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Vasilev G, Kokudeva M, Siliogka E, Padilla N, Shumnalieva R, Della-Morte D, Ricordi C, Mihova A, Infante M, Velikova T. T helper 17 cells and interleukin-17 immunity in type 1 diabetes: From pathophysiology to targeted immunotherapies. World J Diabetes 2025; 16:99936. [DOI: 10.4239/wjd.v16.i4.99936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 12/06/2024] [Accepted: 02/07/2025] [Indexed: 02/28/2025] Open
Abstract
Type 1 diabetes (T1D) is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells, which ultimately results in insulinopenia, hyperglycemia and lifelong need for exogenous insulin therapy. In the pathophysiological landscape of T1D, T helper 17 cells (Th17 cells) and their hallmark cytokine, interleukin (IL)-17, play pivotal roles from disease onset to disease progression. In this narrative mini-review, we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D, providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction. Furthermore, we summarized the main animal and clinical studies that investigated Th17- and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.
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Affiliation(s)
- Georgi Vasilev
- Clinic of Neurology and Department of Emergency Medicine, UMHAT "Sv. Georgi", Plovdiv 4000, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Maria Kokudeva
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria
| | - Elina Siliogka
- Faculty of Medicine, National and Kapodistrian University of Athens, Athens 11527, Attikí, Greece
| | - Nathalia Padilla
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Russka Shumnalieva
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Rheumatology, Clinic of Rheumatology, University Hospital "St. Anna", Medical University-Sofia, Sofia 1612, Bulgaria
| | - David Della-Morte
- Department of Biomedicine and Prevention, Section of Clinical Nutrition and Nutrigenomics, University of Rome Tor Vergata, Rome 00133, Italy
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | | | - Marco Infante
- Section of Diabetes & Metabolic Disorders, UniCamillus, Saint Camillus International University of Health Sciences, Rome 00131, Italy
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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2
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Zhuo Y, Fu S, Qiu Y. Regulation of the immune microenvironment by SUMO in diabetes mellitus. Front Immunol 2025; 16:1506500. [PMID: 40078991 PMCID: PMC11896877 DOI: 10.3389/fimmu.2025.1506500] [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: 10/05/2024] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Post-translational modifications such as SUMOylation are crucial for the functionality and signal transduction of a diverse array of proteins. Analogous to ubiquitination, SUMOylation has garnered significant attention from researchers and has been implicated in the pathogenesis of various human diseases in recent years, such as cancer, neurological lesions, cardiovascular diseases, diabetes mellitus, and so on. The pathogenesis of diabetes, particularly type 1 and type 2 diabetes, has been closely associated with immune dysfunction, which constitutes the primary focus of this review. This review will elucidate the process of SUMOylation and its impact on diabetes mellitus development and associated complications, focusing on its regulatory effects on the immune microenvironment. This article summarizes various signaling pathways at both cellular and molecular levels that are implicated in these processes. Furthermore, it proposes potential new targets for drug development aimed at the prevention and treatment of diabetes mellitus based on insights gained from the SUMOylation process.
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Affiliation(s)
- Yuting Zhuo
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Shangui Fu
- The Second School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yue Qiu
- Department of Endocrinology and Metabolism, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, China
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3
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Aljobaily N, Allard D, Perkins B, Raugh A, Galland T, Jing Y, Stephens WZ, Bettini ML, Hale JS, Bettini M. Autoimmune CD4 + T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes. Immunity 2024; 57:2583-2596.e6. [PMID: 39396521 PMCID: PMC11563894 DOI: 10.1016/j.immuni.2024.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/21/2024] [Accepted: 09/25/2024] [Indexed: 10/15/2024]
Abstract
Self-reactive T cells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4+ T cells despite chronic stimulation. Examination of T cell priming showed that CD4+ T cells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new T cell recruitment, most islet-infiltrating autoimmune CD4+ T cells were TCF1+, although expression was reduced on a per T cell basis. The Tcf7 locus was epigenetically modified in circulating autoimmune CD4+ T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4+ T cell differentiation. This mirrored the epigenetic profile of recently recruited CD4+CD62L+ T cells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4+ T cell priming that allows T cells to fine-tune TCF1 expression and maintain long-term survival and function.
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Affiliation(s)
- Nouf Aljobaily
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Denise Allard
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Bryant Perkins
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Arielle Raugh
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Tessa Galland
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Yi Jing
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - W Zac Stephens
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Matthew L Bettini
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - J Scott Hale
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA
| | - Maria Bettini
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT 84112, USA.
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Golden GJ, Wu VH, Hamilton JT, Amses KR, Shapiro MR, Japp AS, Liu C, Pampena MB, Kuri-Cervantes L, Knox JJ, Gardner JS, Atkinson MA, Brusko TM, Prak ETL, Kaestner KH, Naji A, Betts MR. Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.23.590798. [PMID: 39345402 PMCID: PMC11429609 DOI: 10.1101/2024.04.23.590798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.
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Affiliation(s)
- Gregory J Golden
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Vincent H Wu
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jacob T Hamilton
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Kevin R Amses
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Melanie R Shapiro
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
| | - Alberto Sada Japp
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Chengyang Liu
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Maria Betina Pampena
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Leticia Kuri-Cervantes
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - James J Knox
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jay S Gardner
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Eline T Luning Prak
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Ali Naji
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Michael R Betts
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
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5
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Takeuchi M, Nishio Y, Someya H, Sato T, Yoshimura A, Ito M, Harimoto K. Autoimmune uveitis attenuated in diabetic mice through imbalance of Th1/Th17 differentiation via suppression of AP-1 signaling pathway in Th cells. Front Immunol 2024; 15:1347018. [PMID: 38887289 PMCID: PMC11180723 DOI: 10.3389/fimmu.2024.1347018] [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: 11/30/2023] [Accepted: 04/18/2024] [Indexed: 06/20/2024] Open
Abstract
Purpose Inflammation is involved in the pathogenesis of diabetes, however the impact of diabetes on organ-specific autoimmune diseases remains unexplored. Experimental autoimmune uveoretinitis (EAU) is a widely accepted animal model of human endogenous uveitis. In this study, we investigated the effects of diabetic conditions on the development of EAU using a mouse diabetes model. Methods EAU was induced in wild-type C57BL/6 (WT) mice and Ins2Akita (Akita) mice with spontaneous diabetes by immunization with IRBP peptide. Clinical and histopathological examinations, and analysis of T cell activation state were conducted. In addition, alternations in the composition of immune cell types and gene expression profiles of relevant immune functions were identified using single-cell RNA sequencing. Results The development of EAU was significantly attenuated in immunized Akita (Akita-EAU) mice compared with immunized WT (WT-EAU) mice, although T cells were fully activated in Akita-EAU mice, and the differentiation into Th17 cells and regulatory T (Treg) cells was promoted. However, Th1 cell differentiation was inhibited in Akita-EAU mice, and single-cell analysis indicated that gene expression associated AP-1 signaling pathway (JUN, FOS, and FOSB) was downregulated not only in Th1 cells but also in Th17, and Treg cells in Akita-EAU mice at the onset of EAU. Conclusions In diabetic mice, EAU was significantly attenuated. This was related to selective inhibition of Th1 cell differentiation and downregulated AP-1 signaling pathway in both Th1 and Th17 cells.
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Affiliation(s)
- Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yoshiaki Nishio
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Hideaki Someya
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Kozo Harimoto
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
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Falcon DM, Byrne KA, Sales MA, Erf GF. Spontaneous immunological activities in the target tissue of vitiligo-prone Smyth and vitiligo-susceptible Brown lines of chicken. Front Immunol 2024; 15:1386727. [PMID: 38720888 PMCID: PMC11076693 DOI: 10.3389/fimmu.2024.1386727] [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: 02/15/2024] [Accepted: 04/11/2024] [Indexed: 05/12/2024] Open
Abstract
Introduction Vitiligo is an acquired de-pigmentation disorder characterized by the post-natal loss of epidermal melanocytes (pigment-producing cells) resulting in the appearance of white patches in the skin. The Smyth chicken is the only model for vitiligo that shares all the characteristics of the human condition including: spontaneous post-natal loss of epidermal melanocytes, interactions between genetic, environmental and immunological factors, and associations with other autoimmune diseases. In addition, an avian model for vitiligo has the added benefit of an easily accessible target tissue (a growing feather) that allows for the repeated sampling of an individual and thus the continuous monitoring of local immune responses over time. Methods Using a combination of flow cytometry and gene expression analyses, we sought to gain a comprehensive understanding of the initiating events leading to expression of vitiligo in growing feathers by monitoring the infiltration of leukocytes and concurrent immunological activities in the target tissue beginning prior to visual onset and continuing throughout disease development. Results Here, we document a sequence of immunologically significant events, including characteristic rises in infiltrating B and αβ T cells as well as evidence of active leukocyte recruitment and cell-mediated immune activities (CCL19, IFNG, GZMA) leading up to visual vitiligo onset. Examination of growing feathers from vitiligo-susceptible Brown line chickens revealed anti-inflammatory immune activities which may be responsible for preventing vitiligo (IL10, CTLA4, FOXP3). Furthermore, we detected positive correlations between infiltrating T cells and changes in their T cell receptor diversity supporting a T cell-specific immune response. Conclusion Collectively, these results further support the notion of cell-mediated immune destruction of epidermal melanocytes in the pulp of growing feathers and open new avenues of study in the vitiligo-prone Smyth and vitiligo-susceptible Brown line chickens.
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Affiliation(s)
| | | | | | - Gisela F. Erf
- Division of Agriculture, Department of Poultry Science, University of Arkansas System, Fayetteville, AR, United States
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Ciou JJ, Chien MW, Hsu CY, Liu YW, Dong JL, Tsai SY, Yang SS, Lin SH, Yen BLJ, Fu SH, Sytwu HK. Excess Salt Intake Activates IL-21-Dominant Autoimmune Diabetogenesis via a Salt-Regulated Ste20-Related Proline/Alanine-Rich Kinase in CD4 T Cells. Diabetes 2024; 73:592-603. [PMID: 38241027 PMCID: PMC11031440 DOI: 10.2337/db23-0599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 12/19/2023] [Indexed: 03/22/2024]
Abstract
The fundamental mechanisms by which a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Excess dietary salt intake acts as a risk factor for autoimmune diseases; however, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high salt intake on autoimmune diabetes, nonobese diabetic (NOD) mice were fed a high-salt diet (HSD) or a normal-salt diet (NSD) from 6 to 12 weeks of age and monitored for diabetes development. Our results revealed that the HSD accelerated diabetes progression with more severe insulitis in NOD mice in a CD4+ T-cell-autonomous manner when compared with the NSD group. Moreover, expression of IL-21 and SPAK in splenic CD4+ T cells from HSD-fed mice was significantly upregulated. Accordingly, we generated T-cell-specific SPAK knockout (CKO) NOD mice and demonstrated that SPAK deficiency in T cells significantly attenuated diabetes development in NOD mice by downregulating IL-21 expression in CD4+ T cells. Furthermore, HSD-triggered diabetes acceleration was abolished in HSD-fed SPAK CKO mice when compared with HSD-fed NOD mice, suggesting an essential role of SPAK in salt-exacerbated T-cell pathogenicity. Finally, pharmacological inhibition of SPAK activity using a specific SPAK inhibitor (closantel) in NOD mice ameliorated diabetogenesis, further illuminating the potential of a SPAK-targeting immunotherapeutic approach for autoimmune diabetes. Here, we illustrate that a substantial association between salt sensitivity and the functional impact of SPAK on T-cell pathogenicity is a central player linking high-salt-intake influences to immunopathophysiology of diabetogenesis in NOD mice. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Jing-Jie Ciou
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan
| | - Ming-Wei Chien
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Chao-Yuan Hsu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Wen Liu
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
| | - Jia-Ling Dong
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Shin-Ying Tsai
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Sung-Sen Yang
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shih-Hua Lin
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - B. Lin-Ju Yen
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan
| | - Shin-Huei Fu
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Huey-Kang Sytwu
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli County, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
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Petersone L, Walker LSK. T-cell help in the germinal center: homing in on the role of IL-21. Int Immunol 2024; 36:89-98. [PMID: 38164992 PMCID: PMC10880887 DOI: 10.1093/intimm/dxad056] [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: 11/08/2023] [Accepted: 12/30/2023] [Indexed: 01/03/2024] Open
Abstract
Interleukin 21 (IL-21) is a pleiotropic cytokine that is overproduced in multiple autoimmune settings. Provision of IL-21 from follicular helper T cells is an important component of T-cell help within germinal centers (GC), and the last few years have seen a resurgence of interest in IL-21 biology in the context of the GC environment. While it has been more than a decade since T cell-derived IL-21 was found to upregulate B-cell expression of the GC master transcription factor B-cell lymphoma 6 (Bcl-6) and to promote GC expansion, several recent studies have collectively delivered significant new insights into how this cytokine shapes GC B-cell selection, proliferation, and fate choice. It is now clear that IL-21 plays an important role in GC zonal polarization by contributing to light zone GC B-cell positive selection for dark zone entry as well as by promoting cyclin D3-dependent dark zone inertial cycling. While it has been established that IL-21 can contribute to the modulation of GC output by aiding the generation of antibody-secreting cells (ASC), recent studies have now revealed how IL-21 signal strength shapes the fate choice between GC cycle re-entry and ASC differentiation in vivo. Both provision of IL-21 and sensitivity to this cytokine are finely tuned within the GC environment, and dysregulation of this pathway in autoimmune settings could alter the threshold for germinal center B-cell selection and differentiation, potentially promoting autoreactive B-cell responses.
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Affiliation(s)
- Lina Petersone
- University College London Division of Infection and Immunity, Institute of Immunity and Transplantation, Pears Building, Royal Free Campus, London NW3 2PP, UK
| | - Lucy S K Walker
- University College London Division of Infection and Immunity, Institute of Immunity and Transplantation, Pears Building, Royal Free Campus, London NW3 2PP, UK
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Shahedi F, Foma AM, Mahmoudi-Aznaveh A, Mazlomi MA, Azizi Z, Khorramizadeh MR. Differentiation of Pancreatic Beta Cells: Dual Acting of Inflammatory Factors. Curr Stem Cell Res Ther 2024; 19:832-839. [PMID: 37150985 DOI: 10.2174/1574888x18666230504093649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 05/09/2023]
Abstract
In the past decades, scientists have made outstanding efforts to treat diabetes. However, diabetes treatment is still far from satisfactory due to the complex nature of the disease and the challenges encountered in resolving it. Inflammatory factors are key regulators of the immune system's response to pathological insults, organ neogenesis, rejuvenation of novel cells to replace injured cells and overwhelming disease conditions. Currently, the available treatments for type 1 diabetes include daily insulin injection, pancreatic beta cell or tissue transplantation, and gene therapy. Cell therapy, exploiting differentiation, and reprogramming various types of cells to generate pancreatic insulin-producing cells are novel approaches for the treatment of type 1 diabetes. A better understanding of the inflammatory pathways offers valuable and improved therapeutic options to provide more advanced and better treatments for diabetes. In this review, we investigated different types of inflammatory factors that participate in the pathogenesis of type 1 diabetes, their possible dual impacts on the differentiation, reprogramming, and fusion of other stem cell lines into pancreatic insulin-producing beta cells, and the possibility of applying these factors to improve the treatment of this disease.
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Affiliation(s)
- Faeze Shahedi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arron Munggela Foma
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Azam Mahmoudi-Aznaveh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Mazlomi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Khorramizadeh
- Biosensor Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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10
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Schroderus AM, Poorbaugh J, McElyea S, Beasley S, Zhang L, Näntö-Salonen K, Rintamäki R, Pihlajamäki J, Knip M, Veijola R, Toppari J, Ilonen J, Benschop RJ, Kinnunen T. Evaluation of plasma IL-21 as a potential biomarker for type 1 diabetes progression. Front Immunol 2023; 14:1157265. [PMID: 37415982 PMCID: PMC10321755 DOI: 10.3389/fimmu.2023.1157265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/05/2023] [Indexed: 07/08/2023] Open
Abstract
IL-21 is a multifunctional cytokine linked with the pathophysiology of several autoimmune diseases, including type 1 diabetes. In this study, our aim was to examine plasma IL-21 levels in individuals at different stages of type 1 diabetes progression. We measured plasma IL-21 levels, as well as levels of other key pro-inflammatory cytokines (IL-17A, TNF-α and IL-6), from 37 adults with established type 1 diabetes and 46 healthy age-matched adult controls, as well as from 53 children with newly diagnosed type 1 diabetes, 48 at-risk children positive for type 1 diabetes-associated autoantibodies and 123 healthy age-matched pediatric controls using the ultrasensitive Quanterix SiMoA technology. Adults with established type 1 diabetes had higher plasma IL-21 levels compared to healthy controls. However, the plasma IL-21 levels showed no statistically significant correlation with clinical variables, such as BMI, C-peptide, HbA1c, or hsCRP levels, evaluated in parallel. In children, plasma IL-21 levels were almost ten times higher than in adults. However, no significant differences in plasma IL-21 levels were detected between healthy children, autoantibody-positive at-risk children, and children with newly diagnosed type 1 diabetes. In conclusion, plasma IL-21 levels in adults with established type 1 diabetes were increased, which may be associated with autoimmunity. The physiologically high plasma IL-21 levels in children may, however, reduce the potential of IL-21 as a biomarker for autoimmunity in pediatric subjects.
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Affiliation(s)
- Anna-Mari Schroderus
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | | | | | | | - Lin Zhang
- Eli Lilly and Company, Indianapolis, IN, United States
| | | | - Reeta Rintamäki
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Jussi Pihlajamäki
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Mikael Knip
- Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
- Pediatric Research Center, New Children’s Hospital, Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Riitta Veijola
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Centre for Population Health Research, University of Turku, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | | | - Tuure Kinnunen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
- ISLAB Laboratory Centre, Kuopio, Finland
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11
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Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther 2023; 8:235. [PMID: 37332039 PMCID: PMC10277291 DOI: 10.1038/s41392-023-01471-y] [Citation(s) in RCA: 266] [Impact Index Per Article: 133.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 06/20/2023] Open
Abstract
T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.
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Affiliation(s)
- Lina Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Anjun Jiao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Xin Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
- Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, 710061, China.
- Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, 710061, China.
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12
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Amerio A, Escelsior A, Martino E, Strangio A, Giacomini C, Montagna E, Aguglia A, Bellomo M, Sukkar SG, Saverino D. Dysfunction of Inflammatory Pathways and Their Relationship with Anti-Hypothalamic Autoantibodies in Patients with Anorexia Nervosa. Nutrients 2023; 15:2199. [PMCID: PMC10180712 DOI: 10.3390/nu15092199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/27/2023] [Accepted: 05/03/2023] [Indexed: 06/29/2023] Open
Abstract
Background: Despite several attempts, the etiopathogenesis of anorexia nervosa (AN) is still unknown. However, the activation of the immune response in neuropsychiatric diseases, including AN, is increasingly evident. We aimed to explore immune response parameters in patients with AN and identify the link between the presence of specific autoantibodies for hypothalamic antigens and the inflammatory response. The relationship between inflammatory markers and the duration of the disease has been also investigated. Methods: Twenty-two patients with AN were included, and none were under psychopharmacological treatment or suffering from autoimmune conditions. Serum concentrations of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and IL-21 were determined by ELISA kits. In addition, autoantibodies against hypothalamic antigens are quantitatively evaluated. Results: IL-6, IL-1 β, TNF-α, and TGF-β are significantly increased in patients with AN. A positive correlation with body mass index and with the amount of autoantibody specific for hypothalamic antigens exists. Notably, a progressive reduction of cytokines correlates with the progression of AN. In addition, IL-21 is increased in the blood of patients with AN and negatively correlates with autoantibody concentrations. Conclusions: This study shows that the increased pro-inflammatory phenotype in patients affected by AN correlates with the concentration of autoantibody specific for hypothalamic antigens. Of interest, the pro-inflammatory state seems to be reduced with duration of AN. In addition, IL-21 could work as a stimulant of the immune response, thus possibly increasing the autoreactivity.
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Affiliation(s)
- Andrea Amerio
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, 16126 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Andrea Escelsior
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, 16126 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Eleonora Martino
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Dietetics and Clinical Nutrition Unit, Genoa University, 16132 Genoa, Italy
| | - Antonella Strangio
- Department of Experimental Medicine (DiMeS), Section of Human Anatomy, University of Genoa, 16126 Genoa, Italy
| | - Costanza Giacomini
- Department of Mental Health and Pathological Addictions, Genoa Local Health Authority ASL4, 16043 Chiavari, Italy
| | - Elisa Montagna
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, 16126 Genoa, Italy
| | - Andrea Aguglia
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, 16126 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Marina Bellomo
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Samir Giuseppe Sukkar
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Dietetics and Clinical Nutrition Unit, Genoa University, 16132 Genoa, Italy
| | - Daniele Saverino
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Department of Experimental Medicine (DiMeS), Section of Human Anatomy, University of Genoa, 16126 Genoa, Italy
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13
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Ciecko AE, Wang Y, Harleston S, Drewek A, Serreze DV, Geurts AM, Lin CW, Chen YG. Heterogeneity of Islet-Infiltrating IL-21+ CD4 T Cells in a Mouse Model of Type 1 Diabetes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:935-946. [PMID: 36762954 PMCID: PMC10483376 DOI: 10.4049/jimmunol.2200712] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/29/2023] [Indexed: 02/11/2023]
Abstract
IL-21 is essential for type 1 diabetes (T1D) development in the NOD mouse model. IL-21-expressing CD4 T cells are present in pancreatic islets where they contribute to T1D progression. However, little is known about their phenotype and differentiation states. To fill this gap, we generated, to our knowledge, a novel IL-21 reporter NOD strain to further characterize IL-21+ CD4 T cells in T1D. IL-21+ CD4 T cells accumulate in pancreatic islets and recognize β cell Ags. Single-cell RNA sequencing revealed that CD4 T effector cells in islets actively express IL-21 and they are highly diabetogenic despite expressing multiple inhibitory molecules, including PD-1 and LAG3. Islet IL-21+ CD4 T cells segregate into four phenotypically and transcriptionally distinct differentiation states, that is, less differentiated early effectors, T follicular helper (Tfh)-like cells, and two Th1 subsets. Trajectory analysis predicts that early effectors differentiate into both Tfh-like and terminal Th1 cells. We further demonstrated that intrinsic IL-27 signaling controls the differentiation of islet IL-21+ CD4 T cells, contributing to their helper function. Collectively, our study reveals the heterogeneity of islet-infiltrating IL-21+ CD4 T cells and indicates that both Tfh-like and Th1 subsets produce IL-21 throughout their differentiation process, highlighting the important sources of IL-21 in T1D pathogenesis.
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Affiliation(s)
- Ashley E Ciecko
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
- The Max McGee Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI
| | - Yu Wang
- Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI
| | - Stephanie Harleston
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
- The Max McGee Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI
| | - Amber Drewek
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
- The Max McGee Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI
| | | | - Aron M Geurts
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI
| | - Chien-Wei Lin
- Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI
| | - Yi-Guang Chen
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI
- The Max McGee Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, WI
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14
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Sundaresan B, Shirafkan F, Ripperger K, Rattay K. The Role of Viral Infections in the Onset of Autoimmune Diseases. Viruses 2023; 15:v15030782. [PMID: 36992490 PMCID: PMC10051805 DOI: 10.3390/v15030782] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host's cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. Here we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs.
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Affiliation(s)
- Bhargavi Sundaresan
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
| | - Fatemeh Shirafkan
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
| | - Kevin Ripperger
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
| | - Kristin Rattay
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, 35043 Marburg, Germany
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15
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Umeshappa CS, Solé P, Yamanouchi J, Mohapatra S, Surewaard BGJ, Garnica J, Singha S, Mondal D, Cortés-Vicente E, D’Mello C, Mason A, Kubes P, Serra P, Yang Y, Santamaria P. Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity. Nat Commun 2022; 13:3279. [PMID: 35672409 PMCID: PMC9174212 DOI: 10.1038/s41467-022-30759-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 05/17/2022] [Indexed: 12/11/2022] Open
Abstract
AbstractInvariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (αGalCer), in the context of CD1d, but whether peripheral iNKT cell subsets are terminally differentiated remains unclear. Here we show that mouse and human liver-resident αGalCer/CD1d-binding iNKTs largely correspond to a novel Zbtb16+Tbx21+Gata3+MaflowRorc– subset that exhibits profound transcriptional, phenotypic and functional plasticity. Repetitive in vivo encounters of these liver iNKT (LiNKT) cells with intravenously delivered αGalCer/CD1d-coated nanoparticles (NP) trigger their differentiation into immunoregulatory, IL-10+IL-21-producing Zbtb16highMafhighTbx21+Gata3+Rorc– cells, termed LiNKTR1, expressing a T regulatory type 1 (TR1)-like transcriptional signature. This response is LiNKT-specific, since neither lung nor splenic tissue-resident iNKT cells from αGalCer/CD1d-NP-treated mice produce IL-10 or IL-21. Additionally, these LiNKTR1 cells suppress autoantigen presentation, and recognize CD1d expressed on conventional B cells to induce IL-10+IL-35-producing regulatory B (Breg) cells, leading to the suppression of liver and pancreas autoimmunity. Our results thus suggest that LiNKT cells are plastic for further functional diversification, with such plasticity potentially targetable for suppressing tissue-specific inflammatory phenomena.
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16
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IL-21/IL-21R Regulates the Neutrophil-Mediated Pathologic Immune Response during Chlamydial Respiratory Infection. Mediators Inflamm 2022; 2022:4322092. [PMID: 35693111 PMCID: PMC9177341 DOI: 10.1155/2022/4322092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 03/21/2022] [Accepted: 05/10/2022] [Indexed: 12/28/2022] Open
Abstract
IL-21/IL-21R was documented to participate in the regulation of multiple infection and inflammation. During Chlamydia muridarum (C. muridarum) respiratory infection, our previous study had revealed that the absence of this signal induced enhanced resistance to infection with higher protective Th1/Th17 immune responses. Here, we use the murine model of C. muridarum respiratory infection and IL-21R deficient mice to further identify a novel role of IL-21/IL-21R in neutrophilic inflammation. Resistant IL-21R−/− mice showed impaired neutrophil recruitment to the site of infection. In the absence of IL-21/IL-21R, pulmonary neutrophils also exhibited reduced activation status, including lower CD64 expression, MPO activity, and neutrophil-produced protein production. These results correlated well with the decrease of neutrophil-related chemokines (KC and MIP-2), inflammatory cytokines (IL-6, IL-1β, and TNF-α), and TLR/MyD88 pathway mediators (TLR2, TLR4, and MyD88) in infected lungs of IL-21R−/− mice than normal mice. Complementarily, decreased pulmonary neutrophil infiltration, activity, and levels of neutrophilic chemotactic factors and TLR/MyD88 signal in infected lungs can be corrected by rIL-21 administration. These results revealed that IL-21/IL-21R may aggravate the neutrophil inflammation through regulating TLR/MyD88 signal pathway during chlamydial respiratory infection.
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17
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Liu YW, Fu SH, Chien MW, Hsu CY, Lin MH, Dong JL, Lu RJH, Lee YJ, Chen PY, Wang CH, Sytwu HK. Blimp-1 moulds the epigenetic architecture of IL-21-mediated autoimmune diseases through an autoregulatory circuit. JCI Insight 2022; 7:151614. [PMID: 35503415 PMCID: PMC9220827 DOI: 10.1172/jci.insight.151614] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 04/29/2022] [Indexed: 11/17/2022] Open
Abstract
Positive regulatory domain 1 (PRDM1) encodes B lymphocyte–induced maturation protein 1 (BLIMP1), also known as a master regulator of T cell homeostasis. We observed a negative relationship between Blimp-1 and IL-21 based on our previous data that Blimp-1 overexpression in T cells suppresses autoimmune diabetes while Blimp-1–deficient T cells contribute to colitis in NOD mice. Reanalysis of published data sets also revealed an inverse correlation between PRDM1 and IL21 in Crohn’s disease. Here, we illustrate that Blimp-1 repressed IL-21 by reducing chromatin accessibility and evicting an IL-21 activator, c-Maf, from the Il21 promoter. Moreover, Blimp-1 overexpression–mediated reduction in permissive chromatin structures at the Il21 promoter could override IL-21–accelerated autoimmune diabetogenesis in small ubiquitin-like modifier–defective c-Maf–transgenic mice. An autoregulatory feedback loop to harness IL-21 expression was unveiled by the evidence that IL-21 addition induced time-dependent Blimp-1 expression and subsequently enriched its binding to the Il21 promoter to suppress IL-21 overproduction. Furthermore, intervention of this feedback loop by IL-21 blockade, with IL-21R.Fc administration or IL-21 receptor deletion, attenuated Blimp-1 deficiency–mediated colitis and reinforced the circuit between Blimp-1 and IL-21 in the regulation of autoimmunity. We highlight the translation of Blimp-1–based epigenetic and transcriptomic profiles applicable to a personalized medicine approach in autoimmune diseases.
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Affiliation(s)
- Yu-Wen Liu
- Molecular Cell Biology, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
| | - Shin-Huei Fu
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
| | - Ming-Wei Chien
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
| | - Chao-Yuan Hsu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Ming-Hong Lin
- Department of Microbiology and Immunology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-Ling Dong
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Rita Jui-Hsien Lu
- Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan
| | - Yi-Jing Lee
- Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan
| | - Pao-Yang Chen
- Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan
| | - Chih-Hung Wang
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Huey-Kang Sytwu
- National Institute of Infectious Disease and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
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18
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Krovi SH, Kuchroo VK. Activation pathways that drive CD4 + T cells to break tolerance in autoimmune diseases . Immunol Rev 2022;307:161-190. [PMID: 35142369 PMCID: PMC9255211 DOI: 10.1111/imr.13071] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 12/11/2022]
Abstract
Autoimmune diseases are characterized by dysfunctional immune systems that misrecognize self as non-self and cause tissue destruction. Several cell types have been implicated in triggering and sustaining disease. Due to a strong association of major histocompatibility complex II (MHC-II) proteins with various autoimmune diseases, CD4+ T lymphocytes have been thoroughly investigated for their roles in dictating disease course. CD4+ T cell activation is a coordinated process that requires three distinct signals: Signal 1, which is mediated by antigen recognition on MHC-II molecules; Signal 2, which boosts signal 1 in a costimulatory manner; and Signal 3, which helps to differentiate the activated cells into functionally relevant subsets. These signals are disrupted during autoimmunity and prompt CD4+ T cells to break tolerance. Herein, we review our current understanding of how each of the three signals plays a role in three different autoimmune diseases and highlight the genetic polymorphisms that predispose individuals to autoimmunity. We also discuss the drawbacks of existing therapies and how they can be addressed to achieve lasting tolerance in patients.
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Affiliation(s)
- Sai Harsha Krovi
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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19
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Lee JH, Kim DY, Pantha R, Lee EH, Bae JH, Han E, Song DK, Kwon TK, Im SS. Identification of Pre-Diabetic Biomarkers in the Progression of Diabetes Mellitus. Biomedicines 2021; 10:biomedicines10010072. [PMID: 35052752 PMCID: PMC8773205 DOI: 10.3390/biomedicines10010072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/25/2021] [Accepted: 12/29/2021] [Indexed: 01/11/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a major global health issue. The development of T2DM is gradual and preceded by the pre-diabetes mellitus (pre-DM) stage, which often remains undiagnosed. This study aimed to identify novel pre-DM biomarkers in a high-fat diet (HFD)-induced pre-DM mouse model. Male C57BL/6J mice were fed either a chow diet or HFD for 12 weeks. Serum and liver samples were isolated in a time-dependent manner. Semi-quantitative assessment of secretory cytokines was performed by cytokine array analysis, and 13 cytokines were selected for further analysis based on the changes in expression levels in the pre-DM and T2DM stages. HFD-fed mice gained body weight and exhibited high serum lipid, liver enzyme, glucose, and insulin levels during the progression of pre-DM to T2DM. The mRNA expression of inflammatory and lipogenic genes was elevated in HFD-fed mice The mRNA expression of Fc receptor, IgG, low affinity Iib, lectin, galactose binding, soluble 1, vascular cell adhesion molecule 1, insulin-like growth factor binding protein 5, and growth arrest specific 6 was elevated in the pre-DM, which was confirmed by measuring protein levels. Our study identified novel pre-DM biomarkers that may help to delay or prevent the progression of T2DM.
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Affiliation(s)
- Jae-Ho Lee
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
| | - Do-Young Kim
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
| | - Rubee Pantha
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
| | - Eun-Ho Lee
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
| | - Jae-Hoon Bae
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
| | - Eugene Han
- Department of Internal Medicine, Division of Endocrinology, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Dae-Kyu Song
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
| | - Taeg Kyu Kwon
- Department of Immunology, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Korea; (J.-H.L.); (D.-Y.K.); (R.P.); (E.-H.L.); (J.-H.B.); (D.-K.S.)
- Correspondence: ; Tel.: +82-53-258-7423; Fax: +82-53-258-7412
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20
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Greaves RB, Chen D, Green EA. Thymic B Cells as a New Player in the Type 1 Diabetes Response. Front Immunol 2021; 12:772017. [PMID: 34745148 PMCID: PMC8566354 DOI: 10.3389/fimmu.2021.772017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/01/2021] [Indexed: 12/27/2022] Open
Abstract
Type 1 diabetes (T1d) results from a sustained autoreactive T and B cell response towards insulin-producing β cells in the islets of Langerhans. The autoreactive nature of the condition has led to many investigations addressing the genetic or cellular changes in primary lymphoid tissues that impairs central tolerance- a key process in the deletion of autoreactive T and B cells during their development. For T cells, these studies have largely focused on medullary thymic epithelial cells (mTECs) critical for the effective negative selection of autoreactive T cells in the thymus. Recently, a new cellular player that impacts positively or negatively on the deletion of autoreactive T cells during their development has come to light, thymic B cells. Normally a small population within the thymus of mouse and man, thymic B cells expand in T1d as well as other autoimmune conditions, reside in thymic ectopic germinal centres and secrete autoantibodies that bind selective mTECs precipitating mTEC death. In this review we will discuss the ontogeny, characteristics and functionality of thymic B cells in healthy and autoimmune settings. Furthermore, we explore how in silico approaches may help decipher the complex cellular interplay of thymic B cells with other cells within the thymic microenvironment leading to new avenues for therapeutic intervention.
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Affiliation(s)
- Richard B Greaves
- Centre for Experimental Medicine and Biomedicine, Hull York Medical School, University of York, York, United Kingdom
| | - Dawei Chen
- Centre for Experimental Medicine and Biomedicine, Hull York Medical School, University of York, York, United Kingdom
| | - E Allison Green
- Centre for Experimental Medicine and Biomedicine, Hull York Medical School, University of York, York, United Kingdom
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21
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Khalil RG, Abdel-Moneim A, Yousef AI, Abdel-Rahman H, Zanaty MI, El-Sayed A. Association of interleukin-2, interleukin-21 and interleukin-23 with hyperlipidemia in pediatric type 1 diabetes. Mol Biol Rep 2021; 48:5421-5433. [PMID: 34328597 DOI: 10.1007/s11033-021-06545-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 07/02/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND In type 1 diabetes mellitus (T1DM), cytokines have a central role in orchestrating multicellular relations between β-cells and immune cells. This study aims to investigate the role of interleukin (IL)-21, IL-23, and IL-2, and their association with dyslipidemia in T1DM children. METHODS The sample population consisted of 30 healthy controls and 70 children with T1DM, the latter of which were split into two groups according to the duration of their T1DM diagnosis: recent (≤ 1 year; n = 21) and older (> 1 year; n = 49) diagnoses. RESULTS Fasting blood sugar and glycated hemoglobin levels in all diabetic children were significantly (P < 0.001) higher, whereas levels of plasma C-peptide were markedly (P < 0.001) lower in children with T1DM compared to healthy controls. In older T1DM diagnosis children, the levels of creatinine were noticeably (P < 0.05) increased relative to healthy controls. In all diabetic children, levels of total triglyceride, cholesterol, and low-density lipoprotein were increased significantly (P < 0.001) than those of healthy controls. Furthermore, the IL-21 and IL-23 mRNA expressions of all children with T1DM were elevated significantly (P < 0.001) relative to healthy controls, whereas IL-2 levels revealed a significant (P < 0.001) decrease in all diabetic children. CONCLUSION There was a synergistic interplay between IL-21 and IL-23 with an antagonistic action of IL-2 in T1DM patients, and all three interleukins were associated with dyslipidemia in diabetic children. Importantly, therapies targeting IL-21 and IL-23 are promising targets for preventive strategies against the development of T1DM and its complications.
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Affiliation(s)
- Rehab G Khalil
- Immunology Division, Faculty of Science, Beni-Suef University, Beni Suef, Egypt
| | - Adel Abdel-Moneim
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Salah Salim St., Beni Suef, 62511, Egypt.
| | - Ahmed I Yousef
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Salah Salim St., Beni Suef, 62511, Egypt
| | - Hanan Abdel-Rahman
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Science, Beni-Suef University, Beni Suef, Egypt
| | - Mohamed I Zanaty
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Science, Beni-Suef University, Beni Suef, Egypt
| | - Amr El-Sayed
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Science, Beni-Suef University, Beni Suef, Egypt
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22
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Ren HM, Lukacher AE, Rahman ZSM, Olsen NJ. New developments implicating IL-21 in autoimmune disease. J Autoimmun 2021; 122:102689. [PMID: 34224936 DOI: 10.1016/j.jaut.2021.102689] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 06/23/2021] [Indexed: 01/01/2023]
Abstract
Elevated interleukin (IL)-21 is a common finding in the tissues and/or sera of patients with autoimmune disease. CD4 T cells are the primary producers of IL-21; often the IL-21 producing CD4 T cells will express molecules associated with follicular helper cells (TFH). Recent work has shown that the CD4 T cell-derived IL-21 is able to promote effector functions and memory differentiation of CD8 T cells in chronic infections and cancer. Autoimmunity has similarities to chronic infections and cancer. However, CD4 T cell-derived IL-21:IL21R signaling in CD8 T cells has not been fully appreciated in the context of autoimmunity. In this review, we assess the current knowledge regarding CD4 T cell-derived IL-21 and IL21R signaling within CD8 T cells and evaluate what implications it has within several autoimmune diseases including systemic lupus erythematous, rheumatoid arthritis, juvenile idiopathic arthritis, type 1 diabetes mellitus, psoriasis, Sjögren's syndrome, vitiligo, antiphospholipid syndrome, pemphigus, and giant cell arteritis.
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Affiliation(s)
- Heather M Ren
- MD/PhD Medical Scientist Training Program at Penn State College of Medicine, Penn State College of Medicine, Hershey, PA, 17033, USA; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, 17033, USA.
| | - Aron E Lukacher
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, 17033, USA
| | - Nancy J Olsen
- Devision of Rheumatology, Department of Medicine, Penn State MS Hershey Medical Center, Hershey, PA, 17033, USA
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23
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Xiang K, Xu Z, Hu YQ, He YS, Wu GC, Li TY, Wang XR, Ding LH, Zhang Q, Tao SS, Ye DQ, Pan HF, Wang DG. Circadian clock genes as promising therapeutic targets for autoimmune diseases. Autoimmun Rev 2021; 20:102866. [PMID: 34118460 DOI: 10.1016/j.autrev.2021.102866] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 03/30/2021] [Indexed: 12/31/2022]
Abstract
Circadian rhythm is a natural, endogenous process whose physiological functions are controlled by a set of clock genes. Disturbance of the clock genes have detrimental effects on both innate and adaptive immunity, which significantly enhance pro-inflammatory responses and susceptibility to autoimmune diseases via strictly controlling the individual cellular components of the immune system that initiate and perpetuate the inflammation pathways. Autoimmune diseases, especially rheumatoid arthritis (RA), often exhibit substantial circadian oscillations, and circadian rhythm is involved in the onset and progression of autoimmune diseases. Mounting evidence indicate that the synthetic ligands of circadian clock genes have the property of reducing the susceptibility and clinical severity of subjects. This review supplies an overview of the roles of circadian clock genes in the pathology of autoimmune diseases, including BMAL1, CLOCK, PER, CRY, REV-ERBα, and ROR. Furthermore, summarized some circadian clock genes as candidate genes for autoimmune diseases and current advancement on therapy of autoimmune diseases with synthetic ligands of circadian clock genes. The existing body of knowledge demonstrates that circadian clock genes are inextricably linked to autoimmune diseases. Future research should pay attention to improve the quality of life of patients with autoimmune diseases and reduce the effects of drug preparation on the normal circadian rhythms.
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Affiliation(s)
- Kun Xiang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Zhiwei Xu
- School of Public Health, Faculty of Medicine, University of Queensland, 288 Herston Road, Herston, QLD, 4006, Brisbane, Australia
| | - Yu-Qian Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Yi-Sheng He
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Guo-Cui Wu
- School of Nursing, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| | - Tian-Yu Li
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xue-Rong Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Li-Hong Ding
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qin Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Sha-Sha Tao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, 81 Meishan Road, Hefei, Anhui, China.
| | - De-Guang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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von Scholten BJ, Kreiner FF, Gough SCL, von Herrath M. Current and future therapies for type 1 diabetes. Diabetologia 2021; 64:1037-1048. [PMID: 33595677 PMCID: PMC8012324 DOI: 10.1007/s00125-021-05398-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/22/2020] [Indexed: 12/14/2022]
Abstract
In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes.
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Affiliation(s)
| | | | | | - Matthias von Herrath
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark.
- Type 1 Diabetes Center, The La Jolla Institute for Immunology, La Jolla, CA, USA.
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Allred MG, Chimenti MS, Ciecko AE, Chen YG, Lieberman SM. Characterization of Type I Interferon-Associated Chemokines and Cytokines in Lacrimal Glands of Nonobese Diabetic Mice. Int J Mol Sci 2021; 22:ijms22073767. [PMID: 33916486 PMCID: PMC8038628 DOI: 10.3390/ijms22073767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren’s disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes upregulated in lacrimal glands of NOD mice in a type I IFN-dependent manner. Interleukin (IL)-21 was the highest differentially expressed cytokine gene, and Il21 knockout NOD mice were relatively protected from lacrimal gland inflammation. We defined a set of chemokines upregulated early in disease including Cxcl9 and Cxcl10, which share a receptor, CXCR3. CXCR3+ T cells were enriched in lacrimal glands with a dominant proportion of CXCR3+ regulatory T cells. Together these data define the early cytokine and chemokine signals associated with type I IFN-signaling in the development of lacrimal gland inflammation in NOD mice providing insight into the role of type I IFN in autoimmunity development.
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Affiliation(s)
- Merri-Grace Allred
- Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
- Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA
| | - Michael S. Chimenti
- Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Ashley E. Ciecko
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (A.E.C.); (Y.-G.C.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Yi-Guang Chen
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (A.E.C.); (Y.-G.C.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Scott M. Lieberman
- Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
- Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA
- Correspondence: ; Tel.: +1-319-467-5111
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26
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von Herrath M, Bain SC, Bode B, Clausen JO, Coppieters K, Gaysina L, Gumprecht J, Hansen TK, Mathieu C, Morales C, Mosenzon O, Segel S, Tsoukas G, Pieber TR. Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol 2021; 9:212-224. [PMID: 33662334 DOI: 10.1016/s2213-8587(21)00019-x] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. METHODS This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. FINDINGS Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). INTERPRETATION The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. FUNDING Novo Nordisk.
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Affiliation(s)
| | | | - Bruce Bode
- Atlanta Diabetes Associates, Atlanta, GA, USA; Emory University School of Medicine, Atlanta, GA, USA
| | | | | | | | | | | | - Chantal Mathieu
- Clinical and Experimental Endocrinology, UZ Gasthuisberg, University of Leuven, Leuven, Belgium
| | - Cristobal Morales
- Endocrinology and Nutrition Department, Virgen Macarena Hospital, Seville, Spain
| | - Ofri Mosenzon
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Centre, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | | | - George Tsoukas
- Department of Medicine, McGill University, Montreal, QC, Canada
| | - Thomas R Pieber
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
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Ke Q, Kroger CJ, Clark M, Tisch RM. Evolving Antibody Therapies for the Treatment of Type 1 Diabetes. Front Immunol 2021; 11:624568. [PMID: 33679717 PMCID: PMC7930374 DOI: 10.3389/fimmu.2020.624568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/31/2020] [Indexed: 12/24/2022] Open
Abstract
Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.
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Affiliation(s)
- Qi Ke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Charles J Kroger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Matthew Clark
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland M Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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28
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Clark M, Kroger CJ, Ke Q, Tisch RM. The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes. Front Immunol 2021; 11:615371. [PMID: 33603744 PMCID: PMC7884625 DOI: 10.3389/fimmu.2020.615371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.
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Affiliation(s)
- Matthew Clark
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Charles J Kroger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Qi Ke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland M Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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29
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Pearson JA, McKinney EF, Walker LSK. 100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes. IMMUNOTHERAPY ADVANCES 2021; 1:ltab024. [PMID: 35156097 PMCID: PMC8826223 DOI: 10.1093/immadv/ltab024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/15/2021] [Accepted: 11/20/2021] [Indexed: 02/03/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting.
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Affiliation(s)
- James A Pearson
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK
| | - Eoin F McKinney
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, England, UK
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, England, UK
- Cambridge Centre for Artificial Intelligence in Medicine, University of Cambridge, Cambridge, England, UK
| | - Lucy S K Walker
- Division of Infection and Immunity, Institute or Immunity and Transplantation, University College London, Royal Free Campus, London, UK
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30
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Ge T, Jhala G, Fynch S, Akazawa S, Litwak S, Pappas EG, Catterall T, Vakil I, Long AJ, Olson LM, Krishnamurthy B, Kay TW, Thomas HE. The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice. Front Immunol 2020; 11:588543. [PMID: 33343569 PMCID: PMC7746546 DOI: 10.3389/fimmu.2020.588543] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/04/2020] [Indexed: 01/31/2023] Open
Abstract
Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8+ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8+ T cell proliferation as well as the number of KLRG+ effector and CD44hiCD62Llo effector memory CD8+ T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.
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Affiliation(s)
- Tingting Ge
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia.,Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia
| | - Gaurang Jhala
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia
| | - Stacey Fynch
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia
| | - Satoru Akazawa
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia
| | - Sara Litwak
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia
| | - Evan G Pappas
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia
| | - Tara Catterall
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia
| | - Ishan Vakil
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia.,Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia
| | - Andrew J Long
- AbbVie Bioresearch Center, Worcester, MA, United States
| | - Lisa M Olson
- AbbVie Bioresearch Center, Worcester, MA, United States
| | - Balasubramanian Krishnamurthy
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia.,Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia
| | - Thomas W Kay
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia.,Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia
| | - Helen E Thomas
- Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy, VIC, Australia.,Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia
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Pearson JA, Li Y, Majewska-Szczepanik M, Guo J, Zhang L, Liu Y, Wong FS, Wen L. Insulin-Reactive T Cells Convert Diabetogenic Insulin-Reactive VH125 B Cells Into Tolerogenic Cells by Reducing Germinal Center T:B Cell Interactions in NOD Mice. Front Immunol 2020; 11:585886. [PMID: 33262765 PMCID: PMC7688534 DOI: 10.3389/fimmu.2020.585886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/16/2020] [Indexed: 11/29/2022] Open
Abstract
Insulin is a key autoantigen in Type 1 Diabetes (T1D), targeted by both T and B cells. Therefore, understanding insulin-specific T:B cell interactions is important. We have previously reported an insulin-reactive CD4+ T cell, (designated 2H6). Unlike other insulin-reactive T cells, 2H6 cells protect non-obese diabetic (NOD) mice from T1D development, mediated by TGFβ. To investigate insulin-specific T:B cell interactions, we bred 2H6αβ T cell receptor transgenic NOD mice (2H6) with the insulin-reactive B cell receptor transgenic NOD mice (VH125), generating 2H6VH125 NOD mice. Similar to 2H6 mice, 2H6VH125 mice are protected from T1D development. Interestingly, VH125 B cells did not alter the phenotype of 2H6 T cells; however, 2H6 T cells significantly altered the VH125 B cells by reducing the insulin-reactive non-germinal center (GC) and GC B cells, as well as MHC and costimulatory molecule expression on the B cells. Furthermore, the B cells in 2H6VH125 NOD mice exhibited increased non-insulin-specific and a class switched IgG isotype, which can be recapitulated in vivo in Rag-deficient NOD mice by adoptive transfer. In vitro, VH125 B cells from 2H6VH125 mice suppressed the proliferation of 2H6 T cells to insulin antigen but enhanced TGFβ secretion by 2H6 T cells from 2H6VH125 mice compared to 2H6 mice. In summary, our data showed that 2H6 CD4+ T cells alter the phenotype and function of insulin-reactive B cells from pathogenic to tolerogenic cells. In turn, VH125 B cells also modulate the function of the 2H6 T cells. Thus, promoting the interactions between antigen-specific regulatory T cells and B cells may lead to protection from T1D.
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Affiliation(s)
- James A. Pearson
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Yangyang Li
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
- Department of Endocrinology, Sir Run Run Shaw Hospital, Nanjing Medical University, Nanjing, China
| | - Monika Majewska-Szczepanik
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
- Department of Medical Biology, Jagiellonian University Medical College, Krakow, Poland
| | - Junhua Guo
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
- Department of Rheumatology, People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Li Zhang
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Shaw Hospital, Nanjing Medical University, Nanjing, China
| | - F. Susan Wong
- Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Li Wen
- Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, United States
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Vandamme C, Kinnunen T. B cell helper T cells and type 1 diabetes. Scand J Immunol 2020; 92:e12943. [PMID: 32697399 PMCID: PMC7583378 DOI: 10.1111/sji.12943] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/03/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022]
Abstract
Type 1 diabetes is an autoimmune disease typically starting in childhood that culminates in the destruction of insulin‐producing beta cells in the pancreas. Although type 1 diabetes is considered to be a primarily T cell–mediated disease, B cells clearly participate in the autoimmune process, as autoantibodies recognizing pancreatic islet antigen commonly appear in circulation before the onset of the disease. T cells providing helper functions to B cells have recently been shown to be involved in the pathogenesis of a wide range of antibody‐associated immune disorders. These T cells include CXCR5‐positive follicular T helper (Tfh) cells, and a recently described closely related CXCR5‐negative subset coined peripheral T helper (Tph) cells. Here, we review the current state of knowledge on different B cell helper T cell subsets, focusing on their potential involvement in the development of type 1 diabetes.
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Affiliation(s)
- Céline Vandamme
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Tuure Kinnunen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.,Eastern Finland Laboratory Centre (ISLAB), Kuopio, Finland
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33
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Tangye SG, Ma CS. Regulation of the germinal center and humoral immunity by interleukin-21. J Exp Med 2020; 217:132621. [PMID: 31821441 PMCID: PMC7037251 DOI: 10.1084/jem.20191638] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/28/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
Here we review the critical and non-redundant functions of IL-21 in regulating humoral immune responses. We particularly focus on studies in natura—from individuals from inborn errors of immunity that impact on IL-21 production and/or function. Cytokines play critical roles in regulating the development, survival, differentiation, and function of immune cells. Cytokines exert their function by binding specific receptor complexes on the surface of immune cells and activating intracellular signaling pathways, thereby resulting in induction of specific transcription factors and regulated expression of target genes. While the function of cytokines is often fundamental for the generation of robust and effective immunity following infection or vaccination, aberrant production or function of cytokines can underpin immunopathology. IL-21 is a pleiotropic cytokine produced predominantly by CD4+ T cells. Gene-targeting studies in mice, in vitro analyses of human and murine lymphocytes, and the recent discoveries and analyses of humans with germline loss-of-function mutations in IL21 or IL21R have revealed diverse roles of IL-21 in immune regulation and effector function. This review will focus on recent advances in IL-21 biology that have highlighted its critical role in T cell–dependent B cell activation, germinal center reactions, and humoral immunity and how impaired responses to, or production of, IL-21 can lead to immune dysregulation.
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Affiliation(s)
- Stuart G Tangye
- Immunology Theme, Garvan Institute of Medical Research, Darlinghurst, Australia.,St Vincent's Clinical School, University of New South Wales Sydney, Darlinghurst, Australia.,Clinical Immunogenomics Consortium of Australasia, Darlinghurst, Australia
| | - Cindy S Ma
- Immunology Theme, Garvan Institute of Medical Research, Darlinghurst, Australia.,St Vincent's Clinical School, University of New South Wales Sydney, Darlinghurst, Australia.,Clinical Immunogenomics Consortium of Australasia, Darlinghurst, Australia
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Lu J, Liu J, Li L, Lan Y, Liang Y. Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets. Clin Transl Immunology 2020; 9:e1122. [PMID: 32185024 PMCID: PMC7074462 DOI: 10.1002/cti2.1122] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 01/31/2020] [Accepted: 03/01/2020] [Indexed: 12/17/2022] Open
Abstract
Cytokines play crucial roles in orchestrating complex multicellular interactions between pancreatic β cells and immune cells in the development of type 1 diabetes (T1D) and are thus potential immunotherapeutic targets for this disorder. Cytokines that can induce regulatory functions-for example, IL-10, TGF-β and IL-33-are thought to restore immune tolerance and prevent β-cell damage. By contrast, cytokines such as IL-6, IL-17, IL-21 and TNF, which promote the differentiation and function of diabetogenic immune cells, are thought to lead to T1D onset and progression. However, targeting these dysregulated cytokine networks does not always result in consistent effects because anti-inflammatory or proinflammatory functions of cytokines, responsible for β-cell destruction, are context dependent. In this review, we summarise the current knowledge on the involvement of well-known cytokines in both the initiation and destruction phases of T1D and discuss advances in recently discovered roles of cytokines. Additionally, we emphasise the complexity and implications of cytokine modulation therapy and discuss the ways in which this strategy has been translated into clinical trials.
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Affiliation(s)
- Jingli Lu
- Department of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou China.,Henan Key Laboratory of Precision Clinical Pharmacy Zhengzhou University Zhengzhou China
| | - Jiyun Liu
- Department of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou China.,Henan Key Laboratory of Precision Clinical Pharmacy Zhengzhou University Zhengzhou China
| | - Lulu Li
- Department of Pharmacy Wuhan No.1 Hospital Wuhan China
| | - Yan Lan
- Department of Pharmacy Huangshi Center Hospital Huangshi China
| | - Yan Liang
- Department of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou China.,Henan Key Laboratory of Precision Clinical Pharmacy Zhengzhou University Zhengzhou China
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35
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Iervasi E, Auricchio R, Strangio A, Greco L, Saverino D. Serum IL-21 levels from celiac disease patients correlates with anti-tTG IgA autoantibodies and mucosal damage. Autoimmunity 2020; 53:225-230. [PMID: 32157915 DOI: 10.1080/08916934.2020.1736047] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Objectives: Coeliac disease is a multifactorial disorder influenced by environmental, genetic and immunological factors. Interleukin (IL)-21 has been linked to an increase disease risk and the serum level of IL-21 seems to be increased in CD compared to a healthy control population.Methods: Sera were collected from 160 CD patients, 120 untreated and 40 following a gluten-free diet, and form 45 healthy subjects. Serum IL-21 was evaluated by specific ELISA tests.Results: Our data show that patients with untreated CD display IL-21 concentrations significantly higher than both treated-CD patients (following a gluten-free diet) and controls. In addition, serum IL-21 correlates with serum titres of anti-tTG IgA autoantibodies. Finally, our results show a correlation of this cytokine with duodenal mucosal damage.Conclusions: A role of gluten, as antigen with stimulatory function on IL-21 production, seems to be confirmed by the longitudinal analyses showing that the gluten-free diet decreases to a nearly undetectable amount this cytokine. In addition, the finding of a positive correlation between the serum amount of IL-21 and the grade of duodenal mucosa damage suggests a strong immunomodulatory effect of this cytokine on cytotoxic T lymphocyte functions. This study provides an extra evidence to emerging data on the potential role IL-21 in CD pathogenesis, suggesting its involvement in the development and progression of CD. Significance statement: In untreated CD, serum IL-21 shows higher levels compared with treated CD and healthy subjects. Serum amounts of IL-21 correlate with anti-tTG IgA autoantibodies and with duodenal mucosa damage.
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Affiliation(s)
- Erika Iervasi
- Department of Experimental Medicine, University of Genova, Genova, Italy.,Laboratory of Autoimmunology, Ospedale Policlinico San Martino, Largo Rosanna Benzi, Genova, Italy
| | - Renata Auricchio
- Department of Translational Medical Science, University of Naples Federico II, Napoli, Italy.,European Laboratory for Food-Induced disease (ELFID), University of Naples Federico II, Napoli, Italy
| | - Antonella Strangio
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Luigi Greco
- Department of Translational Medical Science, University of Naples Federico II, Napoli, Italy.,European Laboratory for Food-Induced disease (ELFID), University of Naples Federico II, Napoli, Italy
| | - Daniele Saverino
- Department of Experimental Medicine, University of Genova, Genova, Italy.,Laboratory of Autoimmunology, Ospedale Policlinico San Martino, Largo Rosanna Benzi, Genova, Italy
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36
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Shao F, Zheng P, Yu D, Zhou Z, Jia L. Follicular helper T cells in type 1 diabetes. FASEB J 2019; 34:30-40. [PMID: 31914661 DOI: 10.1096/fj.201901637r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 11/09/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Feng Shao
- Department of Metabolism & Endocrinology The Second Xiangya HospitalCentral South University Changsha China
- Key Laboratory of Diabetes Immunology Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases Changsha China
| | - Peilin Zheng
- Department of Endocrinology, Shenzhen People’s Hospital The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology Shenzhen China
| | - Di Yu
- The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland Australia
- Shandong Analysis and Test Center Shandong Academy of Sciences Jinan China
- China‐Australia Centre for Personalised Immunology Shanghai Renji Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology The Second Xiangya HospitalCentral South University Changsha China
- Key Laboratory of Diabetes Immunology Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases Changsha China
| | - Lijing Jia
- Department of Endocrinology, Shenzhen People’s Hospital The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology Shenzhen China
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37
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Ciecko AE, Foda B, Barr JY, Ramanathan S, Atkinson MA, Serreze DV, Geurts AM, Lieberman SM, Chen YG. Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation. Cell Rep 2019; 29:3073-3086.e5. [PMID: 31801074 PMCID: PMC6914223 DOI: 10.1016/j.celrep.2019.11.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 09/26/2019] [Accepted: 11/04/2019] [Indexed: 01/04/2023] Open
Abstract
Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27-/- and NOD.Il27ra-/- strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.
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Affiliation(s)
- Ashley E Ciecko
- Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Bardees Foda
- Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Molecular Genetics and Enzymology, National Research Centre, Dokki, Egypt
| | - Jennifer Y Barr
- Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Mark A Atkinson
- Departments of Pediatrics, and Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32611, USA
| | - David V Serreze
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
| | - Aron M Geurts
- Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Scott M Lieberman
- Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA
| | - Yi-Guang Chen
- Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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IL-21 regulates SOCS1 expression in autoreactive CD8 + T cells but is not required for acquisition of CTL activity in the islets of non-obese diabetic mice. Sci Rep 2019; 9:15302. [PMID: 31653894 PMCID: PMC6814838 DOI: 10.1038/s41598-019-51636-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 09/30/2019] [Indexed: 12/17/2022] Open
Abstract
In type 1 diabetes, maturation of activated autoreactive CD8+ T cells to fully armed effector cytotoxic T lymphocytes (CTL) occurs within the islet. At present the signals required for the maturation process are poorly defined. Cytokines could potentially provide the necessary "third signal" required to generate fully mature CTL capable of killing insulin-producing β-cells. To determine whether autoreactive CTL within islets respond to cytokines we generated non-obese diabetic (NOD) mice with a reporter for cytokine signalling. These mice express a reporter gene, hCD4, under the control of the endogenous regulatory elements for suppressor of cytokine signalling (SOCS)1, which is itself regulated by pro-inflammatory cytokines. In NOD mice, the hCD4 reporter was expressed in infiltrated islets and the expression level was positively correlated with the frequency of infiltrating CD45+ cells. SOCS1 reporter expression was induced in transferred β-cell-specific CD8+ 8.3T cells upon migration from pancreatic draining lymph nodes into islets. To determine which cytokines induced SOCS1 promoter activity in islets, we examined hCD4 reporter expression and CTL maturation in the absence of the cytokine receptors IFNAR1 or IL-21R. We show that IFNAR1 deficiency does not confer protection from diabetes in 8.3 TCR transgenic mice, nor is IFNAR1 signalling required for SOCS1 reporter upregulation or CTL maturation in islets. In contrast, IL-21R-deficient 8.3 mice have reduced diabetes incidence and reduced SOCS1 reporter activity in islet CTLs. However IL-21R deficiency did not affect islet CD8+ T cell proliferation or expression of granzyme B or IFNγ. Together these data indicate that autoreactive CD8+ T cells respond to IL-21 and not type I IFNs in the islets of NOD mice, but neither IFNAR1 nor IL-21R are required for islet intrinsic CTL maturation.
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39
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Long D, Chen Y, Wu H, Zhao M, Lu Q. Clinical significance and immunobiology of IL-21 in autoimmunity. J Autoimmun 2019; 99:1-14. [PMID: 30773373 DOI: 10.1016/j.jaut.2019.01.013] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 01/31/2019] [Indexed: 12/14/2022]
Abstract
Interleukin-21 (IL-21), an autocrine cytokine predominantly produced by follicular helper T (Tfh) and T helper 17 (Th17) cells, has been proven to play an important role in the immune system, for example, by promoting proliferation and the development of Tfh and Th17 cells, balancing helper T cell subsets, inducing B cell generation and differentiation into plasma cells, and enhancing the production of immunoglobulin. These effects are mainly mediated by activation of the JAK/STAT, MAPK and PI3K pathways. Some IL-21 target genes, such as B lymphocyte induced maturation protein-1 (Blimp-1), suppressor of cytokine signaling (SOCS), CXCR5 and Bcl-6, play important roles in the immune response. Therefore, IL-21 has been linked to autoimmune diseases. Indeed, IL-21 levels are increased in the peripheral blood and tissues of patients with systematic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), immune thrombocytopenia (ITP), primary Sjogren's syndrome (pSS), autoimmune thyroid disease (AITD) and psoriasis. This increased IL-21 even positively associates with Tfh cells, plasma cells, autoantibodies and disease activity in SLE and RA. Additionally, IL-21 has been utilized as a therapeutic target in SLE, RA, T1D and psoriatic mouse models. Profoundly, clinical trials have shown safety and improvement in RA patients. However, tolerance and long-term pharmacodynamics effects with low bioavailability have been found in SLE patients. Therefore, this review aims to summarize the latest progress on IL-21 function and its signaling pathway and discuss the role of IL-21 in the pathogenesis of and therapy for autoimmune diseases, with the hope of providing potential therapeutic and diagnostic strategies for clinical use.
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Affiliation(s)
- Di Long
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China
| | - Yongjian Chen
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China
| | - Haijing Wu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China
| | - Ming Zhao
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China
| | - Qianjin Lu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, PR China.
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40
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Imam S, Prathibha R, Dar P, Almotah K, Al-Khudhair A, Hasan SAM, Salim N, Jilani TN, Mirmira RG, Jaume JC. eIF5A inhibition influences T cell dynamics in the pancreatic microenvironment of the humanized mouse model of Type 1 Diabetes. Sci Rep 2019; 9:1533. [PMID: 30733517 PMCID: PMC6367423 DOI: 10.1038/s41598-018-38341-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/17/2018] [Indexed: 12/14/2022] Open
Abstract
We have developed a transgenic mouse model of Type 1 Diabetes (T1D) in which human GAD65 is expressed in pancreatic β-cells, and human MHC-II is expressed on antigen presenting cells. Induced GAD65 antigen presentation activates T-cells, which initiates the downstream events leading to diabetes. In our humanized mice, we have shown downregulation of eukaryotic translation initiation factor 5 A (elF5A), expressed only in actively dividing mammalian cells. In-vivo inhibition of elF5A hypusination by deoxyhypusine synthase (DHS) inhibitor "GC7" was studied; DHS inhibitor alters the pathophysiology in our mouse model by catalyzing the crucial hypusination and the rate-limiting step of elF5A activation. In our mouse model, we have shown that inhibition of eIF5A resets the pro-inflammatory bias in the pancreatic microenvironment. There was: (a) reduction of Th1/Th17 response, (b) an increase in Treg numbers, (c) debase in IL17 and IL21 cytokines levels in serum, (d) lowering of anti-GAD65 antibodies, and (e) ablation of the ER stress that improved functionality of the β-cells, but minimal effect on the cytotoxic CD8 T-cell (CTL) mediated response. Conclusively, immune modulation, in the case of T1D, may help to manipulate inflammatory responses, decreasing disease severity, and may help manage T1D in early stages of disease. Our study also demonstrates that without manipulating the CTLs mediated response extensively, it is difficult to treat T1D.
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Affiliation(s)
- Shahnawaz Imam
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
| | - R Prathibha
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Pervaiz Dar
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir (SKUAST-K), Shuhama, Srinagar, 190006, Jammu and Kashmir, India
| | - Khalil Almotah
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Ahmed Al-Khudhair
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Syed Abdul-Moiz Hasan
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Nancy Salim
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Talha Naser Jilani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA
| | - Raghavendra G Mirmira
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Juan Carlos Jaume
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
- Center for Diabetes and Endocrine Research (CeDER), Department of Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.
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Li Q, Wang B, Mu K, Zhang J. The pathogenesis of thyroid autoimmune diseases: New T lymphocytes – Cytokines circuits beyond the Th1−Th2 paradigm. J Cell Physiol 2018; 234:2204-2216. [PMID: 30246383 DOI: 10.1002/jcp.27180] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 05/22/2018] [Accepted: 07/17/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Qian Li
- Department of EndocrinologyJinshan Hospital of Fudan UniversityShanghai China
| | - Bin Wang
- Department of EndocrinologyJinshan Hospital of Fudan UniversityShanghai China
| | - Kaida Mu
- Department of EndocrinologyShanghai University of Medicine & Health Sciences Affiliated Zhoupu HospitalShanghai China
| | - Jin‐An Zhang
- Department of EndocrinologyShanghai University of Medicine & Health Sciences Affiliated Zhoupu HospitalShanghai China
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42
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Kroger CJ, Clark M, Ke Q, Tisch RM. Therapies to Suppress β Cell Autoimmunity in Type 1 Diabetes. Front Immunol 2018; 9:1891. [PMID: 30166987 PMCID: PMC6105696 DOI: 10.3389/fimmu.2018.01891] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that is generally considered to be T cell-driven. Accordingly, most strategies of immunotherapy for T1D prevention and treatment in the clinic have targeted the T cell compartment. To date, however, immunotherapy has had only limited clinical success. Although certain immunotherapies have promoted a protective effect, efficacy is often short-term and acquired immunity may be impacted. This has led to the consideration of combining different approaches with the goal of achieving a synergistic therapeutic response. In this review, we will discuss the status of various T1D therapeutic strategies tested in the clinic, as well as possible combinatorial approaches to restore β cell tolerance.
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Affiliation(s)
- Charles J Kroger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Matthew Clark
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Qi Ke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland M Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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43
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Hsu CY, Yeh LT, Fu SH, Chien MW, Liu YW, Miaw SC, Chang DM, Sytwu HK. SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes. J Clin Invest 2018; 128:3779-3793. [PMID: 30059018 DOI: 10.1172/jci98786] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 06/14/2018] [Indexed: 12/19/2022] Open
Abstract
SUMOylation is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated c-Maf in autoimmune diabetes is not completely understood. Here, we report that an age-dependent attenuation of c-Maf SUMOylation in CD4+ T cells is positively correlated with the IL-21-mediated diabetogenesis in NOD mice. Using 2 strains of T cell-specific transgenic NOD mice overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site-mutated c-Maf (Tg-KRc), we demonstrated that Tg-KRc mice developed diabetes more rapidly than Tg-WTc mice in a CD4+ T cell-autonomous manner. Moreover, SUMO-defective c-Maf preferentially transactivated Il21 to promote the development of CD4+ T cells with an extrafollicular helper T cell phenotype and expand the numbers of granzyme B-producing effector/memory CD8+ T cells. Furthermore, SUMO-defective c-Maf selectively inhibited recruitment of Daxx/HDAC2 to the Il21 promoter and enhanced histone acetylation mediated by CREB-binding protein (CBP) and p300. Using pharmacological interference with CBP/p300, we illustrated that CBP30 treatment ameliorated c-Maf-mediated/IL-21-based diabetogenesis. Taken together, our results show that the SUMOylation status of c-Maf has a stronger regulatory effect on IL-21 than the level of c-Maf expression, through an epigenetic mechanism. These findings provide new insights into how SUMOylation modulates the pathogenesis of autoimmune diabetes in a T cell-restricted manner and on the basis of a single transcription factor.
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Affiliation(s)
| | - Li-Tzu Yeh
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Shin-Huei Fu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Ming-Wei Chien
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Wen Liu
- Graduate Institute of Life Sciences and.,Molecular Cell Biology, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
| | - Shi-Chuen Miaw
- Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Deh-Ming Chang
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Huey-Kang Sytwu
- Graduate Institute of Life Sciences and.,Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.,National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan
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44
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Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW. Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes. THE JOURNAL OF IMMUNOLOGY 2018; 201:861-873. [PMID: 29950508 DOI: 10.4049/jimmunol.1701717] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 05/23/2018] [Indexed: 12/29/2022]
Abstract
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (VH125SDNOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in VH125SDNOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
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Affiliation(s)
- Jamie L Felton
- Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Damian Maseda
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; and
| | - Rachel H Bonami
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, TN 37232
| | - Chrys Hulbert
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, TN 37232
| | - James W Thomas
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; and .,Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, Nashville, TN 37232
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Pinto AI, Smith J, Kissack MR, Hogg KG, Green EA. Thymic B Cell-Mediated Attack of Thymic Stroma Precedes Type 1 Diabetes Development. Front Immunol 2018; 9:1281. [PMID: 29930554 PMCID: PMC5999731 DOI: 10.3389/fimmu.2018.01281] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/22/2018] [Indexed: 01/11/2023] Open
Abstract
Type 1 diabetes (T1D) results from a coordinated autoimmune attack of insulin producing beta cells in the pancreas by the innate and adaptive immune systems, beta cell death being predominantly T cell-mediated. In addition to T cells, peripheral B cells are important in T1D progression. The thymus of mice and man also contains B cells, and lately they have been linked to central tolerance of T cells. The role of thymic B cells in T1D is undefined. Here, we show there are abnormalities in the thymic B cell compartment before beta cell destruction and T1D manifestation. Using non-obese diabetic (NOD) mice, we document that preceding T1D development, there is significant accumulation of thymic B cells-partly through in situ development- and the putative formation of ectopic germinal centers. In addition, in NOD mice we quantify thymic plasma cells and observe in situ binding of immunoglobulins to undefined antigens on a proportion of medullary thymic epithelial cells (mTECs). By contrast, no ectopic germinal centers or pronounced intrathymic autoantibodies are detectable in animals not genetically predisposed to developing T1D. Binding of autoantibodies to thymic stroma correlates with apoptosis of mTECs, including insulin-expressing cells. By contrast, apoptosis of mTECs was decreased by 50% in B cell-deficient NOD mice suggesting intrathymic autoantibodies may selectively target certain mTECs for destruction. Furthermore, we observe that these thymic B cell-associated events correlated with an increased prevalence of premature thymic emigration of T cells. Together, our data suggest that the thymus may be a principal autoimmune target in T1D and contributes to disease progression.
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Affiliation(s)
- Ana Isabel Pinto
- Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United Kingdom
| | - Jennifer Smith
- Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Miriam R Kissack
- Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United Kingdom
| | - Karen G Hogg
- Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United Kingdom
| | - E Allison Green
- Centre for Immunology and Infection, Department of Biology, Hull York Medical School, University of York, York, United Kingdom.,Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
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Kaminitz A, Ash S, Askenasy N. Neutralization Versus Reinforcement of Proinflammatory Cytokines to Arrest Autoimmunity in Type 1 Diabetes. Clin Rev Allergy Immunol 2018; 52:460-472. [PMID: 27677500 DOI: 10.1007/s12016-016-8587-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
As physiological pathways of intercellular communication produced by all cells, cytokines are involved in the pathogenesis of inflammatory insulitis as well as pivotal mediators of immune homeostasis. Proinflammatory cytokines including interleukins, interferons, transforming growth factor-β, tumor necrosis factor-α, and nitric oxide promote destructive insulitis in type 1 diabetes through amplification of the autoimmune reaction, direct toxicity to β-cells, and sensitization of islets to apoptosis. The concept that neutralization of cytokines may be of therapeutic benefit has been tested in few clinical studies, which fell short of inducing sustained remission or achieving disease arrest. Therapeutic failure is explained by the redundant activities of individual cytokines and their combinations, which are rather dispensable in the process of destructive insulitis because other cytolytic pathways efficiently compensate their deficiency. Proinflammatory cytokines are less redundant in regulation of the inflammatory reaction, displaying protective effects through restriction of effector cell activity, reinforcement of suppressor cell function, and participation in islet recovery from injury. Our analysis suggests that the role of cytokines in immune homeostasis overrides their contribution to β-cell death and may be used as potent immunomodulatory agents for therapeutic purposes rather than neutralized.
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Affiliation(s)
- Ayelet Kaminitz
- The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202
| | - Shifra Ash
- The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202
| | - Nadir Askenasy
- The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202.
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Andreone L, Gimeno ML, Perone MJ. Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes. Front Endocrinol (Lausanne) 2018; 9:229. [PMID: 29867762 PMCID: PMC5966545 DOI: 10.3389/fendo.2018.00229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Accepted: 04/20/2018] [Indexed: 12/16/2022] Open
Abstract
It is well established that there is a fine-tuned bidirectional communication between the immune and neuroendocrine tissues in maintaining homeostasis. Several types of immune cells, hormones, and neurotransmitters of different chemical nature are involved as communicators between organs. Apart of being key players of the adaptive arm of the immune system, it has been recently described that T lymphocytes are involved in the modulation of metabolism of several tissues in health and disease. Diabetes may result mainly from lack of insulin production (type 1 diabetes) or insufficient insulin and insulin resistance (type 2 diabetes), both influenced by genetic and environmental components. Herein, we discuss accumulating data regarding the role of the adaptive arm of the immune system in the pathogenesis of diabetes; including the action of several hormones and neurotransmitters influencing on central and peripheral T lymphocytes development and maturation, particularly under the metabolic burden triggered by diabetes. In addition, we comment on the role of T-effector lymphocytes in adipose and liver tissues during diabetes, which together enhances pancreatic β-cell stress aggravating the disease.
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Clark M, Kroger CJ, Tisch RM. Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response. Front Immunol 2017; 8:1898. [PMID: 29312356 PMCID: PMC5743904 DOI: 10.3389/fimmu.2017.01898] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/12/2017] [Indexed: 12/16/2022] Open
Abstract
Inflammation is typically induced in response to a microbial infection. The release of proinflammatory cytokines enhances the stimulatory capacity of antigen-presenting cells, as well as recruits adaptive and innate immune effectors to the site of infection. Once the microbe is cleared, inflammation is resolved by various mechanisms to avoid unnecessary tissue damage. Autoimmunity arises when aberrant immune responses target self-tissues causing inflammation. In type 1 diabetes (T1D), T cells attack the insulin producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by in part altering central and peripheral tolerance inducing events. This results in the development and expansion of β cell-specific effector T cells (Teff) which mediate islet inflammation. Unlike protective immunity where inflammation is terminated, autoimmunity is sustained by chronic inflammation. In this review, we will highlight the key events which initiate and sustain T cell-driven pancreatic islet inflammation in nonobese diabetic mice and in human T1D. Specifically, we will discuss: (i) dysregulation of thymic selection events, (ii) the role of intrinsic and extrinsic factors that enhance the expansion and pathogenicity of Teff, (iii) defects which impair homeostasis and suppressor activity of FoxP3-expressing regulatory T cells, and (iv) properties of β cells which contribute to islet inflammation.
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Affiliation(s)
- Matthew Clark
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Charles J Kroger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland M Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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49
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Rydén AK, Perdue NR, Pagni PP, Gibson CB, Ratliff SS, Kirk RK, Friesen TJ, Haase C, Coppieters K, von Herrath MG, Boursalian TE. Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes. J Autoimmun 2017; 84:65-74. [DOI: 10.1016/j.jaut.2017.07.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/28/2017] [Accepted: 07/05/2017] [Indexed: 01/07/2023]
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50
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A Critical Role for IL-21 Receptor Signaling in the Coxsackievirus B3-Induced Myocarditis. Inflammation 2017; 40:1428-1435. [DOI: 10.1007/s10753-017-0586-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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