/01/2024] [Indexed: 09/07/2024]
Abstract
Inflammatory bowel diseases (IBD) are chronic relapsing disorders with increasing prevalence. Knowledge gaps still limit the possibility to develop more specific and effective therapies. Using a dextran sodium sulfate colitis mouse model, we found that inflammation increased the total number and altered the frequencies of leukocytes within colon mesenteric lymph nodes (cMLNs). Although the inflammation reduced the frequency of regulatory T (Treg) cells, their absolute numbers were increased. Increased frequency of colitogenic Th17 cells was also observed. Noteworthy, untreated mice lacking Poly(ADP-ribose)-Polimerase-1 functional gene (PARP-1KO) displayed higher frequency of Treg cells and lower percentage of Th17 cells in cMLNs. In colitic PARP-1KO mice the inflammation driven expansion of the Foxp3 Treg population was more pronounced than in WT mice. Conversely, colitis increased Th17 cells to a lower extent in PARP-1KO mice compared with WT mice, resulting in a more protective Treg/Th17 cell ratio. Consequently PARP-1KO mice developed less severe colitis with reduced expression of inflammatory cytokines. In ex vivo experiments PARP-1KO and WT CD11c dendritic cells (DCs) promoted naïve CD4 T cell differentiation differently, the former sustaining more efficiently the generation of Treg cells, the latter that of Th17 cells. Addition of HMGB1 B box or of dipotassium glycyrrhizate, which sequesters extracellular HMGB1, revealed a role for this alarmin in the regulation exerted by PARP-1 on the stimulating vs. tolerogenic function of DCs during colitis. Moreover, a higher percentage of CD11c DC from PARP-1KO mice expressed CD103, a marker associated with the ability of DC to induce Treg cells, compared with WT DC. Conversely, PARP-1KO DC were including a reduced percentage of CX3CR1+ DC, described to induce Th17 cells. These findings were observed in both splenic and colon lamina propria DC.
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Affiliation(s)
| | | | | | - Salvatore Cucchiara
- Department of Maternal Infantile and Urological Sciences, Sapienza University, Rome, Italy
| | - Laura Stronati
- Department of Molecular Medicine, Sapienza University, Rome, Italy
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7
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Raya Tonetti F, Eguileor A, Mrdjen M, Pathak V, Travers J, Nagy LE, Llorente C. Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology 2024; 80:1342-1371. [PMID: 38691396 PMCID: PMC11801230 DOI: 10.1097/hep.0000000000000924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/20/2024] [Indexed: 05/03/2024]
Abstract
The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.
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Affiliation(s)
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Marko Mrdjen
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Vai Pathak
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jared Travers
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, University Hospital, Cleveland OH
| | - Laura E Nagy
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Magnusen AF, Pandey MK. Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int J Mol Sci 2024; 25:12252. [PMID: 39596318 PMCID: PMC11594573 DOI: 10.3390/ijms252212252] [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: 09/12/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.
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Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Manoj Kumar Pandey
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA
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9
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Obers A, Poch T, Rodrigues G, Christo SN, Gandolfo LC, Fonseca R, Zaid A, Kuai JEY, Lai H, Zareie P, Yakou MH, Dryburgh L, Burn TN, Dosser J, Buquicchio FA, Lareau CA, Walsh C, Judd L, Theodorou MR, Gutbrod K, Dörmann P, Kingham J, Stinear T, Kallies A, Schroeder J, Mueller SN, Park SL, Speed TP, Satpathy AT, Phan TG, Wilhelm C, Zaph C, Evrard M, Mackay LK. Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency. Immunity 2024; 57:2615-2633.e10. [PMID: 39406245 DOI: 10.1016/j.immuni.2024.09.015] [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: 05/21/2023] [Revised: 07/23/2024] [Accepted: 09/21/2024] [Indexed: 11/15/2024]
Abstract
Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that whereas skin TRM cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive TRM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal TRM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated TRM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.
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Affiliation(s)
- Andreas Obers
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Tobias Poch
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Grace Rodrigues
- Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Susan N Christo
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Luke C Gandolfo
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
| | - Raissa Fonseca
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Ali Zaid
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Joey En Yu Kuai
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Hongjin Lai
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Pirooz Zareie
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Marina H Yakou
- Olivia Newton-John Cancer Research Institute, LaTrobe University School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Lachlan Dryburgh
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Thomas N Burn
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - James Dosser
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Frank A Buquicchio
- Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA
| | - Caleb A Lareau
- Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA
| | - Calum Walsh
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Louise Judd
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Maria Rafailia Theodorou
- Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Katharina Gutbrod
- Institute for Molecular Physiology and Biotechnology of Plants, University of Bonn, Bonn, Germany
| | - Peter Dörmann
- Institute for Molecular Physiology and Biotechnology of Plants, University of Bonn, Bonn, Germany
| | - Jenny Kingham
- Australian BioResources Pty Ltd, Moss Vale, NSW, Australia; Animal Services, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia
| | - Tim Stinear
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Axel Kallies
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Jan Schroeder
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Simone L Park
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Terence P Speed
- School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia; Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
| | - Ansuman T Satpathy
- Department of Pathology, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Tri Giang Phan
- Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; St Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia
| | - Christoph Wilhelm
- Immunopathology Unit, Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Colby Zaph
- Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Maximilien Evrard
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
| | - Laura K Mackay
- Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
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10
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Dai YG, Sun D, Liu J, Wei X, Chi L, Wang H. Efficacy and safety of etrolizumab in the treatment of inflammatory bowel disease: a meta-analysis. PeerJ 2024; 12:e17945. [PMID: 39193512 PMCID: PMC11348897 DOI: 10.7717/peerj.17945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
Background To explore the efficacy and safety of etrolizumab in treating inflammatory bowel disease (IBD) through meta-analysis. Method A comprehensive exploration encompassed randomized controlled trials examining the efficacy of etrolizumab in treating IBD across PubMed, Embase, Cochrane library, and Web of Science, with a search deadline of 1 December 2023. Quality assessment leaned on the Cochrane manual's risk-of-bias evaluation, while Stata 15 undertook the data analysis. Result Five randomized controlled studies involving 1682 individuals were finally included, Meta-analysis results suggested that compared with placebo, etrolizumab could improve clinical response (RR = 1.26, 95% CI [1.04-1.51]), clinical remission (RR = 1.26, 95% CI [1.04-1.51]) in IBD patients. Endoscopic alleviate (RR = 2.10, 95% CI [1.56-2.82]), endoscopic improvement (RR = 2.10, 95% CI [1.56-2.82]), endoscopic remission (RR = 2.10, 95% CI [1.56-2.82]), Endoscopic improvement (RR = 1.56, 95% CI [1.30-1.89]), histological remission (RR = 1.62, 95% CI [1.26-2.08]), and did not increase any adverse events (RR = 0.95, 95% CI [0.90-1.01]) and serious adverse events (RR = 0.94, 95% CI [0.68-1.31]). Conclusion According to our current study, etrolizumab is a promising drug in IBD.
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Affiliation(s)
- Yong gang Dai
- Shandong University of Traditional Chinese Medicine, Shandong, China
- Shandong Provincial Third Hospital, Shandong, China
| | - Dajuan Sun
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Jiahui Liu
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Xiunan Wei
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Lili Chi
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Hongya Wang
- Shandong Provincial Third Hospital, Shandong, China
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11
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Ullah H, Arbab S, Tian Y, Chen Y, Liu CQ, Li Q, Li K. Crosstalk between gut microbiota and host immune system and its response to traumatic injury. Front Immunol 2024; 15:1413485. [PMID: 39144142 PMCID: PMC11321976 DOI: 10.3389/fimmu.2024.1413485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 06/04/2024] [Indexed: 08/16/2024] Open
Abstract
Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.
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Affiliation(s)
- Hanif Ullah
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials/Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Safia Arbab
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Yali Tian
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials/Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Yuwen Chen
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials/Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Chang-qing Liu
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials/Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Qijie Li
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials/Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
| | - Ka Li
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials/Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China
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12
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Zhou L, Cai SZ, Dong LL. Recent advances in pathogenesis, diagnosis, and therapeutic approaches for digestive system involvement in systemic lupus erythematosus. J Dig Dis 2024; 25:410-423. [PMID: 39317429 DOI: 10.1111/1751-2980.13307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 09/26/2024]
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of large amounts of autoantibodies and immune complex formation. Because of their atypical clinical symptoms, SLE patients with digestive system involvement may not be recognized or treated precisely and extensively. Clinicians should pay close attention to SLE with digestive system involvement, as these conditions can easily worsen the condition and possibly endanger the patient's life. In this review we summarized the pathogenesis, pathological characteristics, clinical manifestations, diagnosis, and therapies for digestive system involvement in SLE.
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Affiliation(s)
- Liang Zhou
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shao Zhe Cai
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Ling Li Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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13
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Jennings KC, Johnson KE, Hayward MA, Kristich CJ, Salzman NH. CCR2-dependent CX3CR1+ colonic macrophages promote Enterococcus faecalis dissemination. Infect Immun 2024; 92:e0000624. [PMID: 38629806 PMCID: PMC11075457 DOI: 10.1128/iai.00006-24] [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: 01/05/2024] [Accepted: 03/29/2024] [Indexed: 05/08/2024] Open
Abstract
Enterococci are common commensal bacteria that colonize the gastrointestinal tracts of most mammals, including humans. Importantly, these bacteria are one of the leading causes of nosocomial infections. This study examined the role of colonic macrophages in facilitating Enterococcus faecalis infections in mice. We determined that depletion of colonic phagocytes resulted in the reduction of E. faecalis dissemination to the gut-draining mesenteric lymph nodes. Furthermore, we established that trafficking of monocyte-derived CX3CR1-expressing macrophages contributed to E. faecalis dissemination in a manner that was not reliant on CCR7, the conventional receptor involved in lymphatic migration. Finally, we showed that E. faecalis mutants with impaired intracellular survival exhibited reduced dissemination, suggesting that E. faecalis can exploit host immune cell migration to disseminate systemically and cause disease. Our findings indicate that modulation of macrophage trafficking in the context of antibiotic therapy could serve as a novel approach for preventing or treating opportunistic infections by disseminating enteric pathobionts like E. faecalis.
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Affiliation(s)
- Kevin C. Jennings
- Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Kaitlin E. Johnson
- Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Michael A. Hayward
- Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Center for Microbiome Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Christopher J. Kristich
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Center for Infectious Disease Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nita H. Salzman
- Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Center for Microbiome Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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14
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Xiao H, Ulmert I, Bach L, Huber J, Narasimhan H, Kurochkin I, Chang Y, Holst S, Mörbe U, Zhang L, Schlitzer A, Pereira CF, Schraml BU, Baumjohann D, Lahl K. Genomic deletion of Bcl6 differentially affects conventional dendritic cell subsets and compromises Tfh/Tfr/Th17 cell responses. Nat Commun 2024; 15:3554. [PMID: 38688934 PMCID: PMC11061177 DOI: 10.1038/s41467-024-46966-6] [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: 12/08/2022] [Accepted: 03/13/2024] [Indexed: 05/02/2024] Open
Abstract
Conventional dendritic cells (cDC) play key roles in immune induction, but what drives their heterogeneity and functional specialization is still ill-defined. Here we show that cDC-specific deletion of the transcriptional repressor Bcl6 in mice alters the phenotype and transcriptome of cDC1 and cDC2, while their lineage identity is preserved. Bcl6-deficient cDC1 are diminished in the periphery but maintain their ability to cross-present antigen to CD8+ T cells, confirming general maintenance of this subset. Surprisingly, the absence of Bcl6 in cDC causes a complete loss of Notch2-dependent cDC2 in the spleen and intestinal lamina propria. DC-targeted Bcl6-deficient mice induced fewer T follicular helper cells despite a profound impact on T follicular regulatory cells in response to immunization and mounted diminished Th17 immunity to Citrobacter rodentium in the colon. Our findings establish Bcl6 as an essential transcription factor for subsets of cDC and add to our understanding of the transcriptional landscape underlying cDC heterogeneity.
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Affiliation(s)
- Hongkui Xiao
- Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), 2800, Kongens, Lyngby, Denmark
| | - Isabel Ulmert
- Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), 2800, Kongens, Lyngby, Denmark
| | - Luisa Bach
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Johanna Huber
- Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Munich, Germany
| | - Hamsa Narasimhan
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximillians-Universität München, Planegg-Martinsried, Munich, Germany
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Planegg-Martinsried, Munich, Germany
| | - Ilia Kurochkin
- Cell Reprogramming in Hematopoiesis and Immunity Laboratory, Lund Stem Cell Center, Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Yinshui Chang
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Munich, Germany
| | - Signe Holst
- Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), 2800, Kongens, Lyngby, Denmark
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Urs Mörbe
- Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), 2800, Kongens, Lyngby, Denmark
| | - Lili Zhang
- Quantitative Systems Biology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Andreas Schlitzer
- Quantitative Systems Biology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Carlos-Filipe Pereira
- Cell Reprogramming in Hematopoiesis and Immunity Laboratory, Lund Stem Cell Center, Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Barbara U Schraml
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximillians-Universität München, Planegg-Martinsried, Munich, Germany
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Planegg-Martinsried, Munich, Germany
| | - Dirk Baumjohann
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany.
- Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Munich, Germany.
| | - Katharina Lahl
- Section for Experimental and Translational Immunology, Institute for Health Technology, Technical University of Denmark (DTU), 2800, Kongens, Lyngby, Denmark.
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
- Immunology Section, Lund University, Lund, 221 84, Sweden.
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15
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Fan X, Nijman HW, de Bruyn M, Elsinga PH. ImmunoPET provides a novel way to visualize the CD103 + tissue-resident memory T cell to predict the response of immune checkpoint inhibitors. EJNMMI Res 2024; 14:5. [PMID: 38182929 PMCID: PMC10769965 DOI: 10.1186/s13550-023-01062-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 12/17/2023] [Indexed: 01/07/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have made significant progress in oncotherapy improving survival of patients. However, the benefits are limited to only a small subgroup of patients who could achieve durable responses. Early prediction of response may enable treatment optimization and patient stratification. Therefore, developing appropriate biomarkers is critical to monitoring efficacy and assessing patient response to ICIs. MAIN BODY Herein, we first introduce a new potential biomarker, CD103, expressed on tissue-resident memory T cells, and discuss the potential application of CD103 PET imaging in predicting immune checkpoint inhibitor treatment. In addition, we describe the current targets of ImmunoPET and compare these targets with CD103. To assess the benefit of PET imaging, a comparative analysis between ImmunoPET and other imaging techniques commonly employed for tumor diagnosis was performed. Additionally, we compare ImmunoPET and immunohistochemistry (IHC), a widely utilized clinical method for biomarker identification with respect to visualizing the immune targets. CONCLUSION CD103 ImmunoPET is a promising method for determining tumor-infiltrating lymphocytes (TILs) load and response to ICIs, thereby addressing the lack of reliable biomarkers in cancer immunotherapy. Compared to general T cell markers, CD103 is a specific marker for tissue-resident memory T cells, which number increases during successful ICI therapy. ImmunoPET offers noninvasive, dynamic imaging of specific markers, complemented by detailed molecular information from immunohistochemistry (IHC). Radiomics can extract quantitative features from traditional imaging methods, while near-infrared fluorescence (NIRF) imaging aids tumor detection during surgery. In the era of precision medicine, combining such methods will offer a more comprehensive approach to cancer diagnosis and treatment.
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Affiliation(s)
- Xiaoyu Fan
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hans W Nijman
- Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Marco de Bruyn
- Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Philip H Elsinga
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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16
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Bernier-Latmani J, González-Loyola A, Petrova TV. Mechanisms and functions of intestinal vascular specialization. J Exp Med 2024; 221:e20222008. [PMID: 38051275 PMCID: PMC10697212 DOI: 10.1084/jem.20222008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/10/2023] [Accepted: 11/15/2023] [Indexed: 12/07/2023] Open
Abstract
The intestinal vasculature has been studied for the last 100 years, and its essential role in absorbing and distributing ingested nutrients is well known. Recently, fascinating new insights into the organization, molecular mechanisms, and functions of intestinal vessels have emerged. These include maintenance of intestinal epithelial cell function, coping with microbiota-induced inflammatory pressure, recruiting gut-specific immune cells, and crosstalk with other organs. Intestinal function is also regulated at the systemic and cellular levels, such that the postprandial hyperemic response can direct up to 30% of systemic blood to gut vessels, while micron-sized endothelial cell fenestrations are necessary for nutrient uptake. In this review, we will highlight past discoveries made about intestinal vasculature in the context of new findings of molecular mechanisms underpinning gut function. Such comprehensive understanding of the system will pave the way to breakthroughs in nutrient uptake optimization, drug delivery efficiency, and treatment of human diseases.
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Affiliation(s)
- Jeremiah Bernier-Latmani
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | | | - Tatiana V. Petrova
- Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, École polytechnique fédérale de Lausanne, Lausanne, Switzerland
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17
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Liu X, Xu B, Xu X, Wang Z, Luo Y, Gao Y, Ling S, Wang A, Zhou Y, Wang X, Leng SX, Li W, Yao X. Attenuation of allergen-specific immunotherapy for atopic dermatitis by ectopic colonization of Brevundimonas vesicularis in the intestine. Cell Rep Med 2023; 4:101340. [PMID: 38118418 PMCID: PMC10772585 DOI: 10.1016/j.xcrm.2023.101340] [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: 01/06/2023] [Revised: 04/07/2023] [Accepted: 11/22/2023] [Indexed: 12/22/2023]
Abstract
Allergen-specific immunotherapy (AIT) has shown beneficial effects against atopic dermatitis (AD); however, the mechanisms and parameters underlying the efficacy of AIT remain unclear. Here, we report that the community structure and function of the oral and gut microbiota are changed in patients with AD undergoing AIT. Transplantation of fecal microbiota from patients who respond well to AIT improves AD-like dermatitis in mice. The abundance of Brevundimonas vesicularis in the gut of AD patients has been found to be positively correlated with disease severity and is decreased following AIT. Furthermore, we find that B. vesicularis from the oral cavity might ectopically colonize the gut of AD patients. In AD model mice, meanwhile, B. vesicularis promotes the skewing of the Treg/Th17 balance toward Th17 polarization and attenuates the efficacy of ovalbumin-specific immunotherapy. Our findings provide potential strategies for the optimization of AIT for AD via the modulation of the gut microbiota.
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Affiliation(s)
- Xiaochun Liu
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Beilei Xu
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Xiaoqiang Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai 200040, China
| | | | - Yang Luo
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Yingxia Gao
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Shiqi Ling
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Ao Wang
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Yuan Zhou
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China
| | - Xiaokai Wang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong 999077, China
| | - Sean Xiao Leng
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Johns Hopkins Center on Aging and Immune Remodeling, Baltimore, MD, USA.
| | - Wei Li
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai 200040, China.
| | - Xu Yao
- Department of Allergy and Rheumatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China.
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18
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Schenkel JM, Pauken KE. Localization, tissue biology and T cell state - implications for cancer immunotherapy. Nat Rev Immunol 2023; 23:807-823. [PMID: 37253877 PMCID: PMC11448857 DOI: 10.1038/s41577-023-00884-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2023] [Indexed: 06/01/2023]
Abstract
Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy.
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Affiliation(s)
- Jason M Schenkel
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Kristen E Pauken
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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19
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Mehandru S, Colombel JF, Juarez J, Bugni J, Lindsay JO. Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease. Mucosal Immunol 2023; 16:859-870. [PMID: 37574127 PMCID: PMC11141405 DOI: 10.1016/j.mucimm.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023]
Abstract
In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD.
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Affiliation(s)
- Saurabh Mehandru
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Jean-Frederic Colombel
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julius Juarez
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James Bugni
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James O Lindsay
- Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK
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20
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Brown H, Komnick MR, Brigleb PH, Dermody TS, Esterházy D. Lymph node sharing between pancreas, gut, and liver leads to immune crosstalk and regulation of pancreatic autoimmunity. Immunity 2023; 56:2070-2085.e11. [PMID: 37557168 PMCID: PMC11040372 DOI: 10.1016/j.immuni.2023.07.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 05/03/2023] [Accepted: 07/12/2023] [Indexed: 08/11/2023]
Abstract
Lymph nodes (LNs) are critical sites for shaping tissue-specific adaptive immunity. However, the impact of LN sharing between multiple organs on such tailoring is less understood. Here, we describe the drainage hierarchy of the pancreas, liver, and the upper small intestine (duodenum) into three murine LNs. Migratory dendritic cells (migDCs), key in instructing adaptive immune outcome, exhibited stronger pro-inflammatory signatures when originating from the pancreas or liver than from the duodenum. Qualitatively different migDC mixing in each shared LN influenced pancreatic β-cell-reactive T cells to acquire gut-homing and tolerogenic phenotypes proportional to duodenal co-drainage. However, duodenal viral infections rendered non-intestinal migDCs and β-cell-reactive T cells more pro-inflammatory in all shared LNs, resulting in elevated pancreatic islet lymphocyte infiltration. Our study uncovers immune crosstalk through LN co-drainage as a powerful force regulating pancreatic autoimmunity.
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Affiliation(s)
- Hailey Brown
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Macy R Komnick
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Pamela H Brigleb
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Terence S Dermody
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Daria Esterházy
- Department of Pathology, University of Chicago, Chicago, IL, USA.
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21
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Duan S, Cao Y, Chen P, Yang Y, Zhang Y. Circulating and intestinal regulatory T cells in inflammatory bowel disease: A systemic review and meta-analysis. Int Rev Immunol 2023; 43:83-94. [PMID: 37615427 DOI: 10.1080/08830185.2023.2249525] [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: 03/16/2023] [Accepted: 07/17/2023] [Indexed: 08/25/2023]
Abstract
Regulatory T cells (Tregs) play an important immunosuppressive role in inflammatory bowel disease (IBD). However, findings on the quantitative and functional changes of intestinal and circulating Tregs in patients with IBD are rather contradictory. We therefore conducted a meta-analysis on this issue. The pooled effect was assessed using the standardized mean difference (SMD) with a 95% confidence interval (CI), and subgroup analyses were performed to investigate heterogeneity. This analysis included 764 IBD (402 UC and 362 CD) patients and 341 healthy controls (HCs) pooled from 17 eligible studies. The percentage of circulating Tregs was significantly decreased in active IBD patients compared to HCs (SMD = -0.95, p < 0.001) and inactive IBD patients (SMD = -0.80, p < 0.001). There was no difference in the percentage of circulating Tregs between inactive IBD patients and HCs. The suppressive function of circulating Tregs was impaired in active IBD patients according to limited data (SMD = -0.75, p = 0.02). Besides, the percentage of intestinal Tregs was significantly higher in inflamed regions than in non-inflamed regions (SMD = 0.85, p < 0.001). Our study quantitatively summarized the quantitative and functional changes of Tregs and supported the therapeutic potential of Tregs in IBD. Moreover, additional research into the functions and characteristics of intestinal Tregs in IBD is needed.
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Affiliation(s)
- Shihao Duan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yubin Cao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Pingrun Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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22
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Abstract
The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a key role in protection against bacterial and fungal pathogens, and their toxins. Secretory immunoglobulin A (sIgA) is the most abundantly produced antibody at the mucosal surfaces, while Immunoglobulin G (IgG) isotypes play a critical role in systemic protection. IgA and IgG antibodies with reactivity to commensal fungi play an important role in shaping the mycobiota and host antifungal immunity. In this article, we review the latest evidence that establishes a connection between commensal fungi and B cell-mediated antifungal immunity as an additional layer of protection against fungal infections and inflammation.
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Affiliation(s)
- Itai Doron
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Takato Kusakabe
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA
| | - Iliyan D Iliev
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
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23
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Ye M, Xu Z, Tan H, Yang F, Yuan J, Wu Y, Wu Z, Yang A, Chen H, Li X. Allergenicity reduction of cow milk treated by alkaline protease combined with Lactobacillus Plantarum and Lactobacillus helveticus based on epitopes. Food Chem 2023; 421:136180. [PMID: 37105121 DOI: 10.1016/j.foodchem.2023.136180] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023]
Abstract
This paper has investigated the residual allergenicity of cow's milk treated by enzymatic hydrolysis combined with Lactobacillus fermentation (Lb. Plantarum and Lb. helveticus). The treated products were comprehensively evaluated by SDS-PAGE, RP-HPLC, ELISA, and Caco-2 models. And the allergenic changes of residual allergenic peptides were explored by DC-T co-culture. The results showed that alkaline protease was the most suitable protease that targeted to destroy epitopes of milk major allergen than trypsin, pepsin, and papain by prediction. And the residual epitopes were reduced to four which was treated by alkaline protease combined with Lb. helveticus. The transport absorption capacity of treated products was almost twice than milk. Meanwhile, the seven residual allergenic peptides were obtained from treated products. Among them, αs1-casein (AA84-90) can be used as an immune tolerance peptide for further study. Lb. helveticus combined with alkaline protease treatment may be considered promising strategy of protect from cow's milk allergy.
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Affiliation(s)
- Mao Ye
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; School of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Zihao Xu
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; School of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Hongkai Tan
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; School of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Fan Yang
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; School of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Juanli Yuan
- School of Pharmacy Science, Nanchang University, Nanchang 330047, PR China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang, 330047, China
| | - Yong Wu
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, PR China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang, 330047, China
| | - Zhihua Wu
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, PR China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang, 330047, China
| | - Anshu Yang
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, PR China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang, 330047, China
| | - Hongbing Chen
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, PR China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang, 330047, China
| | - Xin Li
- State Key Laboratory Food Science and Technology, Nanchang University, Nanchang 330047, PR China; School of Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Jiangxi Province Key Laboratory of Food Allergy, Nanchang University, Nanchang, 330047, China.
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24
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Schimpel C, Passegger C, Egger S, Tam-Amersdorfer C, Strobl H. A novel 3D cell culture model to study the human small intestinal immune landscape. Eur J Immunol 2023; 53:e2250131. [PMID: 36527196 DOI: 10.1002/eji.202250131] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/21/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Several subsets of mononuclear phagocytes and DCs (MDC) populate the small intestine (SI), and these cells reportedly exert specialized functions in anti-microbial immunity and tolerance. Given the specialized phenotype of these cells, differing from other MDC family members, including their putative circulating blood precursors, local intestinal factors play key instructive roles in their differentiation. We designed an SI cell culture model composed of three intestinal epithelial cell (IEC) types, including absorptive enterocytes (E cells), antigen delivering microfold (M) cells, and mucus-producing goblet (G) cells plus T lymphocytes and soluble B cell-derived factors. This model was used to study the differentiation fate of CD34+ hematopoietic progenitor cell-derived monocyte/DC precursors. Progeny cells can be analyzed after a 3-week co-culture period, mimicking the physiologic turn-over time of intestinal MDC. A dominant monocyte differentiation pathway was suppressed, in favor of partial differentiation along DC and macrophage pathways, with low percentages of cells acquired DC or macrophage markers. Moreover, E and G cells play opposing roles in CX3CR1+ vs CD103dim cell differentiation, indicating that both together might counter-balance M/DC differentiation. Thus, SI epithelial cells suppress M/DC differentiation, supporting a key role for exogenous factors in M/DC differentiation.
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Affiliation(s)
- Christa Schimpel
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Christina Passegger
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Simone Egger
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Carmen Tam-Amersdorfer
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
| | - Herbert Strobl
- Medical University of Graz, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology and Pathophysiology, Graz, Austria
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25
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Laukova M, Glatman Zaretsky A. Regulatory T cells as a therapeutic approach for inflammatory bowel disease. Eur J Immunol 2023; 53:e2250007. [PMID: 36562391 PMCID: PMC10107179 DOI: 10.1002/eji.202250007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022]
Abstract
Foxp3+ T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.
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26
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Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci 2023; 24:ijms24021526. [PMID: 36675038 PMCID: PMC9863490 DOI: 10.3390/ijms24021526] [Citation(s) in RCA: 191] [Impact Index Per Article: 95.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Hector Sánchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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27
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Redondo-Urzainqui A, Hernández-García E, Cook ECL, Iborra S. Dendritic cells in energy balance regulation. Immunol Lett 2023; 253:19-27. [PMID: 36586424 DOI: 10.1016/j.imlet.2022.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/21/2022] [Accepted: 12/26/2022] [Indexed: 12/30/2022]
Abstract
Besides their well-known role in initiating adaptive immune responses, several groups have studied the role of dendritic cells (DCs) in the context of chronic metabolic inflammation, such as in diet-induced obesity (DIO) or metabolic-associated fatty liver disease. DCs also have an important function in maintaining metabolic tissue homeostasis in steady-state conditions. In this review, we will briefly describe the different DC subsets, the murine models available to assess their function, and discuss the role of DCs in regulating energy balance and maintaining tissue homeostasis.
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Affiliation(s)
- Ana Redondo-Urzainqui
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Elena Hernández-García
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Emma Clare Laura Cook
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain.
| | - Salvador Iborra
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid, Madrid, 28040, Spain.
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28
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Filardy AA, Ferreira JRM, Rezende RM, Kelsall BL, Oliveira RP. The intestinal microenvironment shapes macrophage and dendritic cell identity and function. Immunol Lett 2023; 253:41-53. [PMID: 36623708 PMCID: PMC9907447 DOI: 10.1016/j.imlet.2023.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 12/12/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023]
Abstract
The gut comprises the largest body interface with the environment and is continuously exposed to nutrients, food antigens, and commensal microbes, as well as to harmful pathogens. Subsets of both macrophages and dendritic cells (DCs) are present throughout the intestinal tract, where they primarily inhabit the gut-associate lymphoid tissue (GALT), such as Peyer's patches and isolated lymphoid follicles. In addition to their role in taking up and presenting antigens, macrophages and DCs possess extensive functional plasticity and these cells play complementary roles in maintaining immune homeostasis in the gut by preventing aberrant immune responses to harmless antigens and microbes and by promoting host defense against pathogens. The ability of macrophages and DCs to induce either inflammation or tolerance is partially lineage imprinted, but can also be dictated by their activation state, which in turn is determined by their specific microenvironment. These cells express several surface and intracellular receptors that detect danger signals, nutrients, and hormones, which can affect their activation state. DCs and macrophages play a fundamental role in regulating T cells and their effector functions. Thus, modulation of intestinal mucosa immunity by targeting antigen presenting cells can provide a promising approach for controlling pathological inflammation. In this review, we provide an overview on the characteristics, functions, and origins of intestinal macrophages and DCs, highlighting the intestinal microenvironmental factors that influence their functions during homeostasis. Unraveling the mechanisms by which macrophages and DCs regulate intestinal immunity will deepen our understanding on how the immune system integrates endogenous and exogenous signals in order to maintain the host's homeostasis.
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Affiliation(s)
- Alessandra A Filardy
- Laboratório de Imunologia Celular, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil.
| | - Jesuino R M Ferreira
- Laboratório de Imunologia Celular, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil
| | - Rafael M Rezende
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, USA
| | - Brian L Kelsall
- Laboratory of Molecular Immunology, NIAID, National Institutes of Health, USA
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29
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Sterling KG, Dodd GK, Alhamdi S, Asimenios PG, Dagda RK, De Meirleir KL, Hudig D, Lombardi VC. Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease. Int J Mol Sci 2022; 23:13328. [PMID: 36362150 PMCID: PMC9655506 DOI: 10.3390/ijms232113328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer's disease, Parkinson's disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.
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Affiliation(s)
| | - Griffin Kutler Dodd
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Shatha Alhamdi
- Clinical Immunology and Allergy Division, Department of Pediatrics, King Abdullah Specialist Children’s Hospital, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia
| | | | - Ruben K. Dagda
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | | | - Dorothy Hudig
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Vincent C. Lombardi
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
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30
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Abstract
Vitamin A (retinol) is a critical micronutrient required for the control of stem cell functions, cell differentiation, and cell metabolism in many different cell types, both during embryogenesis and in the adult organism. However, we must obtain vitamin A from food sources. Thus, the uptake and metabolism of vitamin A by intestinal epithelial cells, the storage of vitamin A in the liver, and the metabolism of vitamin A in target cells to more biologically active metabolites, such as retinoic acid (RA) and 4-oxo-RA, must be precisely regulated. Here, I will discuss the enzymes that metabolize vitamin A to RA and the cytochrome P450 Cyp26 family of enzymes that further oxidize RA. Because much progress has been made in understanding the regulation of ALDH1a2 (RALDH2) actions in the intestine, one focus of this review is on the metabolism of vitamin A in intestinal epithelial cells and dendritic cells. Another focus is on recent data that 4-oxo-RA is a ligand required for the maintenance of hematopoietic stem cell dormancy and the important role of RARβ (RARB) in these stem cells. Despite this progress, many questions remain in this research area, which links vitamin A metabolism to nutrition, immune functions, developmental biology, and nuclear receptor pharmacology.
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Affiliation(s)
- Lorraine J Gudas
- Department of Pharmacology, and Revlon Pharmaceutical Professor of Pharmacology and Toxicology, Pharmacology Department, and the Meyer Cancer Center of Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065
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31
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Delgado M, Lennon-Duménil AM. How cell migration helps immune sentinels. Front Cell Dev Biol 2022; 10:932472. [PMID: 36268510 PMCID: PMC9577558 DOI: 10.3389/fcell.2022.932472] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/13/2022] [Indexed: 12/01/2022] Open
Abstract
The immune system relies on the migratory capacity of its cellular components, which must be mobile in order to defend the host from invading micro-organisms or malignant cells. This applies in particular to immune sentinels from the myeloid lineage, i.e. macrophages and dendritic cells. Cell migration is already at work during mammalian early development, when myeloid cell precursors migrate from the yolk sac, an extra embryonic structure, to colonize tissues and form the pool of tissue-resident macrophages. Later, this is accompanied by a migration wave of precursors and monocytes from the bone marrow to secondary lymphoid organs and the peripheral tissues. They differentiate into DCs and monocyte-derived macrophages. During adult life, cell migration endows immune cells with the ability to patrol their environment as well as to circulate between peripheral tissues and lymphoid organs. Hence migration of immune cells is key to building an efficient defense system for an organism. In this review, we will describe how cell migratory capacity regulates the various stages in the life of myeloid cells from development to tissue patrolling, and migration to lymph nodes. We will focus on the role of the actin cytoskeletal machinery and its regulators, and how it contributes to the establishment and function of the immune system.
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Neuwirth T, Knapp K, Stary G. (Not) Home alone: Antigen presenting cell - T Cell communication in barrier tissues. Front Immunol 2022; 13:984356. [PMID: 36248804 PMCID: PMC9556809 DOI: 10.3389/fimmu.2022.984356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/13/2022] [Indexed: 11/30/2022] Open
Abstract
Priming of T cells by antigen presenting cells (APCs) is essential for T cell fate decisions, enabling T cells to migrate to specific tissues to exert their effector functions. Previously, these interactions were mainly explored using blood-derived cells or animal models. With great advances in single cell RNA-sequencing techniques enabling analysis of tissue-derived cells, it has become clear that subsets of APCs are responsible for priming and modulating heterogeneous T cell effector responses in different tissues. This composition of APCs and T cells in tissues is essential for maintaining homeostasis and is known to be skewed in infection and inflammation, leading to pathological T cell responses. This review highlights the commonalities and differences of T cell priming and subsequent effector function in multiple barrier tissues such as the skin, intestine and female reproductive tract. Further, we provide an overview of how this process is altered during tissue-specific infections which are known to cause chronic inflammation and how this knowledge could be harnessed to modify T cell responses in barrier tissue.
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Affiliation(s)
- Teresa Neuwirth
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Katja Knapp
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
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Ghilas S, O’Keefe R, Mielke LA, Raghu D, Buchert M, Ernst M. Crosstalk between epithelium, myeloid and innate lymphoid cells during gut homeostasis and disease. Front Immunol 2022; 13:944982. [PMID: 36189323 PMCID: PMC9524271 DOI: 10.3389/fimmu.2022.944982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/29/2022] [Indexed: 12/05/2022] Open
Abstract
The gut epithelium not only provides a physical barrier to separate a noxious outside from a sterile inside but also allows for highly regulated interactions between bacteria and their products, and components of the immune system. Homeostatic maintenance of an intact epithelial barrier is paramount to health, requiring an intricately regulated and highly adaptive response of various cells of the immune system. Prolonged homeostatic imbalance can result in chronic inflammation, tumorigenesis and inefficient antitumor immune control. Here we provide an update on the role of innate lymphoid cells, macrophages and dendritic cells, which collectively play a critical role in epithelial barrier maintenance and provide an important linkage between the classical innate and adaptive arm of the immune system. These interactions modify the capacity of the gut epithelium to undergo continuous renewal, safeguard against tumor formation and provide feedback to the gut microbiome, which acts as a seminal contributor to cellular homeostasis of the gut.
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Affiliation(s)
- Sonia Ghilas
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Ryan O’Keefe
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Lisa Anna Mielke
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Dinesh Raghu
- Mucosal Immunity Laboratory, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Michael Buchert
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
- *Correspondence: Michael Buchert, ; Matthias Ernst,
| | - Matthias Ernst
- Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute, and La Trobe University - School of Cancer Medicine, Heidelberg, VIC, Australia
- *Correspondence: Michael Buchert, ; Matthias Ernst,
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A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut. Immunity 2022; 55:1829-1842.e6. [PMID: 36115337 DOI: 10.1016/j.immuni.2022.08.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 05/20/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022]
Abstract
The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window. In addition to B-1a cells, early-life time-stamped B cells included clonally interrelated IgA plasma cells in the gut and bone marrow. These were actively maintained by B cell memory within gut chronic germinal centers and contained commensal microbiota reactivity. Neonatal rotavirus infection recruited recurrent IgA clones that were distinct from those arising by infection with the same antigen in adults. Finally, gut IgA plasma cells arose from the same hematopoietic progenitors as B-1a cells during ontogeny. Thus, a complex layer of neonatally imprinted B cells confer unique antibody responses later in life.
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Chen Y, Lin J, Xiao L, Zhang X, Zhao L, Wang M, Li L. Gut microbiota in systemic lupus erythematosus: A fuse and a solution. J Autoimmun 2022; 132:102867. [PMID: 35932662 DOI: 10.1016/j.jaut.2022.102867] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 07/05/2022] [Indexed: 12/13/2022]
Abstract
Gut commensals help shape and mold host immune system and deeply influence human health. The disease spectrum of mankind that gut microbiome may associate with is ever-growing, but the mechanisms are still enigmas. Characterized by loss of self-tolerance and sustained self-attack, systemic lupus erythematosus (SLE) is labeled with chronic inflammation, production of autoantibodies and multisystem injury, which so far are mostly incurable. Gut microbiota and their metabolites, now known as important environmental triggers of local/systemic immune responses, have been proposed to be involved in SLE development and progression probably through the following mechanisms: translocation beyond their niches; molecular mimicry to cross-activate immune response targeting self-antigens; epitope spreading to expand autoantibodies spectrum; and bystander activation to promote systemic inflammation. Gut microbiota which varies between individuals may also influence the metabolism and bio-transformation of disease-modifying anti-rheumatic drugs, thus associated with the efficacy and toxicity of these drugs, adding another explanation for heterogenic therapeutic responses. Modulation of gut microbiota via diet, probiotics/prebiotics, antibiotics/phages, fecal microbiota transplantation, or helminth to restore immune tolerance and homeostasis is expected to be a promising neoadjuvant therapy for SLE. We reviewed the advances in this territory and discussed the application prospect of modulating gut microbiota in controlling SLE.
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Affiliation(s)
- Yanfei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Jin Lin
- Department of Rheumatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, China
| | - Lanlan Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, China; Department of Rheumatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences & Peking Union Medical College, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, 100730, China
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences & Peking Union Medical College, NO.1 Da Hua Road, Dong Dan, Beijing, 100730, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
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36
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Yamaguchi T, Iijima H, Yoshihara T, Tani M, Otake Y, Iwatani S, Amano T, Tashiro T, Kurahashi T, Inoue T, Tsujii Y, Hayashi Y, Inoue T, Motooka D, Nakamura S, Shinzaki S, Takehara T. Exacerbation of non-steroidal anti-inflammatory drug-induced enteropathy in C-C chemokine receptor type 7-deficient mice. J Gastroenterol Hepatol 2022; 37:1561-1570. [PMID: 35435994 DOI: 10.1111/jgh.15868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 02/10/2022] [Accepted: 04/08/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Non-steroidal anti-inflammatory drugs (NSAIDs) induce intestinal enteropathy and the pathophysiology is related to immune-mediated mechanisms. We aimed to investigate the role of C-C chemokine receptor type 7 (CCR7) which regulates immune cell migration in NSAID-induced enteropathy. METHODS Injury of the small intestine was evaluated 24 h after the subcutaneous injection of indomethacin in CCR7-deficient (Ccr7-/- ) and wild-type (WT) mice. The cellular profile and cytokine production in intestinal cells were analyzed. Indomethacin-induced enteropathy was evaluated in mice adoptively transferred with CD103+ dendritic cells (DCs) from Ccr7-/- or WT mice. RESULTS Indomethacin induced more severe intestinal injury in Ccr7-/- mice than in WT mice. The major inflammatory cytokines were not increased and the proportion of regulatory T cells following indomethacin injection was not decreased in Ccr7-/- mice compared with WT mice. The expression of interleukin (IL)-22 binding protein (IL-22BP), which inhibits IL-22 activity, was significantly higher in CD103+ DCs from Ccr7-/- mice than those from WT mice. Mice adoptively transferred with CD103+ DCs isolated from Ccr7-/- mice exhibited more severe intestinal injury following indomethacin injection compared with those adoptively transferred with CD103+ DCs of WT mice. Ccr7-/- mice injected with indomethacin showed a significant reduction in regenerating islet-derived 1 (Reg1) mRNA expression, which is regulated by IL-22, in intestinal epithelial cells. CONCLUSIONS C-C chemokine receptor type 7 deficiency exacerbated NSAID-induced enteropathy in association with an altered phenotype of CD103+ DCs that produces IL-22BP. CCR7 contributes to protect the small intestine from NSAID-induced mucosal injury.
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Affiliation(s)
- Toshio Yamaguchi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.,Department of Gastroenterology, Osaka Rosai Hospital, Osaka, Japan
| | - Hideki Iijima
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takeo Yoshihara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mizuki Tani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuriko Otake
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shuko Iwatani
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Amano
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Taku Tashiro
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tomohide Kurahashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takanori Inoue
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Tsujii
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshito Hayashi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Inoue
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisuke Motooka
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Shota Nakamura
- Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Shinichiro Shinzaki
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
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Lança T, Ungerbäck J, Da Silva C, Joeris T, Ahmadi F, Vandamme J, Svensson-Frej M, Mowat AM, Kotarsky K, Sigvardsson M, Agace WW. IRF8 deficiency induces the transcriptional, functional, and epigenetic reprogramming of cDC1 into the cDC2 lineage. Immunity 2022; 55:1431-1447.e11. [PMID: 35830859 DOI: 10.1016/j.immuni.2022.06.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/05/2022] [Accepted: 06/07/2022] [Indexed: 12/13/2022]
Abstract
Conventional dendritic cells (cDCs) consist of two major functionally and phenotypically distinct subsets, cDC1 and cDC2, whose development is dependent on distinct sets of transcription factors. Interferon regulatory factor 8 (IRF8) is required at multiple stages of cDC1 development, but its role in committed cDC1 remains unclear. Here, we used Xcre-cre to delete Irf8 in committed cDC1 and demonstrate that Irf8 is required for maintaining the identity of cDC1. In the absence of Irf8, committed cDC1 acquired the transcriptional, functional, and chromatin accessibility properties of cDC2. This conversion was independent of Irf4 and was associated with the decreased accessibility of putative IRF8, Batf3, and composite AP-1-IRF (AICE)-binding elements, together with increased accessibility of cDC2-associated transcription-factor-binding elements. Thus, IRF8 expression by committed cDC1 is required for preventing their conversion into cDC2-like cells.
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Affiliation(s)
- Telma Lança
- Mucosal Immunology group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - Jonas Ungerbäck
- Division of Molecular Hematology, Lund University, 22184 Lund, Sweden
| | - Clément Da Silva
- Immunology Section, Department of Experimental Medicine, Lund University, BMC D14, 221-84 Lund, Sweden
| | - Thorsten Joeris
- Immunology Section, Department of Experimental Medicine, Lund University, BMC D14, 221-84 Lund, Sweden
| | - Fatemeh Ahmadi
- Immunology Section, Department of Experimental Medicine, Lund University, BMC D14, 221-84 Lund, Sweden
| | - Julien Vandamme
- Mucosal Immunology group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - Marcus Svensson-Frej
- Mucosal Immunology group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark
| | - Allan McI Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| | - Knut Kotarsky
- Immunology Section, Department of Experimental Medicine, Lund University, BMC D14, 221-84 Lund, Sweden
| | - Mikael Sigvardsson
- Division of Molecular Hematology, Lund University, 22184 Lund, Sweden; Department of Physics, Chemistry and Biology, Linköping University, 581 83 Linköping, Sweden
| | - William W Agace
- Mucosal Immunology group, Department of Health Technology, Technical University of Denmark, Kemitorvet, 2800 Kgs. Lyngby, Denmark; Immunology Section, Department of Experimental Medicine, Lund University, BMC D14, 221-84 Lund, Sweden.
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Barreto de Albuquerque J, Altenburger LM, Abe J, von Werdt D, Wissmann S, Martínez Magdaleno J, Francisco D, van Geest G, Ficht X, Iannacone M, Bruggmann R, Mueller C, Stein JV. Microbial uptake in oral mucosa-draining lymph nodes leads to rapid release of cytotoxic CD8 + T cells lacking a gut-homing phenotype. Sci Immunol 2022; 7:eabf1861. [PMID: 35714202 DOI: 10.1126/sciimmunol.abf1861] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The gastrointestinal (GI) tract constitutes an essential barrier against ingested microbes, including potential pathogens. Although immune reactions are well studied in the lower GI tract, it remains unclear how adaptive immune responses are initiated during microbial challenge of the oral mucosa (OM), the primary site of microbial encounter in the upper GI tract. Here, we identify mandibular lymph nodes (mandLNs) as sentinel lymphoid organs that intercept ingested Listeria monocytogenes (Lm). Oral Lm uptake led to local activation and release of antigen-specific CD8+ T cells that constituted most of the early circulating effector T cell (TEFF) pool. MandLN-primed TEFF disseminated to lymphoid organs, lung, and OM and contributed substantially to rapid elimination of target cells. In contrast to CD8+ TEFF generated in mesenteric LN (MLN) during intragastric infection, mandLN-primed TEFF lacked a gut-seeking phenotype, which correlated with low expression of enzymes required for gut-homing imprinting by mandLN stromal and dendritic cells. Accordingly, mandLN-primed TEFF decreased Lm burden in spleen but not MLN after intestinal infection. Our findings extend the concept of regional specialization of immune responses along the length of the GI tract, with CD8+ TEFF generated in the upper GI tract displaying homing profiles that differ from those imprinted by lymphoid tissue of the lower GI tract.
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Affiliation(s)
| | - Lukas M Altenburger
- Department of Oncology, Microbiology and Immunology, University of Fribourg, 1700 Fribourg, Switzerland
| | - Jun Abe
- Department of Oncology, Microbiology and Immunology, University of Fribourg, 1700 Fribourg, Switzerland
| | - Diego von Werdt
- Division of Experimental Pathology, Institute of Pathology, University of Bern, 3008 Bern, Switzerland
| | - Stefanie Wissmann
- Department of Oncology, Microbiology and Immunology, University of Fribourg, 1700 Fribourg, Switzerland
| | - Jose Martínez Magdaleno
- Department of Oncology, Microbiology and Immunology, University of Fribourg, 1700 Fribourg, Switzerland
| | - David Francisco
- Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, 3012 Bern, Switzerland
| | - Geert van Geest
- Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, 3012 Bern, Switzerland
| | - Xenia Ficht
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy.,Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Remy Bruggmann
- Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, 3012 Bern, Switzerland
| | - Christoph Mueller
- Division of Experimental Pathology, Institute of Pathology, University of Bern, 3008 Bern, Switzerland
| | - Jens V Stein
- Department of Oncology, Microbiology and Immunology, University of Fribourg, 1700 Fribourg, Switzerland
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Preparation and identification of monoclonal antibodies against porcine CD103. Appl Microbiol Biotechnol 2022; 106:4005-4015. [PMID: 35599260 DOI: 10.1007/s00253-022-11950-x] [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: 01/19/2022] [Revised: 04/27/2022] [Accepted: 05/02/2022] [Indexed: 11/27/2022]
Abstract
Dendritic cells (DCs) play an important role in activating, regulating, and maintaining the immune response. CD103+ DCs, one of the DC subpopulations, mainly function in the mucosal immune response. They are responsible for capturing and carrying antigens to the relevant lymph nodes to activate the downstream immune responses. However, there is limited available information regarding the function of CD103+ DCs in the porcine mucosal immune response. In this study, two monoclonal antibodies (mAbs) against porcine CD103 were prepared, and their applications were evaluated by enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IFA), and flow cytometry. The produced mAbs (7F3 and 9H3) were both IgG1 subtype with κ chains in the light chain. The 7F3 recognizes a linear epitope (PDLRPRAQVYFSDLE) while 9H3 recognizes another linear epitope (QILDEGQVLLGAVGA). The prepared mAbs could be used in vivo to detect the cells expressing CD103 molecules, giving wide applications of both mAbs. In conclusion, this study successfully prepared 2 mAbs against CD103 protein, and they showed applicability in vivo experiments, which will provide the basis for the study of porcine mucosal immunity. KEY POINTS: • Preparation of monoclonal antibodies against porcine CD103 molecule • Analysis of the distribution of CD103 protein on different cells is possible • Exploration of the CD103+ DCs function in porcine mucosal immunity is possible.
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40
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Bos A, van Egmond M, Mebius R. The role of retinoic acid in the production of immunoglobulin A. Mucosal Immunol 2022; 15:562-572. [PMID: 35418672 DOI: 10.1038/s41385-022-00509-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 03/09/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023]
Abstract
Vitamin A and its derivative retinoic acid (RA) play important roles in the regulation of mucosal immunity. The effect of vitamin A metabolism on T lymphocyte immunity has been well documented, but its role in mucosal B lymphocyte regulation is less well described. Intestinal immunoglobulin A (IgA) is key in orchestrating a balanced gut microbiota composition. Here, we describe the contribution of RA to IgA class switching in tissues including the lamina propria, mesenteric lymph nodes, Peyer's patches and isolated lymphoid follicles. RA can either indirectly skew T cells or directly affect B cell differentiation. IgA levels in healthy individuals are under the control of the metabolism of vitamin A, providing a steady supply of RA. However, IgA levels are altered in inflammatory bowel disease patients, making control of the metabolism of vitamin A a potential therapeutic target. Thus, dietary vitamin A is a key player in regulating IgA production within the intestine, acting via multiple immunological pathways.
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Affiliation(s)
- Amelie Bos
- Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands
| | - Marjolein van Egmond
- Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands.,Amsterdam UMC, Department of Surgery, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands
| | - Reina Mebius
- Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands.
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Iseghohi F, Yahemba AP, Rowaiye AB, Oli AN. Dendritic cells as vaccine targets. VACCINOLOGY AND METHODS IN VACCINE RESEARCH 2022:57-94. [DOI: 10.1016/b978-0-323-91146-7.00010-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Murphy TL, Murphy KM. Dendritic cells in cancer immunology. Cell Mol Immunol 2022; 19:3-13. [PMID: 34480145 PMCID: PMC8752832 DOI: 10.1038/s41423-021-00741-5] [Citation(s) in RCA: 139] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
The clinical success of immune checkpoint therapy (ICT) has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation. Much of the current translational efforts are aimed at enhancing ICT by identifying therapeutic targets that synergize with CTLA4 or PD1/PD-L1 blockade and are solidly developed on the basis of currently accepted principles. Expanding these principles through continuous basic research may help broaden translational efforts. With this mindset, we focused this review on three threads of basic research directly relating to mechanisms underlying ICT. Specifically, this review covers three aspects of dendritic cell (DC) biology connected with antitumor immune responses but are not specifically oriented toward therapeutic use. First, we review recent advances in the development of the cDC1 subset of DCs, identifying important features distinguishing these cells from other types of DCs. Second, we review the antigen-processing pathway called cross-presentation, which was discovered in the mid-1970s and remains an enigma. This pathway serves an essential in vivo function unique to cDC1s and may be both a physiologic bottleneck and therapeutic target. Finally, we review the longstanding field of helper cells and the related area of DC licensing, in which CD4 T cells influence the strength or quality of CD8 T cell responses. Each topic is connected with ICT in some manner but is also a fundamental aspect of cell-mediated immunity directed toward intracellular pathogens.
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Affiliation(s)
- Theresa L. Murphy
- grid.4367.60000 0001 2355 7002Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110 USA
| | - Kenneth M. Murphy
- grid.4367.60000 0001 2355 7002Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110 USA
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Luciani C, Hager FT, Cerovic V, Lelouard H. Dendritic cell functions in the inductive and effector sites of intestinal immunity. Mucosal Immunol 2022; 15:40-50. [PMID: 34465895 DOI: 10.1038/s41385-021-00448-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 02/04/2023]
Abstract
The intestine is constantly exposed to foreign antigens, which are mostly innocuous but can sometimes be harmful. Therefore, the intestinal immune system has the delicate task of maintaining immune tolerance to harmless food antigens while inducing tailored immune responses to pathogens and regulating but tolerating the microbiota. Intestinal dendritic cells (DCs) play a central role in these functions as sentinel cells able to prime and polarize the T cell responses. DCs are deployed throughout the intestinal mucosa but with local specializations along the gut length and between the diffuse effector sites of the gut lamina propria (LP) and the well-organized immune inductive sites comprising isolated lymphoid follicles (ILFs), Peyer's patches (PPs), and other species-specific gut-associated lymphoid tissues (GALTs). Understanding the specificities of each intestinal DC subset, how environmental factors influence DC functions, and how these can be modulated is key to harnessing the therapeutic potential of mucosal adaptive immune responses, whether by enhancing the efficacy of mucosal vaccines or by increasing tolerogenic responses in inflammatory disorders. In this review, we summarize recent findings related to intestinal DCs in steady state and upon inflammation, with a special focus on their functional specializations, highly dependent on their microenvironment.
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Affiliation(s)
| | | | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany.
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Guryanova SV, Kudryashova NA, Kataeva AA, Orozbekova BT, Kolesnikova NV, Chuchalin AG. Novel approaches to increase resistance to acute respiratory infections. RUDN JOURNAL OF MEDICINE 2021. [DOI: 10.22363/2313-0245-2021-25-3-181-195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Relevance . Respiratory infections are the most common in the world. In order to prevent epidemics, there is a need to improve the strategies for organizing medical care and develop new approaches in order to increase the nonspecific resistance, mobilize innate immunity. Objective . The aim of this study was to investigate the effect of glucosaminylmuramyldipeptide (GMDP) on the level of expression of markers of differentiation and activation of functionally significant subpopulations of dendritic cells in peripheral blood mononuclear cells of healthy donors,the second aim was to assess the effectiveness of GMDP in the prevention of acute respiratory infections in an unfavorable epidemiological period of the COVID-19 pandemic. Materials and Methods . An open comparative study included 309 apparently healthy participants, aged 19-22 years. At the first stage of the study, 42 participants (22 female and 20 male) took the drug Licopid 1 mg for 10 days according to the instructions, 1 tablet 3 times a day in order to prevent acute respiratory infections. Peripheral blood sampling was performed before taking the drug (day 0) and the next day after the last dose of the drug (day 12). Evaluation of the expression of markers of differentiation and activation of dendritic cell subpopulations HLA-DR, CD11c, CD123, CD80, CD83, CCR7, CD3, CD14, CD20 was assessed by flow cytometry. At the same time, mRNA was isolated from mononuclear cells of perfusion blood and, after reverse transcription, the level of gene expression was determined by RT PCR. At the next stage, the effectiveness of the prophylactic use of the drug Licopid in 267 students of the Institute of Physical Culture was assessed in order to prevent acute respiratory infections in an unfavorable epidemiological period; the observation period was 12 months. Results and Discussion . A study of the relative quantitative composition of DCs in the peripheral blood of healthy donors by flow cytometry revealed the possibility of an increase in their total number, as well as subpopulations of MDC and PDC under the influence of GMDP. There was a statistically significant increase in the receptors for the chemokine CCR7, which is responsible for the recruitment of DCs to the secondary lymphoid organs. Analysis of the levels of expression of genes XCR1, CD11b , and CD103 showed a statistically significant effect of GMDP on an increase in their expression compared to the baseline level (before GMDP intake), with the mean value being higher in participants undergoing moderate exercise. It was found that the use of the drug Licopid 1mg for the purpose of preventing and reducing the seasonal incidence of acute respiratory infections at the stage of basic training of students of the Institute of Physical Culture contributed to a decrease in the incidence of acute respiratory infections within 12 months of observation after taking the drug. The number of episodes of acute respiratory infections decreased 3.7 times, while the group with 3 or more episodes of acute respiratory infections during the year, which constituted 14.5 % of participants, completely disappeared. The maximum efficiency of GMDP was observed in the track and field command, in which the number of participants who had no episodes of acute respiratory infections during the year increased by 7 times. Conclusion . Our data complement the modern understanding of the molecular mechanism of action of GMDP and substantiate the possibility of its experimental and clinical use in order to develop new strategies for organizing medical care in order to increase the nonspecific resistance of the organism.
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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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Harriman R, Lewis JS. Bioderived materials that disarm the gut mucosal immune system: Potential lessons from commensal microbiota. Acta Biomater 2021; 133:187-207. [PMID: 34098091 DOI: 10.1016/j.actbio.2021.05.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/25/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022]
Abstract
Over the course of evolution, mammals and gut commensal microbes have adapted to coexist with each other. This homeostatic coexistence is dependent on an intricate balance between tolerogenic and inflammatory responses directed towards beneficial, commensal microbes and pathogenic intruders, respectively. Immune tolerance towards the gut microflora is largely sustained by immunomodulatory molecules produced by the commensals, which protect the bacteria from immune advances and maintain the gut's unique tolerogenic microenvironment, as well as systemic homeostasis. The identification and characterization of commensal-derived, tolerogenic molecules could lead to their utilization in biomaterials-inspired delivery schemes involving nano/microparticles or hydrogels, and potentially lead to the next generation of commensal-derived therapeutics. Moreover, gut-on-chip technologies could augment the discovery and characterization of influential commensals by providing realistic in vitro models conducive to finicky microbes. In this review, we provide an overview of the gut immune system, describe its intricate relationships with the microflora and identify major genera involved in maintaining tolerogenic responses and peripheral homeostasis. More relevant to biomaterials, we discuss commensal-derived molecules that are known to interface with immune cells and discuss potential strategies for their incorporation into biomaterial-based strategies aimed at culling inflammatory diseases. We hope this review will bridge the current findings in gut immunology, microbiology and biomaterials and spark further investigation into this emerging field. STATEMENT OF SIGNIFICANCE: Despite its tremendous potential to culminate into revolutionary therapeutics, the synergy between immunology, microbiology, and biomaterials has only been explored at a superficial level. Strategic incorporation of biomaterial-based technologies may be necessary to fully characterize and capitalize on the rapidly growing repertoire of immunomodulatory molecules derived from commensal microbes. Bioengineers may be able to combine state-of-the-art delivery platforms with immunomodulatory cues from commensals to provide a more holistic approach to combating inflammatory disease. This interdisciplinary approach could potentiate a neoteric field of research - "commensal-inspired" therapeutics with the promise of revolutionizing the treatment of inflammatory disease.
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Affiliation(s)
- Rian Harriman
- University of California Davis, Department of Biomedical Engineering, Davis, CA 95616, USA
| | - Jamal S Lewis
- University of California Davis, Department of Biomedical Engineering, Davis, CA 95616, USA.
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47
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de Krijger M, Wildenberg ME, Mookhoek A, Verheul S, de Jonge WJ, Ponsioen CY. Expression of MAdCAM-1 and Gut-homing T Cells in Inflamed Pouch Mucosa. J Crohns Colitis 2021; 15:1491-1499. [PMID: 33675360 DOI: 10.1093/ecco-jcc/jjab041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Pouchitis is a common complication following formation of an ileal pouch-anal anastomosis [IPAA] after proctocolectomy for ulcerative colitis [UC]. Gut-specific lymphocyte trafficking mechanisms have been identified as players in the pathogenesis of UC. In the present study, we aimed to characterise the presence of lymphocyte subsets expressing gut-homing molecules in pouches and peripheral blood of UC patients with and without pouchitis. METHODS Biopsy samples and peripheral blood were collected from 29 patients with an IPAA [seven with active inflammation, 22 without inflammation]. Expression of adhesion molecule MAdCAM-1 was assessed using immunohistochemistry, and flow cytometry was used to characterise expression of integrin α4β7, C-chemokine receptor 9 [CCR9], and CD103 on T cell subsets. RESULTS MAdCAM-1 expression was significantly increased in case of active inflammation in the pouch. T cells expressing integrin α4β7 were abundant in the pouch mucosa, but the frequency of integrin α4β7-expressing T cells was decreased on CD4+ lymphocytes during inflammation. Co-expression of gut-homing markers CCR9 and α4β7 was more pronounced in biopsies compared with peripheral blood, but was not enhanced upon active inflammation. CONCLUSIONS Gut-homing T cells are abundant in pouch mucosa, but the classic hypothesis that the chronic inflammatory state is maintained by an accumulation of α4β7-expressing effector T cells is not supported by our data.
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Affiliation(s)
- Manon de Krijger
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.,Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Manon E Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.,Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Aart Mookhoek
- Department of Pathology, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Sascha Verheul
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.,Department of Surgery, University of Bonn, Bonn, Germany
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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48
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Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
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Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
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49
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Bos AV, Erkelens MN, Koenders STA, van der Stelt M, van Egmond M, Mebius RE. Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells. Front Immunol 2021; 12:671283. [PMID: 34305901 PMCID: PMC8298001 DOI: 10.3389/fimmu.2021.671283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/02/2021] [Indexed: 01/24/2023] Open
Abstract
The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.
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Affiliation(s)
- Amelie V Bos
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
| | - Martje N Erkelens
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
| | - Sebastiaan T A Koenders
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands
| | - Marjolein van Egmond
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands.,Department of Surgery, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
| | - Reina E Mebius
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, location VUmc, Amsterdam, Netherlands
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50
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Hamza KH, Dunér E, Ulmert I, Arias A, Sorobetea D, Lahl K. Minor alterations in the intestinal microbiota composition upon Rotavirus infection do not affect susceptibility to DSS colitis. Sci Rep 2021; 11:13485. [PMID: 34188111 PMCID: PMC8242028 DOI: 10.1038/s41598-021-92796-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/11/2021] [Indexed: 02/06/2023] Open
Abstract
Viral triggers at the intestinal mucosa can have multiple global effects on intestinal integrity, causing elevated intestinal barrier strength and relative protection from subsequent inflammatory bowel disease (IBD) induction in various models. As viruses can interfere with the intestinal immune system both directly and indirectly through commensal bacteria, cause-effect relationships are difficult to define. Due to the complexity of putatively causative factors, our understanding of such virus-mediated protection is currently very limited. We here set out to better understand the impact that adult enteric infection with rotavirus (RV) might have on the composition of the intestinal microbiome and on the severity of IBD. We found that RV infection neither induced significant long-lasting microbiota community changes in the small or large intestine nor affected the severity of subsequent dextran sulfate sodium-induced colitis. Hence, adult murine RV infection does not exert lasting effects on intestinal homeostasis.
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Affiliation(s)
| | - Emma Dunér
- Immunology Section, Lund University, 221 84, Lund, Sweden
| | - Isabel Ulmert
- Section for Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark (DTU), 2800, Kongens Lyngby, Denmark
| | - Armando Arias
- Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha (UCLM), 02008, Albacete, Spain
| | - Daniel Sorobetea
- Immunology Section, Lund University, 221 84, Lund, Sweden
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Katharina Lahl
- Immunology Section, Lund University, 221 84, Lund, Sweden.
- Section for Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark (DTU), 2800, Kongens Lyngby, Denmark.
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