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1
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Xu J, Apetoh L. Go to the scene: T H9 cells superior migration ability to the lungs explains their exceptional anticancer efficacy. J Immunother Cancer 2025; 13:e011522. [PMID: 40295144 PMCID: PMC12039026 DOI: 10.1136/jitc-2025-011522] [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: 01/16/2025] [Accepted: 04/14/2025] [Indexed: 04/30/2025] Open
Abstract
Antibodies against immune checkpoints are now routinely administered as a first line of treatment against metastatic lung cancer. Resistance to immune checkpoint inhibitors is, however, frequent, underscoring the need to find alternative treatments. Adoptive T-cell therapy has recently proven effective in treating patient's refractory to immune checkpoint inhibitors. This provides impetus to characterize the T-cell subsets best able to tackle tumors. The anticancer activities of IL-9-producing CD4 T helper cells (TH9 cells) were identified in melanoma in 2012. TH9 cells feature strong antimelanoma effects thanks to their production of interleukin (IL)-9 and the activation of innate and adaptive immune effectors. The ability of TH9 cells to prevent the growth of triple-negative breast cancer (TNBC) and osteosarcoma (OS), which commonly metastasize to the lungs, is elusive. In this commentary, we discuss the findings of Chen et al reported in the JITC demonstrating that TH9 cells are lung-tropic and eliminate TNBC and OS cells developing in the lungs. We also highlight how these investigations are in line with recent studies indicating that the adoptive transfer of IL-9-producing T cells eliminate aggressive cancers, including hematological tumors like leukemia and solid tumors such as glioblastoma. Altogether, these findings over the past 13 years support the clinical evaluation of TH9 cells in the adoptive therapy of cancer.
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Affiliation(s)
- Jiazhi Xu
- Microbiology and Immunology, Indiana University Indianapolis, Indianapolis, Indiana, USA
| | - Lionel Apetoh
- Microbiology and Immunology, Indiana University Indianapolis, Indianapolis, Indiana, USA
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2
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Schärli S, Luther F, Di Domizio J, Hillig C, Radonjic-Hoesli S, Thormann K, Simon D, Rønnstad ATM, Ruge IF, Fritz BG, Bjarnsholt T, Vallone A, Kezic S, Menden MP, Roesner LM, Werfel T, Thyssen JP, Eyerich S, Gilliet M, Bertschi NL, Schlapbach C. IL-9 sensitizes human T H2 cells to proinflammatory IL-18 signals in atopic dermatitis. J Allergy Clin Immunol 2025; 155:491-504.e9. [PMID: 39521283 DOI: 10.1016/j.jaci.2024.10.027] [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: 06/27/2024] [Revised: 09/28/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND TH2 cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet the upstream regulators that activate TH2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of TH2 cells because it is implicated in AD pathogenesis and has the capacity to activate T cells. OBJECTIVE We sought to decipher the role of IL-18 in TH2 responses in blood and skin of AD patients. METHODS Peripheral blood mononuclear cells and skin biopsy samples from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed by flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-Seq, Western blot, and spatial sequencing. RESULTS IL-18Rα+ TH2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which TH2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R-JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating TH2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by costimulation with IL-9. Mechanistically, IL-18 induced TH2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in TH2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin. CONCLUSION Our data identify a novel IL-9/IL-18 axis that contributes to TH2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD.
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Affiliation(s)
- Stefanie Schärli
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Fabian Luther
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Jeremy Di Domizio
- Department of Dermatology, CHUV University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Christina Hillig
- Computational Health Center, Institute of Computational Biology, Helmholtz Munich, Munich, Germany
| | - Susanne Radonjic-Hoesli
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Kathrin Thormann
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Dagmar Simon
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | | | - Iben Frier Ruge
- Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark
| | - Blaine G Fritz
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Bjarnsholt
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Microbiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Angela Vallone
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sanja Kezic
- Department of Public and Occupational Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands
| | - Michael P Menden
- Computational Health Center, Institute of Computational Biology, Helmholtz Munich, Munich, Germany; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Australia
| | - Lennart M Roesner
- Department of Dermatology and Allergy, Hannover Medical School (MHH), Hannover, Germany
| | - Thomas Werfel
- Department of Dermatology and Allergy, Hannover Medical School (MHH), Hannover, Germany
| | - Jacob P Thyssen
- Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark
| | - Stefanie Eyerich
- Center for Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, Germany
| | - Michel Gilliet
- Department of Dermatology, CHUV University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Nicole L Bertschi
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
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3
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Kim JC, Hu W, Lee M, Bae GH, Park JY, Lee SY, Jeong YS, Park B, Park JS, Zabel BA, Bae YS, Bae YS. Sphingosylphosphorylcholine Promotes Th9 Cell Differentiation Through Regulation of Smad3, STAT5, and β-Catenin Pathways. Immune Netw 2024; 24:e45. [PMID: 39801737 PMCID: PMC11711130 DOI: 10.4110/in.2024.24.e45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/06/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
Sphingosylphosphorylcholine (SPC) is one of sphingomyelin-derived sphingolipids. SPC levels are increased in ascitic fluids of ovarian cancer patients and stratum corneum of atopic dermatitis (AD) patients. SPC has antitumor activity against several cancer cells by reducing proliferation and migration and increasing apoptosis in vitro. SPC can also cause scratching, potentially exacerbating symptoms of AD. However, the role of SPC in modulating immune responses, particularly in the differentiation of Th9 cells, which carry the most powerful antitumor activity among CD4+ T cells, has yet to be investigated. In this study, we found that SPC is another inducer of Th9 cell differentiation by replicating TGF-β. SPC upregulated Smad3, STAT5, and β-catenin signaling pathways. Increased Smad3 and STAT5 signaling pathways by SPC promoted the differentiation of Th9 cells and increased β-catenin signaling pathway resulted in a less-exhausted, memory-like phenotype of Th9 cells. Increased Smad3, STAT5 and β-catenin signaling pathways by SPC were mediated by increased mitochondrial ROS. These results suggest that SPC is an important endogenous inducer of Th9 cell differentiation and may be one of the targets for treating Th9-related diseases, and that enhancing Th9 differentiation by SPC may be helpful in adoptive T cell therapy for cancer treatment.
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Affiliation(s)
- Ji Cheol Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Wonseok Hu
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Mingyu Lee
- Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Korea
| | - Geon Ho Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Ji Ye Park
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Suh Yeon Lee
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Yu Sun Jeong
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Byunghyun Park
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Joon Seong Park
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Brian A. Zabel
- Palo Alto Veterans Institute for Research (PAVIR), VA Palo Alto Health Care Systems (VAPAHCS), Palo Alto, CA 94304, USA
| | - Yong-Soo Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
| | - Yoe-Sik Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Korea
- Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Korea
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4
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Long Y, Dai W, Cai K, Xiao Y, Luo A, Lai Z, Wang J, Xu L, Nie H. Systemic Immune Factors and Risk of Allergic Contact Dermatitis: A Bidirectional Mendelian Randomization Study. Int J Mol Sci 2024; 25:10436. [PMID: 39408763 PMCID: PMC11476522 DOI: 10.3390/ijms251910436] [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: 08/29/2024] [Revised: 09/16/2024] [Accepted: 09/21/2024] [Indexed: 10/20/2024] Open
Abstract
Skin inflammation and immune regulation have been suggested to be associated with allergic contact dermatitis (ACD) progression, but whether the system's immune regulation is a cause or a potential mechanism is still unknown. This study aims to assess the upstream and downstream of systemic immune factors on ACD within a bidirectional Mendelian-randomization design. A bidirectional two-sample MR analysis was employed to implement the results from genome-wide association studies for 52 system immune factors and ACD. Genetic associations with systemic immune factors and ACD were obtained from the IEU Open GWAS project database. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis, MR-Egger, weighted median, MR-pleiotropy residual sum, and outlier (MR-PRESSO) was also used as the sensitivity analyses. Only Tumor necrosis factor ligand superfamily member 11 (TNFS11) from among 52 systemic immune factors was associated with a protective effect of ACD. However, ACD was associated with a decrease in Interleukin-9 (IL9) and an increase in C-X-C motif chemokine 1 (GROα), Tumor necrosis factor ligand superfamily member 10 (TRAIL), C4, and complement factor B of the assessed systemic immune factors. This study identified TNFS11 as the upstream regulator and IL9, GROα, TRAIL, C4, and complement factor B as the downstream regulator of ACD, providing opportunities for new therapeutic exploitation of ACD. Nonetheless, these associations of systemic immune factors need to be verified in vivo.
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Affiliation(s)
| | | | | | | | | | | | | | - Lipeng Xu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; (Y.L.); (W.D.); (K.C.); (Y.X.); (A.L.); (Z.L.); (J.W.)
| | - Hong Nie
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; (Y.L.); (W.D.); (K.C.); (Y.X.); (A.L.); (Z.L.); (J.W.)
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5
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García-Jiménez I, Sans-de San Nicolás L, Curto-Barredo L, Bertolín-Colilla M, Sensada-López E, Figueras-Nart I, Bonfill-Ortí M, Guilabert-Vidal A, Ryzhkova A, Ferran M, Damiani G, Czarnowicki T, Pujol RM, Santamaria-Babí LF. Heterogeneous IL-9 Production by Circulating Skin-Tropic and Extracutaneous Memory T Cells in Atopic Dermatitis Patients. Int J Mol Sci 2024; 25:8569. [PMID: 39201262 PMCID: PMC11354683 DOI: 10.3390/ijms25168569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Interleukin (IL)-9 is present in atopic dermatitis (AD) lesions and is considered to be mainly produced by skin-homing T cells expressing the cutaneous lymphocyte-associated antigen (CLA). However, its induction by AD-associated triggers remains unexplored. Circulating skin-tropic CLA+ and extracutaneous/systemic CLA- memory T cells cocultured with autologous lesional epidermal cells from AD patients were activated with house dust mite (HDM) and staphylococcal enterotoxin B (SEB). Levels of AD-related mediators in response to both stimuli were measured in supernatants, and the cytokine response was associated with different clinical characteristics. Both HDM and SEB triggered heterogeneous IL-9 production by CLA+ and CLA- T cells in a clinically homogenous group of AD patients, which enabled patient stratification into IL-9 producers and non-producers, with the former group exhibiting heightened HDM-specific and total IgE levels. Upon allergen exposure, IL-9 production depended on the contribution of epidermal cells and class II-mediated presentation; it was the greatest cytokine produced and correlated with HDM-specific IgE levels, whereas SEB mildly induced its release. This study demonstrates that both skin-tropic and extracutaneous memory T cells produce IL-9 and suggests that the degree of allergen sensitization reflects the varied IL-9 responses in vitro, which may allow for patient stratification in a clinically homogenous population.
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Affiliation(s)
- Irene García-Jiménez
- Immunologia Translacional, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), 08028 Barcelona, Spain; (I.G.-J.)
| | - Lídia Sans-de San Nicolás
- Immunologia Translacional, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), 08028 Barcelona, Spain; (I.G.-J.)
| | - Laia Curto-Barredo
- Departament de Dermatologia, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), 08003 Barcelona, Spain
| | - Marta Bertolín-Colilla
- Departament de Dermatologia, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), 08003 Barcelona, Spain
| | - Eloi Sensada-López
- Immunologia Translacional, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), 08028 Barcelona, Spain; (I.G.-J.)
| | - Ignasi Figueras-Nart
- Departament de Dermatologia, Hospital de Bellvitge, Universitat de Barcelona (UB), 08907 L’Hospitalet de Llobregat, Spain
| | - Montserrat Bonfill-Ortí
- Departament de Dermatologia, Hospital de Bellvitge, Universitat de Barcelona (UB), 08907 L’Hospitalet de Llobregat, Spain
| | | | - Anna Ryzhkova
- Immunologia Translacional, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), 08028 Barcelona, Spain; (I.G.-J.)
| | - Marta Ferran
- Departament de Dermatologia, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), 08003 Barcelona, Spain
| | - Giovanni Damiani
- Italian Center of Precision Medicine and Chronic Inflammation Milan, 20122 Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, Faculty of Medicine and Surgery, University of Milan, 20122 Milan, Italy
| | - Tali Czarnowicki
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ramon M. Pujol
- Departament de Dermatologia, Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), 08003 Barcelona, Spain
| | - Luis F. Santamaria-Babí
- Immunologia Translacional, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), 08028 Barcelona, Spain; (I.G.-J.)
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6
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Khokhar M, Purohit P. The emerging role of T helper 9 (Th9) cells in immunopathophysiology: A comprehensive review of their effects and responsiveness in various disease states. Int Rev Immunol 2024; 43:341-360. [PMID: 38864109 DOI: 10.1080/08830185.2024.2364586] [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: 01/23/2024] [Revised: 05/10/2024] [Accepted: 05/31/2024] [Indexed: 06/13/2024]
Abstract
Th9 cells, a subset of T-helper cells producing interleukin-9 (IL-9), play a vital role in the adaptive immune response and have diverse effects in different diseases. Regulated by transcription factors like PU.1 and IRF4, and cytokines such as IL-4 and TGF-β, Th9 cells drive tissue inflammation. This review focuses on their emerging role in immunopathophysiology. Th9 cells exhibit immune-mediated cancer cell destruction, showing promise in glioma and cervical cancer treatment. However, their role in breast and lung cancer is intricate, requiring a deeper understanding of pro- and anti-tumor aspects. Th9 cells, along with IL-9, foster T cell and immune cell proliferation, contributing to autoimmune disorders. They are implicated in psoriasis, atopic dermatitis, and infections. In allergic reactions and asthma, Th9 cells fuel pro-inflammatory responses. Targeting Foxo1 may regulate innate and adaptive immune responses, alleviating disease symptoms. This comprehensive review outlines Th9 cells' evolving immunopathophysiological role, emphasizing the necessity for further research to grasp their effects and potential therapeutic applications across diseases.
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Jodhpur, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Jodhpur, India
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7
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Son A, Baral I, Falduto GH, Schwartz DM. Locus of (IL-9) control: IL9 epigenetic regulation in cellular function and human disease. Exp Mol Med 2024; 56:1331-1339. [PMID: 38825637 PMCID: PMC11263352 DOI: 10.1038/s12276-024-01241-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 06/04/2024] Open
Abstract
Interleukin-9 (IL-9) is a multifunctional cytokine with roles in a broad cross-section of human diseases. Like many cytokines, IL-9 is transcriptionally regulated by a group of noncoding regulatory elements (REs) surrounding the IL9 gene. These REs modulate IL-9 transcription by forming 3D loops that recruit transcriptional machinery. IL-9-promoting transcription factors (TFs) can bind REs to increase locus accessibility and permit chromatin looping, or they can be recruited to already accessible chromatin to promote transcription. Ample mechanistic and genome-wide association studies implicate this interplay between IL-9-modulating TFs and IL9 cis-REs in human physiology, homeostasis, and disease.
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Affiliation(s)
- Aran Son
- Neuroscience Department, International School for Advanced Studies (SISSA), via Bonomea 265, Trieste, 34136, Italy
| | - Ishita Baral
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Guido H Falduto
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Daniella M Schwartz
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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8
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Sieminska I, Pieniawska M, Grzywa TM. The Immunology of Psoriasis-Current Concepts in Pathogenesis. Clin Rev Allergy Immunol 2024; 66:164-191. [PMID: 38642273 PMCID: PMC11193704 DOI: 10.1007/s12016-024-08991-7] [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] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8+ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.
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Affiliation(s)
- Izabela Sieminska
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Krakow, Poland
| | - Monika Pieniawska
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
| | - Tomasz M Grzywa
- Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland.
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, USA.
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9
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Zhang XE, Zheng P, Ye SZ, Ma X, Liu E, Pang YB, He QY, Zhang YX, Li WQ, Zeng JH, Guo J. Microbiome: Role in Inflammatory Skin Diseases. J Inflamm Res 2024; 17:1057-1082. [PMID: 38375021 PMCID: PMC10876011 DOI: 10.2147/jir.s441100] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
As the body's largest organ, the skin harbors a highly diverse microbiota, playing a crucial role in resisting foreign pathogens, nurturing the immune system, and metabolizing natural products. The dysregulation of human skin microbiota is implicated in immune dysregulation and inflammatory responses. This review delineates the microbial alterations and immune dysregulation features in common Inflammatory Skin Diseases (ISDs) such as psoriasis, rosacea, atopic dermatitis(AD), seborrheic dermatitis(SD), diaper dermatitis(DD), and Malassezia folliculitis(MF).The skin microbiota, a complex and evolving community, undergoes changes in composition and function that can compromise the skin microbial barrier. These alterations induce water loss and abnormal lipid metabolism, contributing to the onset of ISDs. Additionally, microorganisms release toxins, like Staphylococcus aureus secreted α toxins and proteases, which may dissolve the stratum corneum, impairing skin barrier function and allowing entry into the bloodstream. Microbes entering the bloodstream activate molecular signals, leading to immune disorders and subsequent skin inflammatory responses. For instance, Malassezia stimulates dendritic cells(DCs) to release IL-12 and IL-23, differentiating into a Th17 cell population and producing proinflammatory mediators such as IL-17, IL-22, TNF-α, and IFN-α.This review offers new insights into the role of the human skin microbiota in ISDs, paving the way for future skin microbiome-specific targeted therapies.
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Affiliation(s)
- Xue-Er Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Pai Zheng
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Sheng-Zhen Ye
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 6610072, People’s Republic of China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China
| | - E Liu
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Yao-Bin Pang
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Qing-Ying He
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Yu-Xiao Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Wen-Quan Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, 6610075, People’s Republic of China
| | - Jin-Hao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China
| | - Jing Guo
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 6610072, People’s Republic of China
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10
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Guo J, Zhang H, Lin W, Lu L, Su J, Chen X. Signaling pathways and targeted therapies for psoriasis. Signal Transduct Target Ther 2023; 8:437. [PMID: 38008779 PMCID: PMC10679229 DOI: 10.1038/s41392-023-01655-6] [Citation(s) in RCA: 92] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/10/2023] [Accepted: 09/14/2023] [Indexed: 11/28/2023] Open
Abstract
Psoriasis is a common, chronic, and inflammatory skin disease with a high burden on individuals, health systems, and society worldwide. With the immunological pathologies and pathogenesis of psoriasis becoming gradually revealed, the therapeutic approaches for this disease have gained revolutionary progress. Nevertheless, the mechanisms of less common forms of psoriasis remain elusive. Furthermore, severe adverse effects and the recurrence of disease upon treatment cessation should be noted and addressed during the treatment, which, however, has been rarely explored with the integration of preliminary findings. Therefore, it is crucial to have a comprehensive understanding of the mechanisms behind psoriasis pathogenesis, which might offer new insights for research and lead to more substantive progress in therapeutic approaches and expand clinical options for psoriasis treatment. In this review, we looked to briefly introduce the epidemiology, clinical subtypes, pathophysiology, and comorbidities of psoriasis and systematically discuss the signaling pathways involving extracellular cytokines and intracellular transmission, as well as the cross-talk between them. In the discussion, we also paid more attention to the potential metabolic and epigenetic mechanisms of psoriasis and the molecular mechanistic cascades related to its comorbidities. This review also outlined current treatment for psoriasis, especially targeted therapies and novel therapeutic strategies, as well as the potential mechanism of disease recurrence.
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Affiliation(s)
- Jia Guo
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Hanyi Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Wenrui Lin
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Lixia Lu
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.
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11
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Li Y, Liu H, He C, Lin Y, Ma L, Xue H. IL-9-Producing Th9 Cells Participate in the Occurrence and Development of Iodine-Induced Autoimmune Thyroiditis. Biol Trace Elem Res 2023; 201:5298-5308. [PMID: 36773201 DOI: 10.1007/s12011-023-03598-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
Iodine excess may cause and aggravate autoimmune thyroiditis (AIT), which is regarded as a typical kind of autoimmune disease mainly mediated by CD4+ T cells. Thus far, it is unclear whether T helper (Th) 9 cells, a novel subpopulation of CD4+ T cells, play a potential role in AIT. Therefore, in the present study, changes in Th9 cells were detected in murine models of AIT induced by excess iodine intake to explore the possible immune mechanism. Female C57BL/6 mice were divided into 7 groups (n = 8) and were supplied with water containing 0.005% sodium iodide for 0, 2, 4, 6, 8, 10, and 12 weeks. With the extension of the high-iodine intake duration, the incidence of thyroiditis and the spleen index were significantly increased, and serum thyroglobulin antibody (TgAb) titers and interleukin 9 (IL-9, major cytokine from Th9 cells) concentrations were also increased. Additionally, it was revealed that the percentages of Th9 cells in spleen mononuclear cells (SMCs) and thyroid tissues were both markedly elevated and accompanied by increased mRNA and protein expression of IL-9 and key transcription factors of Th9 cells (PU.1 and IRF-4). Significantly, dynamic changes in Th9 cells were found, with a peak at 8 weeks after high iodine intake, the time point when thyroiditis was the most serious. Importantly, Th9 cells were detected in the areas of infiltrating lymphocytes in thyroid sections. In conclusion, the continuously increasing proportions of Th9 cells may play an important role in the occurrence and development of AIT induced by high iodine intake.
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Affiliation(s)
- Yiwen Li
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China
| | - Hao Liu
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China
| | - Chengyan He
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China
| | - Yawen Lin
- Department of Dermatology, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China
| | - Lei Ma
- Department of Dermatology, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China
| | - Haibo Xue
- Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou, 256603, China.
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12
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Zareinejad M, Mehdipour F, Roshan-Zamir M, Faghih Z, Ghaderi A. Dual Functions of T Lymphocytes in Breast Carcinoma: From Immune Protection to Orchestrating Tumor Progression and Metastasis. Cancers (Basel) 2023; 15:4771. [PMID: 37835465 PMCID: PMC10571747 DOI: 10.3390/cancers15194771] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/23/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Breast cancer (BC) is the most common cancer type in women and the second leading cause of death. Despite recent advances, the mortality rate of BC is still high, highlighting a need to develop new treatment strategies including the modulation of the immune system and immunotherapies. In this regard, understanding the complex function of the involved immune cells and their crosstalk with tumor cells is of great importance. T-cells are recognized as the most important cells in the tumor microenvironment and are divided into several subtypes including helper, cytotoxic, and regulatory T-cells according to their transcription factors, markers, and functions. This article attempts to provide a comprehensive review of the role of T-cell subsets in the prognosis and treatment of patients with BC, and crosstalk between tumor cells and T-cells. The literature overwhelmingly contains controversial findings mainly due to the plasticity of T-cell subsets within the inflammatory conditions and the use of different panels for their phenotyping. However, investigating the role of T-cells in BC immunity depends on a variety of factors including tumor types or subtypes, the stage of the disease, the localization of the cells in the tumor tissue and the presence of different cells or cytokines.
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Affiliation(s)
| | | | | | - Zahra Faghih
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45505, Iran; (M.Z.); (F.M.); (M.R.-Z.)
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-45505, Iran; (M.Z.); (F.M.); (M.R.-Z.)
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13
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Chen C, Zeng J, Lu J. Critical role of epigenetic modification in the pathogenesis of atopic dermatitis. Indian J Dermatol Venereol Leprol 2023; 89:700-709. [PMID: 37067130 DOI: 10.25259/ijdvl_298_2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 10/24/2022] [Indexed: 03/31/2023]
Abstract
Atopic dermatitis is a chronic inflammatory skin disease characterised by recurrent eczema-like lesions and severe pruritus, along with drying and decrustation of skin. Current research relates the pathogenesis of atopic dermatitis mainly to genetic susceptibility, abnormal skin barrier function, immune disorders, Staphylococcus aureus colonisation, microbiological dysfunction and vitamin D insufficiency. Epigenetic modifications are distinct genetic phenotypes resulting from environment-driven changes in chromosome functions in the absence of nuclear DNA sequence variation. Classic epigenetic events include DNA methylation, histone protein modifications and non-coding RNA regulation. Increasing evidence has indicated that epigenetic events are involved in the pathogenesis of atopic dermatitis by their effects on multiple signalling pathways which in turn influence the above factors. This review primarily analyses the function of epigenetic regulation in the pathogenesis of atopic dermatitis. In addition, it tries to make recommendations for personalised epigenetic treatment strategies for atopic dermatitis in the future.
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Affiliation(s)
- Chunli Chen
- Department of Dermatology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jinrong Zeng
- Department of Dermatology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jianyun Lu
- Department of Dermatology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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14
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Son A, Meylan F, Gomez-Rodriguez J, Kaul Z, Sylvester M, Falduto GH, Vazquez E, Haque T, Kitakule MM, Wang C, Manthiram K, Qi CF, Cheng J, Gurram RK, Zhu J, Schwartzberg P, Milner JD, Frischmeyer-Guerrerio PA, Schwartz DM. Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of T H9 cells to promote allergic inflammation. Nat Immunol 2023; 24:1036-1048. [PMID: 37106040 PMCID: PMC10247433 DOI: 10.1038/s41590-023-01501-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 03/27/2023] [Indexed: 04/29/2023]
Abstract
Allergic diseases are a major global health issue. Interleukin (IL)-9-producing helper T (TH9) cells promote allergic inflammation, yet TH9 cell effector functions are incompletely understood because their lineage instability makes them challenging to study. Here we found that resting TH9 cells produced IL-9 independently of T cell receptor (TCR) restimulation, due to STAT5- and STAT6-dependent bystander activation. This mechanism was seen in circulating cells from allergic patients and was restricted to recently activated cells. STAT5-dependent Il9/IL9 regulatory elements underwent remodeling over time, inactivating the locus. A broader 'allergic TH9' transcriptomic and epigenomic program was also unstable. In vivo, TH9 cells induced airway inflammation via TCR-independent, STAT-dependent mechanisms. In allergic patients, TH9 cell expansion was associated with responsiveness to JAK inhibitors. These findings suggest that TH9 cell instability is a negative checkpoint on bystander activation that breaks down in allergy and that JAK inhibitors should be considered for allergic patients with TH9 cell expansion.
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Affiliation(s)
- Aran Son
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Francoise Meylan
- Office of Science and Technology, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Julio Gomez-Rodriguez
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- TCR Therapeutics, Cambridge, MA, USA
| | - Zenia Kaul
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - McKella Sylvester
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Guido H Falduto
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Estefania Vazquez
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Tamara Haque
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Moses M Kitakule
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Division of Pediatric Allergy Immunology and Rheumatology, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
| | - Chujun Wang
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kalpana Manthiram
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Chen-Feng Qi
- Pathology Core, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jun Cheng
- Embryonic Stem Cell and Transgenic Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Rama K Gurram
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jinfang Zhu
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pamela Schwartzberg
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Joshua D Milner
- Division of Pediatric Allergy Immunology and Rheumatology, Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
| | - Pamela A Frischmeyer-Guerrerio
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Daniella M Schwartz
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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15
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Badolati I, van der Heiden M, Brodin D, Zuurveld M, Szilágyi S, Björkander S, Sverremark-Ekström E. Staphylococcus aureus-derived factors promote human Th9 cell polarization and enhance a transcriptional program associated with allergic inflammation. Eur J Immunol 2023; 53:e2250083. [PMID: 36550071 DOI: 10.1002/eji.202250083] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 12/09/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022]
Abstract
T helper (Th) 9 cells, characterized by robust secretion of IL-9, have been increasingly associated with allergic diseases. However, whether and how Th9 cells are modulated by environmental stimuli remains poorly understood. In this study, we show that in vitro exposure of human PBMCs or isolated CD4 T-cells to Staphylococcus (S.) aureus-derived factors, including its toxins, potently enhances Th9 cell frequency and IL-9 secretion. Furthermore, as revealed by RNA sequencing analysis, S. aureus increases the expression of Th9-promoting factors at the transcriptional level, such as FOXO1, miR-155, and TNFRSF4. The addition of retinoic acid (RA) dampens the Th9 responses promoted by S. aureus and substantially changes the transcriptional program induced by this bacterium, while also altering the expression of genes associated with allergic inflammation. Together, our results demonstrate a strong influence of microbial and dietary factors on Th9 cell polarization, which may be important in the context of allergy development and treatment.
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Affiliation(s)
- Isabella Badolati
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Marieke van der Heiden
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - David Brodin
- Bioinformatics and Expression Analysis Core Facility, Karolinska Institutet, Huddinge, Sweden
| | - Marit Zuurveld
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Szilvia Szilágyi
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Sophia Björkander
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
- Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Eva Sverremark-Ekström
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
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16
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Khokhar M, Purohit P, Gadwal A, Tomo S, Bajpai NK, Shukla R. The Differentially Expressed Genes Responsible for the Development of T Helper 9 Cells From T Helper 2 Cells in Various Disease States: Immuno-Interactomics Study. JMIR BIOINFORMATICS AND BIOTECHNOLOGY 2023; 4:e42421. [PMID: 38935935 PMCID: PMC11135241 DOI: 10.2196/42421] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 01/18/2023] [Accepted: 01/25/2023] [Indexed: 06/29/2024]
Abstract
BACKGROUND T helper (Th) 9 cells are a novel subset of Th cells that develop independently from Th2 cells and are characterized by the secretion of interleukin (IL)-9. Studies have suggested the involvement of Th9 cells in variable diseases such as allergic and pulmonary diseases (eg, asthma, chronic obstructive airway disease, chronic rhinosinusitis, nasal polyps, and pulmonary hypoplasia), metabolic diseases (eg, acute leukemia, myelocytic leukemia, breast cancer, lung cancer, melanoma, pancreatic cancer), neuropsychiatric disorders (eg, Alzheimer disease), autoimmune diseases (eg, Graves disease, Crohn disease, colitis, psoriasis, systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atopic dermatitis, eczema), and infectious diseases (eg, tuberculosis, hepatitis). However, there is a dearth of information on its involvement in other metabolic, neuropsychiatric, and infectious diseases. OBJECTIVE This study aims to identify significant differentially altered genes in the conversion of Th2 to Th9 cells, and their regulating microRNAs (miRs) from publicly available Gene Expression Omnibus data sets of the mouse model using in silico analysis to unravel various pathogenic pathways involved in disease processes. METHODS Using differentially expressed genes (DEGs) identified from 2 publicly available data sets (GSE99166 and GSE123501) we performed functional enrichment and network analyses to identify pathways, protein-protein interactions, miR-messenger RNA associations, and disease-gene associations related to significant differentially altered genes implicated in the conversion of Th2 to Th9 cells. RESULTS We extracted 260 common downregulated, 236 common upregulated, and 634 common DEGs from the expression profiles of data sets GSE99166 and GSE123501. Codifferentially expressed ILs, cytokines, receptors, and transcription factors (TFs) were enriched in 7 crucial Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology. We constructed the protein-protein interaction network and predicted the top regulatory miRs involved in the Th2 to Th9 differentiation pathways. We also identified various metabolic, allergic and pulmonary, neuropsychiatric, autoimmune, and infectious diseases as well as carcinomas where the differentiation of Th2 to Th9 may play a crucial role. CONCLUSIONS This study identified hitherto unexplored possible associations between Th9 and disease states. Some important ILs, including CCL1 (chemokine [C-C motif] ligand 1), CCL20 (chemokine [C-C motif] ligand 20), IL-13, IL-4, IL-12A, and IL-9; receptors, including IL-12RB1, IL-4RA (interleukin 9 receptor alpha), CD53 (cluster of differentiation 53), CD6 (cluster of differentiation 6), CD5 (cluster of differentiation 5), CD83 (cluster of differentiation 83), CD197 (cluster of differentiation 197), IL-1RL1 (interleukin 1 receptor-like 1), CD101 (cluster of differentiation 101), CD96 (cluster of differentiation 96), CD72 (cluster of differentiation 72), CD7 (cluster of differentiation 7), CD152 (cytotoxic T lymphocyte-associated protein 4), CD38 (cluster of differentiation 38), CX3CR1 (chemokine [C-X3-C motif] receptor 1), CTLA2A (cytotoxic T lymphocyte-associated protein 2 alpha), CTLA28, and CD196 (cluster of differentiation 196); and TFs, including FOXP3 (forkhead box P3), IRF8 (interferon regulatory factor 8), FOXP2 (forkhead box P2), RORA (RAR-related orphan receptor alpha), AHR (aryl-hydrocarbon receptor), MAF (avian musculoaponeurotic fibrosarcoma oncogene homolog), SMAD6 (SMAD family member 6), JUN (Jun proto-oncogene), JAK2 (Janus kinase 2), EP300 (E1A binding protein p300), ATF6 (activating transcription factor 6), BTAF1 (B-TFIID TATA-box binding protein associated factor 1), BAFT (basic leucine zipper transcription factor), NOTCH1 (neurogenic locus notch homolog protein 1), GATA3 (GATA binding protein 3), SATB1 (special AT-rich sequence binding protein 1), BMP7 (bone morphogenetic protein 7), and PPARG (peroxisome proliferator-activated receptor gamma, were able to identify significant differentially altered genes in the conversion of Th2 to Th9 cells. We identified some common miRs that could target the DEGs. The scarcity of studies on the role of Th9 in metabolic diseases highlights the lacunae in this field. Our study provides the rationale for exploring the role of Th9 in various metabolic disorders such as diabetes mellitus, diabetic nephropathy, hypertensive disease, ischemic stroke, steatohepatitis, liver fibrosis, obesity, adenocarcinoma, glioblastoma and glioma, malignant neoplasm of stomach, melanoma, neuroblastoma, osteosarcoma, pancreatic carcinoma, prostate carcinoma, and stomach carcinoma.
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Nitin Kumar Bajpai
- Department of Nephrology, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Ravindra Shukla
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
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17
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Kamiya S, Ikegami I, Yanagi M, Takaki H, Kamekura R, Sato T, Kobayashi K, Kamiya T, Kamada Y, Abe T, Inoue KI, Hida T, Uhara H, Ichimiya S. Functional Interplay between IL-9 and Peptide YY Contributes to Chronic Skin Inflammation. J Invest Dermatol 2022; 142:3222-3231.e5. [PMID: 35850207 DOI: 10.1016/j.jid.2022.06.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 06/10/2022] [Accepted: 06/11/2022] [Indexed: 01/05/2023]
Abstract
Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14CRE/ERTIl9raΔ/Δ mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14CRE/ERTIl9raΔ/Δ mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14WTIl9rafl/fl mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14CRE/ERTIl9raΔ/Δ epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.
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Affiliation(s)
- Shiori Kamiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ippei Ikegami
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Yanagi
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromi Takaki
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Taiki Sato
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Keiju Kobayashi
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takafumi Kamiya
- Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuka Kamada
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takaya Abe
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Ken-Ichi Inoue
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Tokimasa Hida
- Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hisashi Uhara
- Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
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18
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Yu J, Zhao Q, Wang X, Zhou H, Hu J, Gu L, Hu Y, Zeng F, Zhao F, Yue C, Zhou P, Li G, Li Y, Wu W, Zhou Y, Li J. Pathogenesis, multi-omics research, and clinical treatment of psoriasis. J Autoimmun 2022; 133:102916. [PMID: 36209691 DOI: 10.1016/j.jaut.2022.102916] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/08/2022] [Accepted: 09/12/2022] [Indexed: 11/07/2022]
Abstract
Psoriasis is a common inflammatory skin disease involving interactions between keratinocytes and immune cells that significantly affects the quality of life. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes and excessive infiltration of immune cells in the dermis and epidermis. The immune mechanism underlying this disease has been elucidated in the past few years. Research shows that psoriasis is regulated by the complex interactions among immune cells, such as keratinocytes, dendritic cells, T lymphocytes, neutrophils, macrophages, natural killer cells, mast cells, and other immune cells. An increasing number of signaling pathways have been found to be involved in the pathogenesis of psoriasis, which has prompted the search for new treatment targets. In the past decades, studies on the pathogenesis of psoriasis have focused on the development of targeted and highly effective therapies. In this review, we have discussed the relationship between various types of immune cells and psoriasis and summarized the major signaling pathways involved in the pathogenesis of psoriasis, including the PI3K/AKT/mTOR, JAK-STAT, JNK, and WNT pathways. In addition, we have discussed the results of the latest omics research on psoriasis and the epigenetics of the disease, which provide insights regarding its pathogenesis and therapeutic prospects; we have also summarized its treatment strategies and observations of clinical trials. In this paper, the various aspects of psoriasis are described in detail, and the limitations of the current treatment methods are emphasized. It is necessary to improve and innovate treatment methods from the molecular level of pathogenesis, and further provide new ideas for the treatment and research of psoriasis.
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Affiliation(s)
- Jiadong Yu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Qixiang Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Xiaoyan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Hong Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Jing Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Linna Gu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Yawen Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Fanlian Zeng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Fulei Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Chengcheng Yue
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Pei Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Guolin Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Ya Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Wenling Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Yifan Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China
| | - Jiong Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, 1 Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, China.
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19
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Contreras JA, Aslanyan V, Albrecht DS, Mack WJ, Alzheimer's Disease Neuroimaging Initiative (ADNI), Pa J. Higher baseline levels of CSF inflammation increase risk of incident mild cognitive impairment and Alzheimer's disease dementia. ALZHEIMER'S & DEMENTIA (AMSTERDAM, NETHERLANDS) 2022; 14:e12346. [PMID: 36187197 PMCID: PMC9484791 DOI: 10.1002/dad2.12346] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/06/2022] [Accepted: 06/28/2022] [Indexed: 11/22/2022]
Abstract
Introduction Few studies have investigated how neuroinflammation early in the disease course may affect Alzheimer's disease (AD) progression over time despite evidence that neuroinflammation is associated with AD. Methods Research participants with cerebrospinal fluid (CSF) biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study. Cox models were used to investigate whether baseline CSF neuroinflammation was associated with incident mild cognitive impairment (MCI) or AD. Moderating effects of sex and apolipoprotein E (APOE) ε4 were also examined. Results Elevated levels of tumor necrosis factor α (TNF-α), interleukin (IL)-9, and IL-12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE ε4 were observed, such that women with elevated TNF-α and all APOE ε4 carriers with elevated IL-9 levels had shorter times to conversion. In addition, TNF-α mediated the relationship between elevated IL-12p40 and IL-9. Discussion Elevated neuroinflammation markers are associated with incident MCI/AD, and the factors of sex and APOE ε4 status modify the time to conversion.
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Affiliation(s)
- Joey A. Contreras
- Alzheimer's Disease Cooperative Study (ADCS)Department of NeurosciencesUniversity of CaliforniaSan DiegoCaliforniaUSA
- Mark and Mary Stevens Neuroimaging and Informatics InstituteDepartment of NeurologyUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Vahan Aslanyan
- Mark and Mary Stevens Neuroimaging and Informatics InstituteDepartment of NeurologyUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
- Department of Population and Public Health SciencesKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Daniel S. Albrecht
- Mark and Mary Stevens Neuroimaging and Informatics InstituteDepartment of NeurologyUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Wendy J. Mack
- Department of Population and Public Health SciencesKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | | | - Judy Pa
- Alzheimer's Disease Cooperative Study (ADCS)Department of NeurosciencesUniversity of CaliforniaSan DiegoCaliforniaUSA
- Mark and Mary Stevens Neuroimaging and Informatics InstituteDepartment of NeurologyUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
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20
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Sharma J, Mudalagiriyappa S, Nanjappa SG. T cell responses to control fungal infection in an immunological memory lens. Front Immunol 2022; 13:905867. [PMID: 36177012 PMCID: PMC9513067 DOI: 10.3389/fimmu.2022.905867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022] Open
Abstract
In recent years, fungal vaccine research emanated significant findings in the field of antifungal T-cell immunity. The generation of effector T cells is essential to combat many mucosal and systemic fungal infections. The development of antifungal memory T cells is integral for controlling or preventing fungal infections, and understanding the factors, regulators, and modifiers that dictate the generation of such T cells is necessary. Despite the deficiency in the clear understanding of antifungal memory T-cell longevity and attributes, in this review, we will compile some of the existing literature on antifungal T-cell immunity in the context of memory T-cell development against fungal infections.
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Affiliation(s)
| | | | - Som Gowda Nanjappa
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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21
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Hassanzadeh Y, Yaghobi R, Pakzad P, Geramizadeh B. Risk assessment of Human cytomegalovirus infection in solid organ transplantation: Insight into
CD4
+
T cell subsets. Scand J Immunol 2022. [DOI: 10.1111/sji.13212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Yashgin Hassanzadeh
- Department of Microbiology, North Tehran Branch Islamic Azad University Tehran Iran
| | - Ramin Yaghobi
- Shiraz Transplant Research Center Shiraz University of Medical Sciences Shiraz Iran
| | - Parviz Pakzad
- Department of Microbiology, North Tehran Branch Islamic Azad University Tehran Iran
| | - Bita Geramizadeh
- Shiraz Transplant Research Center Shiraz University of Medical Sciences Shiraz Iran
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22
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Al-shami SJ, Department of Dermatology, ”Elias” University Emergency Hospital, Bucharest, Romania, Sandru F, Dumitrascu MC, Popa A, Department of Dermatology, ”Elias” University Emergency Hospital, Bucharest, Romania, ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, Department of Dermatology, ”Elias” University Emergency Hospital, Bucharest, Romania. The intestinal microbiome and the role of probiotics/prebiotics in the therapeutic approach of atopic dermatitis: A review. ROMANIAN JOURNAL OF MILITARY MEDICINE 2022. [DOI: 10.55453/rjmm.2022.125.3.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Atopic dermatitis (AD) is the most common chronic inflammatory skin condition, characterized by multiple recurrent eczematous lesions and intense itchiness. It is a multifactorial skin disorder involving an association between genetic and environmental factors that lead to a defect of the epithelial barrier in conjunction with immunological dysregulation. Over the last decade, there has been an increasing understanding of the role of the human microbiota in preserving skin integrity and that a shift in the homeostasis of these microorganisms may lead to dysbiosis and disease. Diversity in the intestinal microbiome and its role in the etiopathogenesis of AD has been described and has become of great interest. In this report, we have reviewed the importance of the gut microbiome and the possible mechanism in the pathogenesis of AD as well as the therapeutic impact of probiotics and prebiotics
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23
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Ouyang K, Oparaugo N, Nelson AM, Agak GW. T Cell Extracellular Traps: Tipping the Balance Between Skin Health and Disease. Front Immunol 2022; 13:900634. [PMID: 35795664 PMCID: PMC9250990 DOI: 10.3389/fimmu.2022.900634] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/23/2022] [Indexed: 11/30/2022] Open
Abstract
The role of extracellular traps (ETs) in the innate immune response against pathogens is well established. ETs were first identified in neutrophils and have since been identified in several other immune cells. Although the mechanistic details are not yet fully understood, recent reports have described antigen-specific T cells producing T cell extracellular traps (TETs). Depending on their location within the cutaneous environment, TETs may be beneficial to the host by their ability to limit the spread of pathogens and provide protection against damage to body tissues, and promote early wound healing and degradation of inflammatory mediators, leading to the resolution of inflammatory responses within the skin. However, ETs have also been associated with worse disease outcomes. Here, we consider host-microbe ET interactions by highlighting how cutaneous T cell-derived ETs aid in orchestrating host immune responses against Cutibacterium acnes (C. acnes), a commensal skin bacterium that contributes to skin health, but is also associated with acne vulgaris and surgical infections following joint-replacement procedures. Insights on the role of the skin microbes in regulating T cell ET formation have broad implications not only in novel probiotic design for acne treatment, but also in the treatment for other chronic inflammatory skin disorders and autoimmune diseases.
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Affiliation(s)
- Kelsey Ouyang
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
- Division of Dermatology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
- David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Nicole Oparaugo
- David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Amanda M. Nelson
- Department of Dermatology, Penn State University College of Medicine, Hershey, PA, United States
| | - George W. Agak
- Division of Dermatology, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
- *Correspondence: George W. Agak,
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24
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Sylvester M, Son A, Schwartz DM. The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations. Front Immunol 2022; 13:818039. [PMID: 35281022 PMCID: PMC8907424 DOI: 10.3389/fimmu.2022.818039] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/02/2022] [Indexed: 12/30/2022] Open
Abstract
Autoinflammatory diseases are a group of clinical syndromes characterized by constitutive overactivation of innate immune pathways. This results in increased production of or responses to monocyte- and neutrophil-derived cytokines such as interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Type 1 interferon (IFN). By contrast, clinical allergy is caused by dysregulated type 2 immunity, which is characterized by expansion of T helper 2 (Th2) cells and eosinophils, as well as overproduction of the associated cytokines IL-4, IL-5, IL-9, and IL-13. Traditionally, type 2 immune cells and autoinflammatory effectors were thought to counter-regulate each other. However, an expanding body of evidence suggests that, in some contexts, autoinflammatory pathways and cytokines may potentiate type 2 immune responses. Conversely, type 2 immune cells and cytokines can regulate autoinflammatory responses in complex and context-dependent manners. Here, we introduce the concepts of autoinflammation and type 2 immunity. We proceed to review the mechanisms by which autoinflammatory and type 2 immune responses can modulate each other. Finally, we discuss the epidemiology of type 2 immunity and clinical allergy in several monogenic and complex autoinflammatory diseases. In the future, these interactions between type 2 immunity and autoinflammation may help to expand the spectrum of autoinflammation and to guide the management of patients with various autoinflammatory and allergic diseases.
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Affiliation(s)
- McKella Sylvester
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Aran Son
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Daniella M Schwartz
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
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25
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Matos TR, Gehad A, Teague JE, Dyring-Andersen B, Benezeder T, Dowlatshahi M, Crouch J, Watanabe Y, O'Malley JT, Kupper TS, Yang C, Watanabe R, Clark RA. Central memory T cells are the most effective precursors of resident memory T cells in human skin. Sci Immunol 2022; 7:eabn1889. [PMID: 35452256 PMCID: PMC9435065 DOI: 10.1126/sciimmunol.abn1889] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The circulating precursor cells that give rise to human resident memory T cells (TRM) are poorly characterized. We used an in vitro differentiation system and human skin-grafted mice to study TRM generation from circulating human memory T cell subsets. In vitro TRM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4+ T cells and granzyme B production in CD8+ T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (TEM) had the highest conversion rate to TRM in vitro and in vivo, but central memory T cells (TCM) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of TRM. In summary, TCM are highly efficient precursors of human skin TRM, a feature that may underlie their known association with effective long-term immunity.
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Affiliation(s)
- Tiago R Matos
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.,Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Ahmed Gehad
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jessica E Teague
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Beatrice Dyring-Andersen
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Theresa Benezeder
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Dermatology, Medical University of Graz, Graz, Austria
| | - Mitra Dowlatshahi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jack Crouch
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yoshinori Watanabe
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - John T O'Malley
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Thomas S Kupper
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Chao Yang
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rei Watanabe
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Rachael A Clark
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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26
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Reitermaier R, Ayub T, Staller J, Kienzl P, Fortelny N, Vieyra-Garcia PA, Worda C, Fiala C, Staud C, Eppel W, Scharrer A, Krausgruber T, Elbe-Bürger A. The molecular and phenotypic makeup of fetal human skin T lymphocytes. Development 2022; 149:dev199781. [PMID: 34604909 PMCID: PMC8601710 DOI: 10.1242/dev.199781] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022]
Abstract
The adult human skin contains a vast number of T cells that are essential for skin homeostasis and pathogen defense. T cells are first observed in the skin at the early stages of gestation; however, our understanding of their contribution to early immunity has been limited by their low abundance and lack of comprehensive methodologies for their assessment. Here, we describe a new workflow for isolating and expanding significant amounts of T cells from fetal human skin. Using multiparametric flow cytometry and in situ immunofluorescence, we found a large population with a naive phenotype and small populations with a memory and regulatory phenotype. Their molecular state was characterized using single-cell transcriptomics and TCR repertoire profiling. Importantly, culture of total fetal skin biopsies facilitated T cell expansion without a substantial impact on their phenotype, a major prerequisite for subsequent functional assays. Collectively, our experimental approaches and data advance the understanding of fetal skin immunity and potential use in future therapeutic interventions.
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Affiliation(s)
- René Reitermaier
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Tanya Ayub
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Julia Staller
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Philip Kienzl
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Nikolaus Fortelny
- Department of Biosciences, University of Salzburg, Salzburg 5020, Austria
| | | | - Christof Worda
- Department of Obstetrics & Gynecology, Medical University of Vienna, Vienna 1090, Austria
| | - Christian Fiala
- Gynmed Clinic, Vienna 1150, Austria
- Department of Women's and Children's Health, Division of Obstetrics and Gynaecology, Karolinska Institute and Karolinska University Hospital, Stockholm 171 77, Sweden
| | - Clement Staud
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna 1090, Austria
| | - Wolfgang Eppel
- Department of Obstetrics & Gynecology, Medical University of Vienna, Vienna 1090, Austria
| | - Anke Scharrer
- Department of Pathology, Medical University of Vienna, Vienna 1090, Austria
| | - Thomas Krausgruber
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
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27
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Oh S, Li K, Prince A, Wheeler ML, Hamade H, Nguyen C, Michelsen KS, Underhill DM. Pathogen size alters C-type lectin receptor signaling in dendritic cells to influence CD4 Th9 cell differentiation. Cell Rep 2022; 38:110567. [PMID: 35354044 PMCID: PMC9052946 DOI: 10.1016/j.celrep.2022.110567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 01/18/2022] [Accepted: 03/03/2022] [Indexed: 11/26/2022] Open
Abstract
Dectin-1 recognizes β-glucan in fungal cell walls, and activation of Dectin-1 in dendritic cells (DCs) influences immune responses against fungi. Although many studies have shown that DCs activated via Dectin-1 induce different subsets of T helper cells according to different cytokine milieus, the mechanisms underlying such differences remain unknown. By harnessing polymorphic Candida albicans and polystyrene beads of different sizes, we find that target size influences production of cytokines that control differentiation of T helper cell subsets. Hyphal C. albicans and large beads activate DCs but cannot be phagocytosed due to their sizes, which prolongs the duration of Dectin-1 signaling. Transcriptomic analysis reveals that expression of Il33 is significantly increased by larger targets, and increased IL-33 expression promotes TH9 responses. Expression of IL-33 is regulated by the Dectin-1-SYK-PLCγ-CARD9-ERK pathway. Altogether, our study demonstrates that size of fungi can be a determining factor in how DCs induce context-appropriate adaptive immune responses. Oh et al. show that dendritic cells exposed to C. albicans hyphae more strongly induce IL-9-producing T cells compared with cells exposed to yeast. They find that this TH9 response is driven in large part by Dectin-1 sensing microbe size, leading to elevated production of IL-33.
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Affiliation(s)
- Seeun Oh
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Graduate Program in Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Kai Li
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Alexander Prince
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Matthew L Wheeler
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Hussein Hamade
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; The Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Christopher Nguyen
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Kathrin S Michelsen
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; The Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - David M Underhill
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; The Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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28
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Ulrich BJ, Kharwadkar R, Chu M, Pajulas A, Muralidharan C, Koh B, Fu Y, Gao H, Hayes TA, Zhou HM, Goplen NP, Nelson AS, Liu Y, Linnemann AK, Turner MJ, Licona-Limón P, Flavell RA, Sun J, Kaplan MH. Allergic airway recall responses require IL-9 from resident memory CD4 + T cells. Sci Immunol 2022; 7:eabg9296. [PMID: 35302861 PMCID: PMC9295820 DOI: 10.1126/sciimmunol.abg9296] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4+ T cells that secreted IL-9 as an obligate effector cytokine. IL-9-secreting cells had a resident memory T cell phenotype, and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall-specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4+ T cell population was required for an allergen recall response.
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Affiliation(s)
- Benjamin J Ulrich
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Rakshin Kharwadkar
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Michelle Chu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Abigail Pajulas
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Charanya Muralidharan
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Byunghee Koh
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yongyao Fu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hongyu Gao
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Tristan A Hayes
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hong-Ming Zhou
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Nick P Goplen
- Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Rochester, MN 55902, USA
| | - Andrew S Nelson
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Amelia K Linnemann
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Matthew J Turner
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Paula Licona-Limón
- Departamento de Biologia Celular y del Desarrollo, Instituto de Fisiologia Celular, Universidad Nacional Autónoma de México, Mexico City 04020, Mexico
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA
- Howard Hughes Medical Institute, Yale University, New Haven, CT 06510, USA
| | - Jie Sun
- Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Rochester, MN 55902, USA
| | - Mark H Kaplan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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29
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Roediger B, Schlapbach C. T cells in the skin: lymphoma and inflammatory skin disease. J Allergy Clin Immunol 2022; 149:1172-1184. [PMID: 35247433 DOI: 10.1016/j.jaci.2022.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 11/17/2022]
Abstract
T cells are established contributors to the pathogenesis of atopic dermatitis (AD) and psoriasis, yet whether they are the key drivers or simply unwitting participants remains incompletely understood. Conversely, malignant T cells are the undisputed culprits of cutaneous T cell lymphoma (CTCL), a group of diseases that share key clinical, histopathological and molecular features with inflammatory skin disease (ISD). Here, we compare the pathogenesis of ISD and CTCL and discuss the resulting insights. Recurrent, skin-limited disease implicates skin-resident T cells (TRM) in both ISD and CTCL. In CTCL, malignant T cells recruit benign T cells into inflammatory skin lesions, a disease-amplifying function also proposed for pathogenic T cells in ISD. Mechanistically, cytokines produced by malignant T cells in CTCL and by pathogenic T cells in ISD, respectively, are likely both necessary and sufficient to drive skin inflammation and pruritus, which in turn promotes skin barrier dysfunction and dysbiosis. Therapies for ISD target T cell effector functions but do not address the chronicity of disease while treatments for CTCL target malignant T cells but not primarily the symptoms of the disease. By integrating our understanding of ISD and CTCL, important insights into pathogenesis and therapy can be made which may improve the lives of sufferers of both disease groups.
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Affiliation(s)
- Ben Roediger
- Autoimmunity, Transplantation and Inflammation (ATI), Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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30
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Chronic Inflammation as the Underlying Mechanism of the Development of Lung Diseases in Psoriasis: A Systematic Review. Int J Mol Sci 2022; 23:ijms23031767. [PMID: 35163689 PMCID: PMC8836589 DOI: 10.3390/ijms23031767] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/30/2022] [Accepted: 02/02/2022] [Indexed: 01/04/2023] Open
Abstract
Psoriasis is a systemic inflammatory disease caused by dysfunctional interactions between the innate and adaptive immune responses. The systemic inflammation in psoriasis may be associated with the development of comorbidities, including lung diseases. In this review, we aimed to provide a summary of the evidence regarding the prevalence of lung diseases in patients with psoriasis and the potential underlying mechanisms. Twenty-three articles published between March 2010 and June 2021 were selected from 195 initially identified records. The findings are discussed in terms of the prevalence of asthma, chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, pulmonary hypertension, and sarcoidosis in psoriasis. A higher prevalence of lung diseases in psoriasis has been confirmed in asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, and pulmonary hypertension. These conditions are important as they are previously unrecognized causes of morbidity and mortality in psoriasis. The development of lung diseases in patients with psoriasis can be explained by several mechanisms, including common risk factors, shared immune and molecular characteristics associated with chronic inflammation, as well as other mechanisms. Understanding the prevalence of lung diseases in psoriasis and their underlying mechanisms can help implement appropriate preventative and therapeutic strategies to address respiratory diseases in patients with psoriasis.
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31
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The Role of Interleukins in the Pathogenesis of Dermatological Immune-Mediated Diseases. Adv Ther 2022; 39:4474-4508. [PMID: 35997892 PMCID: PMC9395905 DOI: 10.1007/s12325-022-02241-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/22/2022] [Indexed: 01/30/2023]
Abstract
Autoimmune inflammatory diseases are primarily characterized by deregulated expression of cytokines, which drive pathogenesis of these diseases. A number of approved and experimental therapies utilize monoclonal antibodies against cytokine proteins. Cytokines can be classified into different families including the interleukins, which are secreted and act on leukocytes, the tumor necrosis factor (TNF) family, as well as chemokine proteins. In this review article, we focus on the interleukin family of cytokines, of which 39 members have been identified to this date. We outline the role of each of these interleukins in the immune system, and various dermatological inflammatory diseases with a focused discussion on the pathogenesis of psoriasis and atopic dermatitis. In addition, we describe the roles of various interleukins in psychiatric, cardiovascular, and gastrointestinal comorbidities. Finally, we review clinical efficacy and safety data from emerging late-phase anti-interleukin therapies under development for psoriasis and atopic dermatitis. Collectively, additional fundamental and clinical research remains necessary to fully elucidate the roles of various interleukin proteins in the pathogenesis of inflammatory dermatologic diseases, and treatment outcomes in patients.
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de Jesús-Gil C, Sans-de San Nicolàs L, García-Jiménez I, Ferran M, Pujol RM, Santamaria-Babí LF. Human CLA + Memory T Cell and Cytokines in Psoriasis. Front Med (Lausanne) 2021; 8:731911. [PMID: 34778294 PMCID: PMC8585992 DOI: 10.3389/fmed.2021.731911] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/08/2021] [Indexed: 01/11/2023] Open
Abstract
Psoriasis is a common inflammatory skin condition resulting from the interplay between epidermal keratinocytes and immunological cellular components. This sustained inflammation is essentially driven by pro-inflammatory cytokines with the IL-23/IL-17 axis playing a critical central role, as proved by the clinical efficacy of their blockade in patients. Among all the CD45R0+ memory T cell subsets, those with special tropism for cutaneous tissues are identified by the expression of the Cutaneous Lymphocyte-associated Antigen (CLA) carbohydrate on their surface, that is induced during T cell maturation particularly in the skin-draining lymph nodes. Because of their ability to recirculate between the skin and blood, circulating CLA+ memory T cells reflect the immune abnormalities found in different human cutaneous conditions, such as psoriasis. Based on this premise, studying the effect of different environmental microbial triggers and psoriatic lesional cytokines on CLA+ memory T cells, in the presence of autologous epidermal cells from patients, revealed important IL-17 cytokines responses that are likely to enhance the pro-inflammatory loop underlying the development of psoriatic lesions. The goal of this mini-review is to present latest data regarding cytokines implicated in plaque and guttate psoriasis immunopathogenesis from the prism of CLA+ memory T cells, that are specifically related to the cutaneous immune system.
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Affiliation(s)
- Carmen de Jesús-Gil
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Lídia Sans-de San Nicolàs
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Irene García-Jiménez
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
| | - Marta Ferran
- Department of Dermatology, Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ramon M Pujol
- Department of Dermatology, Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Luis F Santamaria-Babí
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Parc Científic de Barcelona, Barcelona, Spain
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Kumar S, Marathe S, Dhamija B, Zambare U, Bilala R, Warang S, Nayak C, Purwar R. Presence and the roles of IL-9/Th9 axis in vitiligo. Pigment Cell Melanoma Res 2021; 34:966-972. [PMID: 33834624 DOI: 10.1111/pcmr.12978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/16/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022]
Abstract
Immune dysregulation is critical in vitiligo pathogenesis. Although the presence and roles of numerous CD4+ T-cell subsets have been described, the presence of Th9 cells and more importantly, roles of IL-9 on melanocyte functions are not explored yet. Here, we quantified the T helper cell subsets including Th9 cells in vitiligo patients by multicolor flowcytometry. There was an increased frequency of skin-homing (CLA+ ) and systemic (CLA- ) Th9 cells in vitiligo patients compared to healthy donors. However, there was no difference in Th9 cell frequency in vitiligo patients with early and chronic disease. There was negligible IL-9 receptor (IL-9R) expression on human primary melanocytes (HPMs); however, IFNγ upregulated IL-9R expression on HPMs. Functionally, IL-9/IL-9R signaling reduced the production of IFNγ-induced toxic reactive oxygen species (ROS) in HPMs. There was no effect of IL-9 on expression of genes responsible for melanosome formation (MART1, TYRP1, and DCT), melanin synthesis (TYR), and melanocyte-inducing transcription factor (MITF) in HPMs. In conclusion, this study identifies the presence of Th9 cells in vitiligo and their roles in reducing the oxidative stress of melanocytes, which might be useful in designing effective therapeutics.
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Affiliation(s)
- Sushant Kumar
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay (IIT Bombay), Mumbai, India
| | - Soumitra Marathe
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay (IIT Bombay), Mumbai, India
| | - Bhavuk Dhamija
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay (IIT Bombay), Mumbai, India
| | - Uddhao Zambare
- Skin and Venereal Diseases Department, TNMC and BYL Nair Charitable Hospital, Mumbai, India
| | - Richa Bilala
- Skin and Venereal Diseases Department, TNMC and BYL Nair Charitable Hospital, Mumbai, India
| | - Sanyogita Warang
- Skin and Venereal Diseases Department, TNMC and BYL Nair Charitable Hospital, Mumbai, India
| | - Chitra Nayak
- Skin and Venereal Diseases Department, TNMC and BYL Nair Charitable Hospital, Mumbai, India
| | - Rahul Purwar
- Department of Biosciences & Bioengineering, Indian Institute of Technology Bombay (IIT Bombay), Mumbai, India
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Abstract
CD4 T cell effector subsets not only profoundly affect cancer progression, but recent evidence also underscores their critical contribution to the anticancer efficacy of immune checkpoint inhibitors. In 2012, the two seminal studies suggested the superior antimelanoma activity of TH9 cells over other T cell subsets upon adoptive T cell transfer. While these findings provided great impetus to investigate further the unique functions of TH9 cells and explore their relevance in cancer immunotherapy, the following questions still remain outstanding: are TH9 cell anticancer functions restricted to melanoma? What are the factors favouring TH9 cell effector functions? What is the contribution of TH9 cells to cancer immunotherapy treatments? Can TH9 cells be identified in humans and, if so, what is their clinical relevance? By reviewing the studies addressing these questions, we will discuss how TH9 cells could be therapeutically harnessed for cancer immunotherapy strategies.
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Affiliation(s)
- Isis Benoit-Lizon
- INSERM, U1231, Dijon, France; Faculté de Médecine, Université de Bourgogne Franche Comté, Dijon, France
| | - Lionel Apetoh
- INSERM, U1231, Dijon, France; Faculté de Médecine, Université de Bourgogne Franche Comté, Dijon, France; Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
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35
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Bertschi NL, Bazzini C, Schlapbach C. The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum Update 2021. Int Arch Allergy Immunol 2021; 182:365-380. [PMID: 33845475 DOI: 10.1159/000515144] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/09/2021] [Indexed: 11/19/2022] Open
Abstract
T helper (TH) cells have evolved into distinct subsets that mediate specific immune responses to protect the host against a myriad of infectious and noninfectious challenges. However, if dysregulated, TH-cell subsets can cause inflammatory disease. Emerging evidence now suggests that human allergic disease is caused by a distinct subpopulation of pathogenic TH2 cells. Pathogenic TH2 cells from different type-2-driven diseases share a core phenotype and show overlapping functional attributes. The unique differentiation requirements, activating signals, and metabolic characteristics of pathogenic TH2 cells are just being discovered. A better knowledge of this particular TH2 cell population will enable the specific targeting of disease-driving pathways in allergy. In this review, we introduce a rational for classifying TH cells into distinct subsets, discuss the current knowledge on pathogenic TH2 cells, and summarize their involvement in allergic diseases.
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Affiliation(s)
- Nicole L Bertschi
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Cecilia Bazzini
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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36
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Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity. J Immunol Res 2021; 2021:8816055. [PMID: 33748292 PMCID: PMC7943311 DOI: 10.1155/2021/8816055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/12/2021] [Accepted: 02/17/2021] [Indexed: 01/02/2023] Open
Abstract
CD4+T helper (Th) cells are important mediators of immune responses in asthma and cancer. When counteracted by different classes of pathogens, naïve CD4+T cells undergo programmed differentiation into distinct types of Th cells. Th cells orchestrate antigen-specific immune responses upon their clonal T-cell receptor (TCR) interaction with the appropriate peptide antigen presented on MHC class II molecules expressed by antigen-presenting cells (APCs). T helper 9 (Th9) cells and regulatory T (Treg) cells and their corresponding cytokines have critical roles in tumor and allergic immunity. In the context of asthma and cancer, the dynamic internal microenvironment, along with chronic inflammatory stimuli, influences development, differentiation, and function of Th9 cells and Treg cells. Furthermore, the dysregulation of the balance between Th9 cells and Treg cells might trigger aberrant immune responses, resulting in development and exacerbation of asthma and cancer. In this review, the development, differentiation, and function of Th9 cells and Treg cells, which are synergistically regulated by various factors including cytokine signals, transcriptional factors (TFs), costimulatory signals, microenvironment cues, metabolic pathways, and different signal pathways, will be discussed. In addition, we focus on the recent progress that has helped to achieve a better understanding of the roles of Th9 cells and Treg cells in allergic airway inflammation and tumor immunity. We also discuss how various factors moderate their responses in asthma and cancer. Finally, we summarize the recent findings regarding potential mechanisms for regulating the balance between Th9 and Treg cells in asthma and cancer. These advances provide opportunities for novel therapeutic strategies that are aimed at reestablishing the balance of these cells in the diseases.
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Mauro D, Simone D, Bucci L, Ciccia F. Novel immune cell phenotypes in spondyloarthritis pathogenesis. Semin Immunopathol 2021; 43:265-277. [PMID: 33569634 PMCID: PMC7990868 DOI: 10.1007/s00281-021-00837-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/06/2021] [Indexed: 02/08/2023]
Abstract
Spondyloarthritis (SpA) is a heterogeneous group of chronic inflammatory diseases of unknown etiology. Over time, the plethora of cellular elements involved in its pathogenesis has progressively enriched together with the definition of specific cytokine pathways. Recent evidence suggests the involvement of new cellular mediators of inflammation in the pathogenesis of SpA or new subgroups of known cellular mediators. The research in this sense is ongoing, and it is clear that this challenge aimed at identifying new cellular actors involved in the perpetuation of the inflammatory process in AxSpA is not a mere academic exercise but rather aims to define a clear cellular hierarchy. Such a definition could pave the way for new targeted therapies, which could interfere with the inflammatory process and specific pathways that trigger immune system dysregulation and stromal cell activity, ultimately leading to significant control of the inflammation and new bone formation in a significant number of patients. In this review, we will describe the recent advances in terms of new cellular actors involved in the pathogenesis of SpA, focusing our attention on stromal cells and innate and adaptive immunity cells.
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Affiliation(s)
- Daniele Mauro
- Dipartimento di Medicina di Precisione, Section of Rheumatology, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Davide Simone
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Laura Bucci
- Dipartimento di Medicina di Precisione, Section of Rheumatology, Università degli Studi della Campania L. Vanvitelli, Naples, Italy
| | - Francesco Ciccia
- Dipartimento di Medicina di Precisione, Section of Rheumatology, Università degli Studi della Campania L. Vanvitelli, Naples, Italy.
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38
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de Jesús-Gil C, Sans-de San Nicolàs L, Ruiz-Romeu E, Ferran M, Soria-Martínez L, García-Jiménez I, Chiriac A, Casanova-Seuma JM, Fernández-Armenteros JM, Owens S, Celada A, Howell MD, Pujol RM, Santamaria-Babí LF. Interplay between Humoral and CLA + T Cell Response against Candida albicans in Psoriasis. Int J Mol Sci 2021; 22:ijms22041519. [PMID: 33546306 PMCID: PMC7913574 DOI: 10.3390/ijms22041519] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 12/15/2022] Open
Abstract
Candida albicans (CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA- cutaneous lymphocyte antigen (CLA)+/- T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1, n = 52), and also healthy individuals (n = 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2, n = 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA+ T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA+ Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which Candida albicans exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients.
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Affiliation(s)
- Carmen de Jesús-Gil
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; (C.d.J.-G.); (L.S.-d.S.N.); (E.R.-R.); (L.S.-M.); (I.G.-J.)
| | - Lídia Sans-de San Nicolàs
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; (C.d.J.-G.); (L.S.-d.S.N.); (E.R.-R.); (L.S.-M.); (I.G.-J.)
| | - Ester Ruiz-Romeu
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; (C.d.J.-G.); (L.S.-d.S.N.); (E.R.-R.); (L.S.-M.); (I.G.-J.)
| | - Marta Ferran
- Department of Dermatology, Hospital del Mar, 08003 Barcelona, Spain; (M.F.); (R.M.P.)
| | - Laura Soria-Martínez
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; (C.d.J.-G.); (L.S.-d.S.N.); (E.R.-R.); (L.S.-M.); (I.G.-J.)
| | - Irene García-Jiménez
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; (C.d.J.-G.); (L.S.-d.S.N.); (E.R.-R.); (L.S.-M.); (I.G.-J.)
| | - Anca Chiriac
- Department of Dermatophysiology, Apollonia University, 700613 Iasi, Romania;
| | - Josep Manel Casanova-Seuma
- Department of Dermatology, Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain; (J.M.C.-S.); (J.M.F.-A.)
| | | | - Sherry Owens
- Translational Sciences, Incyte Corporation, Wilmington, DE 19803, USA; (S.O.); (M.D.H.)
| | - Antonio Celada
- Macrophage Biology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain;
| | - Michael D. Howell
- Translational Sciences, Incyte Corporation, Wilmington, DE 19803, USA; (S.O.); (M.D.H.)
| | - Ramòn María Pujol
- Department of Dermatology, Hospital del Mar, 08003 Barcelona, Spain; (M.F.); (R.M.P.)
| | - Luis Francisco Santamaria-Babí
- Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain; (C.d.J.-G.); (L.S.-d.S.N.); (E.R.-R.); (L.S.-M.); (I.G.-J.)
- Correspondence: ; Tel.: +34-677375160
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Sun Z, Kim JH, Kim SH, Kim HR, Zhang K, Pan Y, Ko MK, Kim BM, Chu H, Lee HR, Kim HL, Kim JH, Fu X, Hyun YM, Yun KN, Kim JY, Lee DW, Song SY, Lin CP, Clark RA, Lee KH, Kupper TS, Park CO. Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis. J Allergy Clin Immunol 2021; 147:1764-1777. [PMID: 33516870 DOI: 10.1016/j.jaci.2020.11.049] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD). OBJECTIVE We aimed to investigate the role of NKT cells in AD development, especially in skin. METHODS Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice. RESULTS CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. CONCLUSIONS CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.
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Affiliation(s)
- ZhengWang Sun
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hye Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Seo Hyeong Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Ran Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - KeLun Zhang
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Youdong Pan
- Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - Min Kyung Ko
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Bo Mi Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Howard Chu
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hee Ra Lee
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Li Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hyung Kim
- Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Xiujun Fu
- Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass
| | - Young-Min Hyun
- Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea
| | - Ki Na Yun
- Biomedical Omics Group, Korea Basic Science Institute, Ochang, Korea
| | - Jin Young Kim
- Biomedical Omics Group, Korea Basic Science Institute, Ochang, Korea
| | - Dong Won Lee
- Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Yong Song
- Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Yonsei University College of Medicine, Seoul, Korea
| | - Charles P Lin
- Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass
| | - Rachael A Clark
- Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - Kwang Hoon Lee
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea.
| | - Thomas S Kupper
- Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
| | - Chang Ook Park
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
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Chatzileontiadou DSM, Sloane H, Nguyen AT, Gras S, Grant EJ. The Many Faces of CD4 + T Cells: Immunological and Structural Characteristics. Int J Mol Sci 2020; 22:E73. [PMID: 33374787 PMCID: PMC7796221 DOI: 10.3390/ijms22010073] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/20/2020] [Accepted: 12/21/2020] [Indexed: 12/14/2022] Open
Abstract
As a major arm of the cellular immune response, CD4+ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4+ T cells play an integral role in the development and activation of B cells and CD8+ T cells. CD4+ T cells are incredibly heterogeneous, and can be divided into six main lineages based on distinct profiles, namely T helper 1, 2, 17 and 22 (Th1, Th2, Th17, Th22), regulatory T cells (Treg) and T follicular helper cells (Tfh). Recent advances in structural biology have allowed for a detailed characterisation of the molecular mechanisms that drive CD4+ T cell recognition. In this review, we discuss the defining features of the main human CD4+ T cell lineages and their role in immunity, as well as their structural characteristics underlying their detection of pathogens.
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Affiliation(s)
- Demetra S. M. Chatzileontiadou
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
| | - Hannah Sloane
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
| | - Andrea T. Nguyen
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
| | - Stephanie Gras
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
- Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia
| | - Emma J. Grant
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; (D.S.M.C.); (H.S.); (A.T.N.); (S.G.)
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Vieyra-Garcia PA, Wolf P. A deep dive into UV-based phototherapy: Mechanisms of action and emerging molecular targets in inflammation and cancer. Pharmacol Ther 2020; 222:107784. [PMID: 33316286 DOI: 10.1016/j.pharmthera.2020.107784] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
UV-based phototherapy (including psoralen plus UVA (PUVA), UVB and UVA1) has a long, successful history in the management of numerous cutaneous disorders. Photoresponsive diseases are etiologically diverse, but most involve disturbances in local (and occasionally systemic) inflammatory cells and/or abnormalities in keratinocytes that trigger inflammation. UV-based phototherapy works by regulating the inflammatory component and inducing apoptosis of pathogenic cells. This results in a fascinating and complex network of simultaneous events-immediate transcriptional changes in keratinocytes, immune cells, and pigment cells; the emergence of apoptotic bodies; and the trafficking of antigen-presenting cells in skin-that quickly transform the microenvironment of UV-exposed skin. Molecular elements in this system of UV recognition and response include chromophores, metabolic byproducts, innate immune receptors, neurotransmitters and mediators such as chemokines and cytokines, antimicrobial peptides, and platelet activating factor (PAF) and PAF-like molecules that simultaneously shape the immunomodulatory effects of UV and their interplay with the microbiota of the skin and beyond. Phototherapy's key effects-proapoptotic, immunomodulatory, antipruritic, antifibrotic, propigmentary, and pro-prebiotic-promote clinical improvement in various skin diseases such as psoriasis, atopic dermatitis (AD), graft-versus-host disease (GvHD), vitiligo, scleroderma, and cutaneous T-cell lymphoma (CTCL) as well as prevention of polymorphic light eruption (PLE). As understanding of phototherapy improves, new therapies (UV- and non-UV-based) are being developed that will modify regulatory T-cells (Treg), interact with (resident) memory T-cells and /or utilize agonists and antagonists as well as antibodies targeting soluble molecules such as cytokines and chemokines, transcription factors, and a variety of membrane-associated receptors.
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Affiliation(s)
- Pablo A Vieyra-Garcia
- Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, Graz A-8036, Austria.
| | - Peter Wolf
- Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, Graz A-8036, Austria.
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42
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Kasatskaya SA, Ladell K, Egorov ES, Miners KL, Davydov AN, Metsger M, Staroverov DB, Matveyshina EK, Shagina IA, Mamedov IZ, Izraelson M, Shelyakin PV, Britanova OV, Price DA, Chudakov DM. Functionally specialized human CD4 + T-cell subsets express physicochemically distinct TCRs. eLife 2020; 9:57063. [PMID: 33289628 PMCID: PMC7773335 DOI: 10.7554/elife.57063] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 12/04/2020] [Indexed: 12/26/2022] Open
Abstract
The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.
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Affiliation(s)
- Sofya A Kasatskaya
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation.,Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
| | - Kristin Ladell
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Evgeniy S Egorov
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
| | - Kelly L Miners
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Alexey N Davydov
- Adaptive Immunity Group, Central European Institute of Technology, Brno, Czech Republic
| | - Maria Metsger
- Adaptive Immunity Group, Central European Institute of Technology, Brno, Czech Republic
| | - Dmitry B Staroverov
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.,Institute of Translational Medicine, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
| | - Elena K Matveyshina
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation
| | - Irina A Shagina
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.,Institute of Translational Medicine, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
| | - Ilgar Z Mamedov
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.,Institute of Translational Medicine, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
| | - Mark Izraelson
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.,Institute of Translational Medicine, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
| | - Pavel V Shelyakin
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation.,Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
| | - Olga V Britanova
- Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.,Institute of Translational Medicine, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
| | - David A Price
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.,Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Dmitriy M Chudakov
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation.,Genomics of Adaptive Immunity Department, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.,Institute of Translational Medicine, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
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Aghamajidi A, Raoufi E, Parsamanesh G, Jalili A, Salehi-Shadkami M, Mehrali M, Mohsenzadegan M. The attentive focus on T cell-mediated autoimmune pathogenesis of psoriasis, lichen planus and vitiligo. Scand J Immunol 2020; 93:e13000. [PMID: 33190330 DOI: 10.1111/sji.13000] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 09/16/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022]
Abstract
T cell-mediated autoimmune skin diseases develop as a result of the aberrant immune response to the skin cells with T cells playing a central role. These chronic inflammatory skin diseases encompass various types including psoriasis, lichen planus and vitiligo. These diseases show similarities in their immune-pathophysiology. In the last decade, immunomodulating agents have been very successful in the management of these diseases thanks to a better understanding of the pathophysiology. In this review, we will discuss the immunopathogenic mechanisms and highlight the role of T lymphocytes in psoriasis, lichen planus and vitiligo. This study could provide new insights into a better understanding of targeted therapeutic pathways and biological therapies.
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Affiliation(s)
- Azin Aghamajidi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ehsan Raoufi
- Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Gilda Parsamanesh
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ahmad Jalili
- Dermatology & Skin Care, Buergenstock Medical Center, Obbuergen, Switzerland
| | - Mohammad Salehi-Shadkami
- Student Research Committee, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marjan Mehrali
- Student Research Committee, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Monireh Mohsenzadegan
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
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T-bet and STAT6 Coordinately Suppress the Development of IL-9-Mediated Atopic Dermatitis-Like Skin Inflammation in Mice. J Invest Dermatol 2020; 141:1274-1285.e5. [PMID: 33068596 DOI: 10.1016/j.jid.2020.08.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 07/31/2020] [Accepted: 08/11/2020] [Indexed: 12/19/2022]
Abstract
T-bet and signal transducer and activator of transcription (STAT) 6 are critical factors for helper T-cell differentiation in humans and mice. Additionally, polymorphisms in TBX21 (T-bet) and STAT6 are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T-bet-/- STAT6-/-) mice. Unexpectedly, T-bet-/- STAT6-/- mice but not T-bet-/- mice or STAT6-/- mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4+ T cells infiltrated into the skin of T-bet-/- STAT6-/- mice. Adoptive transfer of CD4+ T cells of T-bet-/- STAT6-/- mice into severe combined immunodeficient mice induced the accumulation of eosinophils and mast cells in the skin, whereas depletion of CD4+ T cells ameliorated the dermatitis in T-bet-/- STAT6-/- mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet-/- STAT6-/- CD4+ T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet-/- STAT6-/- mice. T-bet-/- STAT6-/- CD4+ T cells expressed functional thymic stromal lymphopoietin receptors and produced large amounts of IL-9 on thymic stromal lymphopoietin stimulation. These results indicate that T-bet and STAT6 coordinately suppress atopic dermatitis-like skin inflammation, possibly by inhibiting thymic stromal lymphopoietin-dependent IL-9 production in CD4+ T cells.
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45
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Midde HS, Priyadarssini M, Rajappa M, Munisamy M, Mohan Raj PS, Singh S, Priyadarshini G. Interleukin-9 serves as a key link between systemic inflammation and angiogenesis in psoriasis. Clin Exp Dermatol 2020; 46:50-57. [PMID: 32516443 DOI: 10.1111/ced.14335] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/01/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Psoriasis is a T helper cell-mediated chronic immune-mediated inflammatory disease affecting mainly the skin, although systemic pathological effects are also observed. Cytokine-mediated interaction between T lymphocytes and keratinocytes lead to excessive proliferation of keratinocytes, which in turn leads to formation of a proinflammatory milieu and finally to psoriatic plaque formation. AIM To measure interleukin (IL)-9, IL-17 and vascular endothelial growth factor (VEGF) levels in patients with psoriasis compared with controls, and to evaluate the effect of methotrexate (MTX) monotherapy on the aforesaid cytokine levels in psoriasis. METHODS This cohort study included 54 patients with psoriasis and 54 age- and sex-matched healthy controls (HCs). IL-9, IL-17 and VEGF levels were measured by using commercially available ELISA kits. Patients with psoriasis who were on MTX monotherapy were followed up for a period of 3 months. RESULTS Patients with psoriasis had increased levels of IL-9, IL-17 and VEGF at baseline, compared with the HC group. After 3 months of MTX monotherapy, Psoriasis Area Severity Index (PASI), Dermatology Life Quality Index (DLQI) and levels of cytokines (IL-9, IL-17 and VEGF) were significantly decreased compared with baseline. PASI and DLQI at baseline also showed a positive correlation with IL-9, IL-17 and VEGF. CONCLUSION Our results suggest the existence of a proinflammatory milieu in psoriasis, with increased levels of IL-9, IL-17 and the proangiogenic growth factor VEGF, showing an increasing trend with increasing disease severity and impaired quality of life (QoL). MTX treatment helps to reduce levels of IL-9, IL-17 and VEGF, thereby limiting disease progression and improving QoL in psoriasis.
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Affiliation(s)
- H S Midde
- Departments, Department of, Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - M Priyadarssini
- Departments, Department of, Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - M Rajappa
- Departments, Department of, Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - M Munisamy
- Department, Dermatology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - P S Mohan Raj
- Departments, Department of, Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - S Singh
- Departments, Department of, Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - G Priyadarshini
- Departments, Department of, Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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46
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IL-9-producing T cells: potential players in allergy and cancer. Nat Rev Immunol 2020; 21:37-48. [PMID: 32788707 DOI: 10.1038/s41577-020-0396-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2020] [Indexed: 01/03/2023]
Abstract
IL-9-producing CD4+ T cells have been considered to represent a distinct T helper cell (TH cell) subset owing to their unique developmental programme in vitro, their expression of distinct transcription factors (including PU.1) and their copious production of IL-9. It remains debatable whether these cells represent a truly unique TH cell subset in vivo, but they are closely related to the T helper 2 (TH2) cells that are detected in allergic diseases. In recent years, increasing evidence has also indicated that IL-9-producing T cells may have potent abilities in eradicating advanced tumours, particularly melanomas. Here, we review the latest literature on the development of IL-9-producing T cells and their functions in disease settings, with a particular focus on allergy and cancer. We also discuss recent ideas concerning the therapeutic targeting of these cells in patients with chronic allergic diseases and their potential use in cancer immunotherapy.
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47
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A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin. Sci Rep 2020; 10:11164. [PMID: 32636404 PMCID: PMC7341892 DOI: 10.1038/s41598-020-67430-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/01/2020] [Indexed: 12/31/2022] Open
Abstract
Human skin contains a population of memory T cells that supports tissue homeostasis and provides protective immunity. The study of human memory T cells is often restricted to in vitro studies and to human PBMC serving as primary cell source. Because the tissue environment impacts the phenotype and function of memory T cells, it is crucial to study these cells within their tissue. Here we utilized immunodeficient NOD-scid IL2rγnull (NSG) mice that carried in vivo-generated engineered human skin (ES). ES was generated from human keratinocytes and fibroblasts and was initially devoid of skin-resident immune cells. Upon adoptive transfer of human PBMC, this reductionist system allowed us to study human T cell recruitment from a circulating pool of T cells into non-inflamed human skin in vivo. Circulating human memory T cells preferentially infiltrated ES and showed diverse functional profiles of T cells found in fresh human skin. The chemokine and cytokine microenvironment of ES closely resembled that of non-inflamed human skin. Upon entering the ES T cells assumed a resident memory T cell-like phenotype in the absence of infection, and a proportion of these cutaneous T cells can be locally activated upon injection of monocyte derived dendritic cells (moDCs) that presented Candida albicans. Interestingly, we found that CD69+ memory T cells produced higher levels of effector cytokines in response to Candida albicans, compared to CD69- T cells. Overall, this model has broad utility in many areas of human skin immunology research, including the study of immune-mediated skin diseases.
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Amezcua Vesely MC, Pallis P, Bielecki P, Low JS, Zhao J, Harman CCD, Kroehling L, Jackson R, Bailis W, Licona-Limón P, Xu H, Iijima N, Pillai PS, Kaplan DH, Weaver CT, Kluger Y, Kowalczyk MS, Iwasaki A, Pereira JP, Esplugues E, Gagliani N, Flavell RA. Effector T H17 Cells Give Rise to Long-Lived T RM Cells that Are Essential for an Immediate Response against Bacterial Infection. Cell 2020; 178:1176-1188.e15. [PMID: 31442406 DOI: 10.1016/j.cell.2019.07.032] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 03/19/2019] [Accepted: 07/17/2019] [Indexed: 12/20/2022]
Abstract
Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing effector (TH17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exTH17 TRM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, γδ T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exTH17 TRM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design.
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Affiliation(s)
- Maria Carolina Amezcua Vesely
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
| | - Paris Pallis
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Piotr Bielecki
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Jun Siong Low
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Jun Zhao
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
| | - Christian C D Harman
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
| | - Lina Kroehling
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Ruaidhrí Jackson
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Will Bailis
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Paula Licona-Limón
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Hao Xu
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Norifumi Iijima
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Padmini S Pillai
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Koch Institute for Integrative Cancer Research and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Daniel H Kaplan
- Department of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Casey T Weaver
- Departments of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yuval Kluger
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Applied Mathematics Program, Yale University, New Haven, CT 06511, USA
| | | | - Akiko Iwasaki
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
| | - Joao P Pereira
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Enric Esplugues
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Laboratory of Molecular and Cellular Immunology, Principe Felipe Research Center (CIPF), 46012 Valencia, Spain
| | - Nicola Gagliani
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; I. Medical Department and Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf 20246 Hamburg, Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden.
| | - Richard A Flavell
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
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Zhang XM, Liu CY, Shao ZH. Advances in the role of helper T cells in autoimmune diseases. Chin Med J (Engl) 2020; 133:968-974. [PMID: 32187054 PMCID: PMC7176439 DOI: 10.1097/cm9.0000000000000748] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Indexed: 02/06/2023] Open
Abstract
Autoimmune diseases are primary immune diseases in which autoreactive antibodies or sensitized lymphocytes destroy and damage tissue and cellular components, resulting in tissue damage and organ dysfunction. Helper T cells may be involved in the pathogenesis of autoimmune diseases under certain conditions. This review summarizes recent research on the role of helper T cells in autoimmune diseases from two aspects, helper T cell-mediated production of autoantibodies by B cells and helper T cell-induced activation of abnormal lymphocytes, and provides ideas for the treatment of autoimmune diseases. The abnormal expression of helper T cells promotes the differentiation of B cells that produce autoantibodies, which leads to the development of different diseases. Among them, abnormal expression of Th2 cells and T follicular helper cells is more likely to cause antibody-mediated autoimmune diseases. In addition, abnormal activation of helper T cells also mediates autoimmune diseases through the production of abnormal cytokines and chemokines. Helper T cells play an essential role in the pathogenesis of autoimmune diseases, and a full understanding of their role in autoimmune diseases is helpful for providing ideas for the treatment of autoimmune diseases.
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Affiliation(s)
- Xiao-Mei Zhang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
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50
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Micossé C, von Meyenn L, Steck O, Kipfer E, Adam C, Simillion C, Seyed Jafari SM, Olah P, Yawlkar N, Simon D, Borradori L, Kuchen S, Yerly D, Homey B, Conrad C, Snijder B, Schmidt M, Schlapbach C. Human "T H9" cells are a subpopulation of PPAR-γ + T H2 cells. Sci Immunol 2020; 4:4/31/eaat5943. [PMID: 30658968 DOI: 10.1126/sciimmunol.aat5943] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 11/26/2018] [Indexed: 12/24/2022]
Abstract
Although TH1, TH2, and TH17 cells are well-defined TH cell lineages in humans, it remains debated whether IL-9-producing TH cells represent a bona fide "TH9" lineage. Our understanding of the cellular characteristics and functions of IL-9-producing TH cells in humans is still nascent. Here, we report that human IL-9-producing TH cells express the chemokine receptors CCR4 and CCR8, produce high levels of IL-5 and IL-13, and express TH2 lineage-associated transcription factors. In these cells, IL-9 production is activation dependent, transient, and accompanied by down-regulation of TH2 cytokines, leading to an apparent "TH9" phenotype. IL-9+ TH2 cells can be distinguished from "conventional" TH2 cells based on their expression of the transcription factor PPAR-γ. Accordingly, PPAR-γ is induced in naïve TH cells by priming with IL-4 and TGF-β ("TH9" priming) and is required for IL-9 production. In line with their identity as early activated TH2 cells, IL-9+ TH2 cells are found in acute allergic skin inflammation in humans. We propose that IL-9-producing TH cells are a phenotypically and functionally distinct subpopulation of TH2 cells that depend on PPAR-γ for full effector functions.
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Affiliation(s)
- Claire Micossé
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Leonhard von Meyenn
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Oliver Steck
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Enja Kipfer
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christian Adam
- Department of Dermatology, University Hospital Würzburg, Würzburg, Germany
| | - Cedric Simillion
- Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - S Morteza Seyed Jafari
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Peter Olah
- Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Nikhil Yawlkar
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Dagmar Simon
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Luca Borradori
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Stefan Kuchen
- Department of Rheumatology, Immunology and Allergology, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Daniel Yerly
- Department of Rheumatology, Immunology and Allergology, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Bernhard Homey
- Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Curdin Conrad
- Department of Dermatology, University Hospital CHUV, Lausanne, Switzerland
| | - Berend Snijder
- Institute of Molecular Systems Biology, ETH, Zurich, Switzerland
| | - Marc Schmidt
- Department of Dermatology, University Hospital Würzburg, Würzburg, Germany
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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