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Luo S, Zhang L, Wei C, Guo C, Meng Z, Zeng H, Hou L, Wang L, Liu Z, Du Y, Tan S, Zhang Y, Xu X, Liang L, Zhou Y. TCL1A in naïve B cells as a therapeutic target for type 1 diabetes. EBioMedicine 2025; 113:105593. [PMID: 39946833 PMCID: PMC11872515 DOI: 10.1016/j.ebiom.2025.105593] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/24/2025] [Accepted: 01/25/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by "self" immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different populations of B cells, particularly in the early stages of T1D, has not been fully elucidated. METHODS In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to investigate immune cell populations in patients with newly diagnosed T1D, their relative controls and age-matched healthy controls. Phosphoprotein microarray analysis was employed to investigate changes in protein phosphorylation in B cells. Furthermore, we developed a siRNA-based nanomedicine and evaluated its therapeutic potential in the NOD mouse. The integration of scRNA-seq, flow cytometry, phosphoprotein microarrays, and functional assays established a robust framework for understanding and targeting B cell-mediated autoimmunity in T1D. FINDINGS Using single-cell RNA sequencing, we discovered that patients with T1D exhibited increased humoural immunity in the early stage of T1D. Specifically, the population of naïve B cells increased in patients with newly diagnosed T1D who expressed elevated levels of the AKT kinase coactivator TCL1A. Using a protein phosphorylation microarray, we confirmed that TCL1A knockdown specifically impaired AKT2 phosphorylation and affected B cell survival and proliferation. Notably, we discovered that the naïve B cell population increased and TCL1A expression was upregulated in NOD mice that developed T1D. Both the levels of naïve B cells and TCL1A were strongly associated with glucose intolerance in T1D mice. Importantly, treatment with a siRNA-based nanomedicine targeting Tcl1a mRNA effectively reduced the number of naïve B cells, prevented the loss of pancreatic β cells, and improved glucose intolerance in T1D mice. INTERPRETATION Using single-cell RNA-seq, we have not only uncovered a naïve B cell specific gene that may contribute to the pathogenesis of T1D but also highlighted the potential of siRNA-based nanomedicine for treating T1D. The clinical translation of these findings offers a new approach for the treatment of T1D. FUNDING See Acknowledgements.
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Affiliation(s)
- Siweier Luo
- Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Lina Zhang
- Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Chunfang Wei
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Chipeng Guo
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Zhe Meng
- Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Honghui Zeng
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330000, China
| | - Lele Hou
- Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Le Wang
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Zulin Liu
- Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Yufei Du
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Shiyu Tan
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Yating Zhang
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
| | - Xiaoding Xu
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.
| | - Liyang Liang
- Department of Paediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.
| | - Yiming Zhou
- Basic and Translational Medical Research Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.
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Hilliard BK, Prendergast JE, Smith MJ. Dia-B-Ties: B Cells in the Islet-Immune-Cell Interface in T1D. Biomolecules 2025; 15:332. [PMID: 40149868 PMCID: PMC11940010 DOI: 10.3390/biom15030332] [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: 02/08/2025] [Revised: 02/20/2025] [Accepted: 02/22/2025] [Indexed: 03/29/2025] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that affects an estimated 30 million people worldwide and results in a lifelong dependency of exogenous insulin treatments. While T1D is characterized by T-cell driven-destruction of the insulin-secreting β cells, B lymphocytes play a key role in the islet-immune interface. B cells are an essential intermediary between islet cells and other immune-cell populations. Through antigen presentation, cytokine secretion, and antibody production, B cells play a role in activating autoreactive islet-specific T cells, thus potentiating pancreatic inflammation in the early stages of T1D. Despite this, their role in disease development remains an understudied feature of T1D with significant therapeutic potential. Herein, we will discuss the current knowledge of the islet-immune-cell interface within T1D through the lens of B lymphocytes. We will also consider knowledge gaps that may be limiting further therapeutic opportunities.
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Affiliation(s)
- Brandon K. Hilliard
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Jessica E. Prendergast
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Mia J. Smith
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
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Okamura T, Kitagawa N, Kitagawa N, Sakai K, Sumi M, Kobayashi G, Imai D, Matsui T, Hamaguchi M, Fukui M. Single-cell analysis reveals islet autoantigen's immune activation in type 1 diabetes patients. J Clin Biochem Nutr 2025; 76:64-84. [PMID: 39896168 PMCID: PMC11782777 DOI: 10.3164/jcbn.24-86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 06/24/2024] [Indexed: 02/04/2025] Open
Abstract
In this study, we used single-cell sequencing, which can comprehensively detect the type and number of transcripts per cell, to efficiently stimulate peripheral blood mononuclear cells of type 1 diabetic patients with overlapping peptides of GAD, IA-2, and insulin antigens, and performed gene expression analysis by single-cell variable-diversity-joining sequencing and T-cell receptor repertoire analysis. Twenty male patients with type 1 diabetes mellitus participating in the KAMOGAWA-DM cohort were included. Four of them were randomly selected for BD Rhapsody system after reacting peripheral blood mononuclear cells with overlapping peptides of GAD, IA-2, and insulin antigen. Peripheral blood mononuclear cells were clustered into CD8+ T cells, CD4+ T cells, granulocytes, natural killer cells, dendritic cells, monocytes, and B cells based on Seurat analysis. In the insulin group, gene expression of inflammatory cytokines was elevated in cytotoxic CD8+ T cells and Th1 and Th17 cells, and gene expression related to exhaustion was elevated in regulatory T cells. In T cell receptors of various T cells, the T cell receptor β chain was monoclonally increased in the TRBV28/TRBJ2-7 pairs. This study provides insights into the pathogenesis of type 1 diabetes and provides potential targets for the treatment of type 1 diabetes.
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Affiliation(s)
- Takuro Okamura
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Noriyuki Kitagawa
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
- Department of Diabetology, Kameoka Municipal Hospital, 1-1 Shinonoda, Shino-cho, Kameoka 621-8585, Japan
| | - Nobuko Kitagawa
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Kimiko Sakai
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Madoka Sumi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Genki Kobayashi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Dan Imai
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takaaki Matsui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokoji, Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
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Wang YN, Li R, Huang Y, Chen H, Nie H, Liu L, Zou X, Zhong J, Zheng B, Gong Q. The role of B cells in the pathogenesis of type 1 diabetes. Front Immunol 2024; 15:1450366. [PMID: 39776900 PMCID: PMC11703732 DOI: 10.3389/fimmu.2024.1450366] [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: 06/18/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Type 1 diabetes (T1D) is a metabolic disorder caused by a complete lack of insulin, primarily manifested by hyperglycemia. The mechanisms underlying the onset of T1D are complex, involving genetics, environment, and various unknown factors, leading to the infiltration of various immune components into the islets. Besides T cells, B cells are now considered important contributors to the pathogenesis of T1D, according to recent studies. In non-obese diabetic (NOD) mice, the absence of B cells prevents the development of T1D, and B-cell depletion can even restore the function of pancreatic β cells, emphasizing their involvement in the development of T1D. Naturally, besides pathogenic B cells, regulatory B cells (Bregs) might have a protective function in T1D. This article examines the mechanisms behind B-cell tolerance and the defects in B-cell tolerance checkpoints in T1D. We explored possible functions of B cells in T1D, including the role of islet autoantibodies in T1D, T-B cell interactions, and the role of Bregs in the pathogenesis of T1D. We also summarized the advances of B cell-targeted therapy, exploring new methods for intervention and treatment of T1D.
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Affiliation(s)
- Ya-nan Wang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Ruihua Li
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Yaxuan Huang
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Hui Chen
- Department of Laboratory Medicine, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Hao Nie
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Lian Liu
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Xiaoting Zou
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bing Zheng
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
- Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, Hubei, China
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5
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Liu Y, Liu X, Liu D, Zhou S, Zhang J, Hu J, Liao G, Liao J, Guo Z, Li Y, Yang S, Li S, Chen H, Guo Y, Li M, Fan L, Li L, Zhao M. Identification of immune cell infiltration pattern in diabetic nephropathy. Genes Dis 2024; 11:101197. [PMID: 39171122 PMCID: PMC11337715 DOI: 10.1016/j.gendis.2023.101197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/01/2023] [Indexed: 08/23/2024] Open
Affiliation(s)
- Yongguang Liu
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Xiaoyou Liu
- Department of Organ Transplantation, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Ding Liu
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Song Zhou
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Jie Zhang
- Department of Organ Transplantation, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Jianmin Hu
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Guorong Liao
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Jun Liao
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Zefeng Guo
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Yuzhu Li
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Siqiang Yang
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Shichao Li
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Hua Chen
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Ying Guo
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Min Li
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Lipei Fan
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Liuyang Li
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Ming Zhao
- Department of Organ Transplantation, Zhujiang Hospital of the Southern Medical University, Guangzhou, Guangdong 510280, China
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Serreze DV, Dwyer JR, Racine JJ. Advancing Animal Models of Human Type 1 Diabetes. Cold Spring Harb Perspect Med 2024; 14:a041587. [PMID: 38886067 PMCID: PMC11444302 DOI: 10.1101/cshperspect.a041587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to "humanize" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.
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Fukasawa T, Yoshizaki-Ogawa A, Enomoto A, Yamashita T, Miyagawa K, Sato S, Yoshizaki A. Single cell analysis in systemic sclerosis - A systematic review. Immunol Med 2024; 47:118-129. [PMID: 38818750 DOI: 10.1080/25785826.2024.2360690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 05/17/2024] [Indexed: 06/01/2024] Open
Abstract
In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively.
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Affiliation(s)
- Takemichi Fukasawa
- Department of Dermatology, Systemic sclerosis center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Department of Clinical Cannabinoid Research, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Asako Yoshizaki-Ogawa
- Department of Dermatology, Systemic sclerosis center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Atsushi Enomoto
- Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Takashi Yamashita
- Department of Dermatology, Systemic sclerosis center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Kiyoshi Miyagawa
- Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, Systemic sclerosis center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Ayumi Yoshizaki
- Department of Dermatology, Systemic sclerosis center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Department of Clinical Cannabinoid Research, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Yang Z, Zhang Z, Li L, Jing Z, Ma Y, Lan T, Li Y, Lin Z, Fang W, Zhang J, Zhang J, Liang X, Wu B, Zheng Y, Zhang X. Bioengineered Artificial Extracellular Vesicles Presenting PD-L1 and Gal-9 Ameliorate New-Onset Type 1 Diabetes. Diabetes 2024; 73:1325-1335. [PMID: 38771941 DOI: 10.2337/db23-0987] [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: 12/13/2023] [Accepted: 05/05/2024] [Indexed: 05/23/2024]
Abstract
An important factor in the development of type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and galectin-9 (Gal-9), in β-cells. Therefore, modulation of pancreas-infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating new-onset T1D. We genetically engineered macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict islet autoreactive T lymphocytes and protect β-cells from destruction. Intriguingly, overexpression of Gal-9 stimulated macrophage polarization to the M2 phenotype with immunosuppressive attributes. Alternatively, both PD-L1- and Gal-9-presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhered to T cells via the interaction of programmed cell death protein 1/PD-L1 or T-cell immunoglobulin mucin 3/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T-cell apoptosis and splenic regulatory T (Treg) cell formation in vitro. Notably, PD-L1-Gal-9 aEVs efficaciously reversed new-onset hyperglycemia in NOD mice, prevented T1D progression, and decreased the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas, which together contributed to the preservation of residual β-cell survival and mitigation of hyperglycemia. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Zhaoxin Yang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Zhirang Zhang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Liyan Li
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Zhangyan Jing
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Yumeng Ma
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Tianyu Lan
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Yuan Li
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Zhongda Lin
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Wenli Fang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Jinxie Zhang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Jinling Zhang
- Department of Gynaecology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, China
| | - Xin Liang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Key Laboratory of Stem Cell and Regenerative Tissue Engineering, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong, China
| | - Benqing Wu
- Center for Medical Experiments (CME), Benqing Laboratory, Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Yi Zheng
- Center for Medical Experiments (CME), Benqing Laboratory, Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Xudong Zhang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China
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9
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Fuhri Snethlage CM, de Wit D, Wortelboer K, Rampanelli E, Hanssen NMJ, Nieuwdorp M. Can fecal microbiota transplantations modulate autoimmune responses in type 1 diabetes? Immunol Rev 2024; 325:46-63. [PMID: 38752578 DOI: 10.1111/imr.13345] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin-producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high-throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota-host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota-host immunity encounters in murine models and to shape the course of human type 1 diabetes.
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Affiliation(s)
- Coco M Fuhri Snethlage
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - Douwe de Wit
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - Koen Wortelboer
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
| | - Elena Rampanelli
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity (AII), Amsterdam, The Netherlands
| | - Nordin M J Hanssen
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
- Amsterdam Diabeter Center, Amsterdam UMC, Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Center, Location AMC, Amsterdam, The Netherlands
- Amsterdam Diabeter Center, Amsterdam UMC, Amsterdam, The Netherlands
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10
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Fukasawa T, Yoshizaki-Ogawa A, Sato S, Yoshizaki A. The role of B cells in systemic sclerosis. J Dermatol 2024; 51:904-913. [PMID: 38321641 DOI: 10.1111/1346-8138.17134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 01/13/2024] [Indexed: 02/08/2024]
Abstract
Systemic sclerosis (SSc) is a rare and refractory systemic disease characterized by fibrosis and vasculopathy in the presence of autoimmune abnormalities. While the exact cause of SSc is incompletely understood, the specific autoantibodies identified in SSc are closely linked to disease severity and prognosis, indicating a significant role of autoimmune abnormalities in the pathogenesis of SSc. Although the direct pathogenic mechanisms of autoantibodies in SSc are not fully elucidated, numerous prior investigations have demonstrated the involvement of B cells in the pathogenesis of SSc through various mechanisms. Additionally, several clinical trials have explored the efficacy of B-cell depletion therapy for SSc, with many reporting positive outcomes. However, the role of B cells in SSc pathogenesis is multifaceted, as they can both promote inflammation and exert inhibitory functions. This article provides an overview of the involvement of B cells in SSc development, incorporating the latest research findings.
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Affiliation(s)
- Takemichi Fukasawa
- Department of Dermatology, Systemic Sclerosis Center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Department of Clinical Cannabinoid Research, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Asako Yoshizaki-Ogawa
- Department of Dermatology, Systemic Sclerosis Center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, Systemic Sclerosis Center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Ayumi Yoshizaki
- Department of Dermatology, Systemic Sclerosis Center, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
- Department of Clinical Cannabinoid Research, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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11
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Zhou T, Fang YL, Tian TT, Wang GX. Pathological mechanism of immune disorders in diabetic kidney disease and intervention strategies. World J Diabetes 2024; 15:1111-1121. [PMID: 38983817 PMCID: PMC11229953 DOI: 10.4239/wjd.v15.i6.1111] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/29/2024] [Accepted: 04/15/2024] [Indexed: 06/11/2024] Open
Abstract
Diabetic kidney disease is one of the most severe chronic microvascular complications of diabetes and a primary cause of end-stage renal disease. Clinical studies have shown that renal inflammation is a key factor determining kidney damage during diabetes. With the development of immunological technology, many studies have shown that diabetic nephropathy is an immune complex disease, and that most patients have immune dysfunction. However, the immune response associated with diabetic nephropathy and autoimmune kidney disease, or caused by ischemia or infection with acute renal injury, is different, and has a com-plicated pathological mechanism. In this review, we discuss the pathogenesis of diabetic nephropathy in immune disorders and the intervention mechanism, to provide guidance and advice for early intervention and treatment of diabetic nephropathy.
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Affiliation(s)
- Tong Zhou
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun 130021, Jilin Province, China
| | - Yi-Lin Fang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun 130021, Jilin Province, China
| | - Tian-Tian Tian
- School of Public Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Gui-Xia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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12
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Stock AJ, Gonzalez Paredes P, de Almeida LP, Kosanke SD, Chetlur S, Budde H, Wakenight P, Zwingman TA, Rosen AB, Allenspach EJ, Millen KJ, Buckner JH, Rawlings DJ, Gorman JA. The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner. Front Immunol 2024; 15:1349601. [PMID: 38487540 PMCID: PMC10937421 DOI: 10.3389/fimmu.2024.1349601] [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: 12/04/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.
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Affiliation(s)
- Amanda J. Stock
- Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology, Oklahoma City, OK, United States
| | - Pierina Gonzalez Paredes
- Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology, Oklahoma City, OK, United States
| | | | - Stanley D. Kosanke
- Heartland Veterinary Pathology Services, PLLC, Edmond, OK, United States
| | - Srinivaas Chetlur
- Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology, Oklahoma City, OK, United States
| | - Hannah Budde
- Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology, Oklahoma City, OK, United States
| | - Paul Wakenight
- Seattle Children’s Research Institute, Center for Integrative Brain Research, Seattle, WA, United States
| | - Theresa A. Zwingman
- Seattle Children’s Research Institute, Center for Integrative Brain Research, Seattle, WA, United States
| | - Aaron B.I. Rosen
- Seattle Children’s Research Institute, Center for Immunity and Immunotherapies, Seattle, WA, United States
| | - Eric J. Allenspach
- Seattle Children’s Research Institute, Center for Immunity and Immunotherapies, Seattle, WA, United States
- Department of Pediatrics, School of Medicine, University of Washington, Seattle, WA, United States
| | - Kathleen J. Millen
- Seattle Children’s Research Institute, Center for Integrative Brain Research, Seattle, WA, United States
- Department of Pediatrics, School of Medicine, University of Washington, Seattle, WA, United States
| | - Jane H. Buckner
- Benaroya Research Institute at Virginia Mason, Center for Translational Immunology, Seattle, WA, United States
| | - David J. Rawlings
- Seattle Children’s Research Institute, Center for Immunity and Immunotherapies, Seattle, WA, United States
- Department of Pediatrics, School of Medicine, University of Washington, Seattle, WA, United States
- Department of Immunology, School of Medicine, University of Washington, Seattle, WA, United States
| | - Jacquelyn A. Gorman
- Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology, Oklahoma City, OK, United States
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13
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Stock AJ, Gonzalez-Paredes P, Previato de Almeida L, Kosanke SD, Chetlur S, Budde H, Wakenight P, Zwingman TA, Rosen AB, Allenspach E, Millen KJ, Buckner JH, Rawlings DJ, Gorman JA. The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.20.576482. [PMID: 38328221 PMCID: PMC10849491 DOI: 10.1101/2024.01.20.576482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 ( IFIH1 ), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1 A946T ) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1 A946T risk variant, ( IFIH1 R ) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1 R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1 R compared to non-risk Ifih1 ( Ifih1 NR ) mice and a significant acceleration of diabetes onset in Ifih1 R females. Ifih1 R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1 NR , indicative of increased IFN I signaling. Ifih1 R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8 + T cells. Our results indicate that IFIH1 R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1 R in NOD mice, which will be important to consider for the development of therapeutics for T1D.
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14
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Apley KD, Griffith AS, Downes GM, Ross P, Farrell MP, Kendall P, Berkland CJ. CD22L Conjugation to Insulin Attenuates Insulin-Specific B Cell Activation. Bioconjug Chem 2023; 34:2077-2088. [PMID: 37883211 PMCID: PMC11034786 DOI: 10.1021/acs.bioconjchem.3c00391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Pancreatic islet-reactive B lymphocytes promote Type 1 diabetes (T1D) by presenting an antigen to islet-destructive T cells. Teplizumab, an anti-CD3 monoclonal, delays T1D onset in patients at risk, but additional therapies are needed to prevent the disease entirely. Therefore, bifunctional molecules were designed to selectively inhibit T1D-promoting anti-insulin B cells by conjugating a ligand for the B cell inhibitory receptor CD22 (i.e., CD22L) to insulin, which permit these molecules to concomitantly bind to anti-insulin B cell receptors (BCRs) and CD22. Two prototypes were synthesized: 2:2 insulin-CD22L conjugate on a 4-arm PEG backbone, and 1:1 insulin-CD22L direct conjugate. Transgenic mice (125TgSD) expressing anti-insulin BCRs provided cells for in vitro testing. Cells were cultured with constructs for 3 days, then assessed by flow cytometry. Duplicate wells with anti-CD40 simulated T cell help. A 2-insulin 4-arm PEG control caused robust proliferation and activation-induced CD86 upregulation. Anti-CD40 further boosted these effects. This may indicate that BCR-cross-linking occurs when antigens are tethered by the PEG backbone as soluble insulin alone has no effect. Addition of CD22L via the 2:2 insulin-CD22L conjugate restored B cell properties to that of controls without an additional beneficial effect. In contrast, the 1:1 insulin-CD22L direct conjugate significantly reduced anti-insulin B cell proliferation in the presence of anti-CD40. CD22L alone had no effect, and the constructs did not affect the WT B cells. Thus, multivalent antigen constructs tend to activate anti-insulin B cells, while monomeric antigen-CD22L conjugates reduce B cell activation in response to simulated T cell help and reduce pathogenic B cell numbers without harming normal cells. Therefore, monomeric antigen-CD22L conjugates warrant futher study and may be promising candidates for preclinical trials to prevent T1D without inducing immunodeficiency.
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Affiliation(s)
- Kyle D Apley
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
| | - Amber S Griffith
- Department of Medicine, Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, United States
| | - Grant M Downes
- Bioengineering Graduate Program, University of Kansas, Lawrence, Kansas 66045, United States
| | - Patrick Ross
- Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
| | - Mark P Farrell
- Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
| | - Peggy Kendall
- Department of Medicine, Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, United States
| | - Cory J Berkland
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, United States
- Bioengineering Graduate Program, University of Kansas, Lawrence, Kansas 66045, United States
- Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas 66045, United States
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri 63130, United States
- Department of Chemistry, Washington University, St. Louis, Missouri 63130, United States
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15
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Kabakchieva P, Assyov Y, Gerasoudis S, Vasilev G, Peshevska-Sekulovska M, Sekulovski M, Lazova S, Miteva DG, Gulinac M, Tomov L, Velikova T. Islet transplantation-immunological challenges and current perspectives. World J Transplant 2023; 13:107-121. [PMID: 37388389 PMCID: PMC10303418 DOI: 10.5500/wjt.v13.i4.107] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/16/2023] [Accepted: 06/06/2023] [Indexed: 06/16/2023] Open
Abstract
Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.
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Affiliation(s)
- Plamena Kabakchieva
- Clinic of Internal Diseases, Naval Hospital-Varna, Military Medical Academy, Varna 9010, Bulgaria
| | - Yavor Assyov
- Clinic of Endocrinology, Department of Internal Diseases, University Hospital "Alexandrovska", Medical University-Sofia, Sofia 1434, Bulgaria
| | | | - Georgi Vasilev
- Department of Neurology, Faculty of Medicine, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
| | - Monika Peshevska-Sekulovska
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Anesthesiology and Intensive Care, University hospital Lozenetz, Sofia 1407, Bulgaria
| | - Snezhina Lazova
- Department of Pediatric, University Hospital "N. I. Pirogov", Sofia 1606, Bulgaria
- Department of Healthcare, Faculty of Public Health "Prof. Tsekomir Vodenicharov, MD, DSc", Medical University of Sofia, Sofia 1527, Bulgaria
| | | | - Milena Gulinac
- Department of General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
| | - Latchezar Tomov
- Department of Informatics, New Bulgarian University, Sofia 1618, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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16
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McNitt DH, Joosse BA, Thomas JW, Bonami RH. Productive Germinal Center Responses Depend on the Nature of Stimuli Received by Anti-Insulin B Cells in Type 1 Diabetes-Prone Mice. Immunohorizons 2023; 7:384-397. [PMID: 37261716 PMCID: PMC10448785 DOI: 10.4049/immunohorizons.2300036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 05/09/2023] [Indexed: 06/02/2023] Open
Abstract
Islet autoantibodies, including those directed at insulin, predict type 1 diabetes (T1D) in mice and humans and signal immune tolerance breach by B lymphocytes. High-affinity insulin autoantibodies and T follicular helper cell involvement implicate germinal centers (GCs) in T1D. The VH125SD BCR transgenic model, in which 1-2% of peripheral B lymphocytes recognize insulin, enables direct study of insulin-binding B cells. Our prior studies showed that anti-insulin B cell receptor transgene site-directed to H chain locus mice fail to generate insulin Ab following T-dependent immunization, but it was unclear whether anti-insulin B cells were blocked for GC initiation, survival, or differentiation into Ab-secreting cells. Here, we show that insulin-binding B cells in T1D-prone anti-insulin B cell receptor transgene site-directed to H chain locus mice can spontaneously adopt a GC phenotype and undergo class switching to the IgG1 isotype, with little if any switching to IgG2b. T-dependent immunizations with insulin SRBC or insulin CFA drove anti-insulin B lymphocytes to adopt a GC phenotype, despite blunted insulin Ab production. Dual immunization against self (insulin) and foreign (4-hydroxy-3-nitrophenylacetyl hapten conjugated to keyhole limpet hemocyanin) Ags showed an anti-insulin (but not anti-4-hydroxy-3-nitrophenylacetyl) Ab block that tracked with increased expression of the apoptosis marker, activated caspase 3, in self-reactive GC B cells. Finally, T-independent immunization with insulin conjugated to Brucella abortus ring test Ag released immune tolerance to allow robust expansion of anti-insulin GC B cells and IgG-switched insulin Ab production. Overall, these data pinpoint GC survival and Ab-secreting cell differentiation as immune tolerance blocks that limit T-dependent, but not T-independent, stimulation of anti-insulin B cell responses.
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Affiliation(s)
- Dudley H. McNitt
- Division of Rheumatology and Immunology, Department of
Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Bryan A. Joosse
- Division of Rheumatology and Immunology, Department of
Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - James W. Thomas
- Division of Rheumatology and Immunology, Department of
Medicine, Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and
Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Rachel H. Bonami
- Division of Rheumatology and Immunology, Department of
Medicine, Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and
Immunology, Vanderbilt University Medical Center, Nashville, TN
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17
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Güneş S, Wu J, Özyılmaz B, Deveci Sevim R, Ünüvar T, Anık A. Cooccurring Type 1 Diabetes Mellitus and Autoimmune Thyroiditis in a Girl with Craniofrontonasal Syndrome: Are EFNB1 Variants Associated with Autoimmunity? Pharmaceuticals (Basel) 2022; 15:ph15121535. [PMID: 36558986 PMCID: PMC9784758 DOI: 10.3390/ph15121535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Craniofrontonasal syndrome (CFNS), also known as craniofrontonasal dysplasia, is an X-linked inherited developmental malformation caused by mutations in the ephrin B1 (EFNB1) gene. The main phenotypic features of the syndrome are coronal synostosis, hypertelorism, bifid nasal tip, dry and curly hair, and longitudinal splitting of nails. A 9-year-and-11-month-old girl with CFNS was admitted due to polyuria, polydipsia, fatigue, and abdominal pain. On physical examination, she had the classical phenotypical features of CFNS. Genetic tests revealed a c.429_430insT (p.Gly144TrpfsTer31) heterozygote variant in the EFNB1 coding region. The patient was diagnosed with type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis based on laboratory findings and symptoms. The mother of the patient, who had the same CFNS phenotype and EFNB1 variant, was screened for autoimmune diseases and was also with autoimmune thyroiditis. This is the first report describing the association of CFNS with T1DM and autoimmune thyroiditis in patients with EFNB1 mutation.
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Affiliation(s)
- Sebla Güneş
- Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Aydın Adnan Menderes University, 09100 Aydın, Turkey
| | - Jiangping Wu
- Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QU H2X 0A9, Canada
| | - Berk Özyılmaz
- Genetic Diagnosis Center, Tepecik Training and Research Hospital, University of Health Sciences, 35020 Izmir, Turkey
| | - Reyhan Deveci Sevim
- Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Aydın Adnan Menderes University, 09100 Aydın, Turkey
| | - Tolga Ünüvar
- Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Aydın Adnan Menderes University, 09100 Aydın, Turkey
| | - Ahmet Anık
- Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Aydın Adnan Menderes University, 09100 Aydın, Turkey
- Correspondence: ; Tel.: +90-5325684340
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18
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Kovoor E, Chauhan SK, Hajrasouliha A. Role of inflammatory cells in pathophysiology and management of diabetic retinopathy. Surv Ophthalmol 2022; 67:1563-1573. [PMID: 35914582 PMCID: PMC11082823 DOI: 10.1016/j.survophthal.2022.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 07/18/2022] [Accepted: 07/25/2022] [Indexed: 02/05/2023]
Abstract
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes mellitus. Several inflammatory cells and proteins, including macrophages and microglia, cytokines, and vascular endothelial growth factors, are found to play a significant role in the development and progression of DR. Inflammatory cells play a significant role in the earliest changes seen in DR including the breakdown of the blood retinal barrier leading to leakage of blood into the retina. They also have an important role in the pathogenesis of more advanced stage of proliferative diabetic retinopathy, leading to neovascularization, vitreous hemorrhage, and tractional retinal detachment. In this review, we examine the function of numerous inflammatory cells involved in the pathogenesis, progression, and role as a potential therapeutic target in DR. Additionally, we explore the role of inflammation following treatment of DR.
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Affiliation(s)
- Elias Kovoor
- Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Sunil K Chauhan
- Schepens Eye Institute, Harvard Medical School, Boston, MA, USA
| | - Amir Hajrasouliha
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
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19
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Renman E, Ekici R, Sundström M, Lejon K. HSC70 is a novel binding partner involved in the capture of immunoglobulins on B cells in the NOD mouse. Autoimmunity 2022; 55:520-528. [PMID: 36120986 DOI: 10.1080/08916934.2022.2117307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
B cells have been shown to be essential for Type 1 diabetes development in the non-obese diabetic mouse, where their contribution as antigen presenting cells has been emphasised. Other important functions for B cells include surface capture of immunoglobulins and transportation of immune complexes, with subsequent endocytosis, antigen processing and antigen presentation. We have previously demonstrated that NOD B cells capture IgM and IgG immune complexes through an unknown surface molecule. In this study, we revealed the presumptive immunoglobulin-binding molecule to be HSC70. Moreover, we detected increased levels of HSC70 on NOD B cells. HSC70 has been shown to play a role in antigen processing and presentation as well as being important in several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. Due to its protein stabilising properties, increased HSC70 could contribute to enhanced self-antigen collection and presentation and thereby contribute to the development of Type 1 diabetes.
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Affiliation(s)
- Emma Renman
- Department of Clinical Microbiology Umeå, Umeå University, Umeå, Sweden
| | - Rifat Ekici
- Department of Clinical Microbiology Umeå, Umeå University, Umeå, Sweden
| | - Mia Sundström
- Department of Clinical Microbiology Umeå, Umeå University, Umeå, Sweden
| | - Kristina Lejon
- Department of Clinical Microbiology Umeå, Umeå University, Umeå, Sweden
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Scherm MG, Wyatt RC, Serr I, Anz D, Richardson SJ, Daniel C. Beta cell and immune cell interactions in autoimmune type 1 diabetes: How they meet and talk to each other. Mol Metab 2022; 64:101565. [PMID: 35944899 PMCID: PMC9418549 DOI: 10.1016/j.molmet.2022.101565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/08/2022] [Accepted: 07/27/2022] [Indexed: 10/31/2022] Open
Abstract
Background Scope of review Major conclusions
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Yoshizaki A, Fukasawa T, Ebata S, Yoshizaki-Ogawa A, Sato S. Involvement of B cells in the development of systemic sclerosis. Front Immunol 2022; 13:938785. [PMID: 35967355 PMCID: PMC9365989 DOI: 10.3389/fimmu.2022.938785] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
Systemic sclerosis (SSc) is a rare intractable systemic disease that causes fibrosis and vasculopathy against a background of autoimmune abnormalities. Although the etiology is not yet fully understood, the type of autoantibodies detected in SSc is closely associated with disease severity and prognosis, supporting that those autoimmune abnormalities play an important role in the pathogenesis of SSc. Although the direct pathogenicity of autoantibodies found in SSc is unknown, many previous studies have shown that B cells are involved in the development of SSc through a variety of functions. Furthermore, a number of clinical studies have been conducted in which B-cell depletion therapy has been tried for SSc, and many of these studies have found B-cell depletion therapy to be effective for SSc. However, the involvement of B cells in pathogenesis is complex, as they not only promote inflammation but also play an inhibitory role. This article outlines the role of B cells in the development of SSc, including the latest research.
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22
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Chen M, Zhang Q, Wei Y, Wan Q, Xu M, Chen X. Anti-CD20 therapy ameliorates β cell function and rebalances Th17/Treg cells in NOD mice. Endocrine 2022; 76:44-52. [PMID: 35067899 DOI: 10.1007/s12020-021-02965-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 12/12/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Anti-CD20 therapy delays type 1 diabetes mellitus (T1DM) progression in both nonobese diabetic (NOD) mice and new-onset patients. The mechanism is not completely defined. This study aimed to investigate the effects of anti-CD20 therapy on T helper 17 (Th17) cells and regulatory T cells (Tregs) in NOD mice. The role of B cell depletion in T1DM development was also examined. METHODS NOD mice were randomly divided into two groups. The mice in the experimental group were treated with an anti-CD20 antibody, while the control mice were treated with an isotype-matched control antibody. After treatment, islet morphology and inflammation, Th17 and Treg cell frequencies in the pancreas and spleen, serum cytokine and anti-glutamic acid decarboxylase (GAD) antibody levels, interleukin (IL)-17A levels in the pancreas and spleen, insulin expression in islet cells and islet β cell function were measured. RESULTS Decreased blood glucose and increased insulin secretion were found in the exprimental group compared with the CON group. A lower islet inflammation score was also found in the experimental group. Decreased Th17 cell and IL-17A levels and augmented Treg cell levels were found in the spleen and pancreas after anti-CD20 treatment. The serum levels of B cell activating factor (BAFF), IL-17A, IL-17F, IL-23 and anti-GAD autoantibodies were decreased in the experimental group, while higher serum levels of IL-10 and transforming growth factor (TGF)-β were found. CONCLUSION Anti-CD20 therapy might have some beneficial effects that improve β cell function by relieving islet inflammation through regulation of Th17/Treg cells and the proinflammatory/anti-inflammatory balance.
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Affiliation(s)
- Min Chen
- Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, China
| | - Qianhui Zhang
- Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, China
| | - Yanhong Wei
- Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, China
| | - Qianqian Wan
- Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, China
| | - Min Xu
- Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, China
| | - Xiaoqi Chen
- Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuhan, China.
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23
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Jiang R, Qin Y, Wang Y, Xu X, Chen H, Xu K, Zhang M. Dynamic Number and Function of IL-10-Producing Regulatory B Cells in the Immune Microenvironment at Distinct Stages of Type 1 Diabetes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1034-1041. [PMID: 35140133 DOI: 10.4049/jimmunol.2100357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 12/17/2021] [Indexed: 01/12/2023]
Abstract
The critical role of IL-10-producing B cells (B10 cells) with a unique CD1dhiCD5+ phenotype in suppressing autoimmune responses and relieving inflammation has been demonstrated in several models of autoimmune diseases. However, the regulatory role of B10 cells in T cell-mediated autoimmune responses during the natural history of type 1 diabetes is unclear. In this study, we used the NOD mouse model of autoimmune diabetes to clarify the changes and potential mechanisms of B10 cells for disease. Compared with B10 cells present in the 4-wk-old normoglycemic NOD mice, the frequency of B10 cells was increased in the insulitis and diabetic NOD mice, with the highest proportion in the insulitis NOD mice. The changes in the relative number of B10 cells were most pronounced in the pancreas-draining lymph nodes. The pathogenic T cells, including Th1 and Th17 cells, remarkably increased. The assays in vitro showed that B10 cells in the NOD mice did not inhibit the proliferation of CD4+CD25- T cells. They also had no regulatory effect on IFN-γ and IL-4 secretion or on Foxp3 expression of T cells. B10 cells suppressed T cell-mediated autoimmune responses via an IL-10-dependent pathway. In contrast, B10 cells in the NOD mice exhibited a significant reduction in IL-10 production. In summary, a defect in the number and function of B10 cells may participate in the development and progression of type 1 diabetes.
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Affiliation(s)
- Ruimei Jiang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Endocrinology, Fuyang People's Hospital, Fuyang, China; and
| | - Yao Qin
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yueshu Wang
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinyu Xu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Heng Chen
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kuanfeng Xu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mei Zhang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China;
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Khosravi-Maharlooei M, Madley R, Borsotti C, Ferreira LMR, Sharp RC, Brehm MA, Greiner DL, Parent AV, Anderson MS, Sykes M, Creusot RJ. Modeling human T1D-associated autoimmune processes. Mol Metab 2022; 56:101417. [PMID: 34902607 PMCID: PMC8739876 DOI: 10.1016/j.molmet.2021.101417] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/19/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. SCOPE OF REVIEW Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. MAJOR CONCLUSIONS To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.
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Affiliation(s)
- Mohsen Khosravi-Maharlooei
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Rachel Madley
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Chiara Borsotti
- Department of Health Sciences, Histology laboratory, Università del Piemonte Orientale, Novara, Italy
| | - Leonardo M R Ferreira
- Departments of Microbiology & Immunology, and Regenerative Medicine & Cell Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Robert C Sharp
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Michael A Brehm
- Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Dale L Greiner
- Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Audrey V Parent
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | - Mark S Anderson
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Remi J Creusot
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
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25
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Sudhir PR, Lin TD, Zhang Q. HLA Allele-Specific Quantitative Profiling of Type 1 Diabetic B Lymphocyte Immunopeptidome. J Proteome Res 2022; 21:250-264. [PMID: 34932366 PMCID: PMC8742597 DOI: 10.1021/acs.jproteome.1c00842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Peptide ligands presented by human leukocyte antigen (HLA) molecules on the cell surface represent the immunopeptidome that could be utilized for identification of antigenic peptides for immunotherapy and prevention of autoimmune diseases. Although T-cells are well-known key players in the destruction of pancreatic beta-cells in type 1 diabetes (T1D), increasing evidence points toward a role for B-cells in disease pathogenesis. However, as antigen presenting cells, little is known about the comprehensive immunopeptidome of B cells and their changes in the context of T1D. We performed HLA allele-specific quantitative immunopeptidomics using B lymphocytes derived from T1D patients and healthy controls. Hundreds of HLA-I and HLA-II immunopeptides were identified as differentially regulated in T1D per HLA allele for B cells sharing identical HLA alleles. The results were further validated using additional T1D and healthy B cells with partially overlapped HLA alleles. Differentially expressed immunopeptides were confirmed with targeted proteomics and for reactivity using known T-cell assays in the immune epitope database. Considering samples with identical HLA alleles are difficult to obtain for T1D and other similar HLA-restricted diseases, our work represents a viable approach to better understand HLA allele-specific antigen presentation and may facilitate identification of immunopeptides for therapeutic applications in autoimmune diseases. Data are available via ProteomeXchange with identifier PXD026184.
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Affiliation(s)
- Putty-Reddy Sudhir
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, 28081, USA
| | - Tai-Du Lin
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, 28081, USA
| | - Qibin Zhang
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, 28081, USA,Department of Chemistry & Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27412, USA,Corresponding author: Qibin Zhang ()
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26
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Bazyar S, O’Brien ET, Benefield T, Roberts VR, Kumar RJ, Gupta GP, Zhou O, Lee YZ. Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator. Cancers (Basel) 2021; 14:155. [PMID: 35008319 PMCID: PMC8750301 DOI: 10.3390/cancers14010155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/15/2021] [Accepted: 12/23/2021] [Indexed: 12/30/2022] Open
Abstract
Spatially fractionated radiotherapy has been shown to have effects on the immune system that differ from conventional radiotherapy (CRT). We compared several aspects of the immune response to CRT relative to a model of spatially fractionated radiotherapy (RT), termed microplanar radiotherapy (MRT). MRT delivers hundreds of grays of radiation in submillimeter beams (peak), separated by non-radiated volumes (valley). We have developed a preclinical method to apply MRT by a commercial small animal irradiator. Using a B16-F10 murine melanoma model, we first evaluated the in vitro and in vivo effect of MRT, which demonstrated significant treatment superiority relative to CRT. Interestingly, we observed insignificant treatment responses when MRT was applied to Rag-/- and CD8-depleted mice. An immuno-histological analysis showed that MRT recruited cytotoxic lymphocytes (CD8), while suppressing the number of regulatory T cells (Tregs). Using RT-qPCR, we observed that, compared to CRT, MRT, up to the dose that we applied, significantly increased and did not saturate CXCL9 expression, a cytokine that plays a crucial role in the attraction of activated T cells. Finally, MRT combined with anti-CTLA-4 ablated the tumor in half of the cases, and induced prolonged systemic antitumor immunity.
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Affiliation(s)
- Soha Bazyar
- Department of Radiation Oncology, University of Maryland, Maryland, MD 21201, USA;
| | - Edward Timothy O’Brien
- Department of Physics and Astronomy, The University of North Carolina, Chapel Hill, NC 27514, USA;
| | - Thad Benefield
- Department of Radiology, The University of North Carolina, Chapel Hill, NC 27514, USA;
| | | | - Rashmi J. Kumar
- Medical Scientist Training Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA;
| | - Gaorav P. Gupta
- Department of Radiation Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA;
| | - Otto Zhou
- Department of Applied Physics Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA;
| | - Yueh Z. Lee
- Department of Radiology, The University of North Carolina, Chapel Hill, NC 27514, USA;
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
- Biomedical Research Imaging Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Zou X, Wang S, Zhang Y, Wang X, Zhang R, Yang W, Li Y. AIRE-overexpressing BMDCs suppress T FH cells through ICOSL to prevent and attenuate autoimmune diabetes in NOD mice. Int Immunopharmacol 2021; 99:107979. [PMID: 34293711 DOI: 10.1016/j.intimp.2021.107979] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
The strong genetic association between autoimmune regulator (AIRE) and autoimmune diseases indicates its critical role in immune tolerance. AIRE deficiency is thought to promote the development of follicular helper T (TFH) cells, which are considered to be essential in B cell proliferation. Excessive TFH cell generation is a key step towards the development of autoimmune diseases, including type 1 diabetes. However, the potential mechanism by which AIRE contributes to the generation and function of the TFH cell population has remained elusive. We show that AIRE reduced TFH cell generation by inhibiting the expression of inducible costimulatory ligand (ICOSL), interleukin (IL)-6 and IL-27 in dendritic cells (DCs). To understand the precise impact of AIRE-overexpressing bone marrow-derived DCs (AIRE-BMDCs) on type 1 diabetes progression and the associated molecular mechanisms, we transferred AIRE-BMDCs to recipient NOD mice and found that transplantation of AIRE-BMDCs can prevent or delay the onset of diabetes, attenuate diabetes after the establishment of overt hyperglycaemia, and lead to the inhibition of autoreactive pathological TFH cells and germinal centre (GC) B cells. To further determine the potential mechanism underlying this TFH cell depletion, BMDCs were cotransferred with recombinant mouse ICOSL (ICOSLG protein). We demonstrated that NOD mice were more susceptible to diabetes when they received AIRE-BMDCs and ICOSLG than when they received only mock-vehicle BMDCs (GFP-BMDCs). In addition, we did not observe the reversal of diabetes in any mice subjected to this cotransfer system. A single cycle of ICOSLG treatment temporarily promoted TFH cell proliferation and GC development. Our results reveal a mechanistic role of AIRE-BMDCs in the initiation of TFH cell differentiation, and the AIRE-mediated decrease in ICOSL expression in BMDCs plays a critical role. The effect of decreased ICOSL expression in type 1 diabetes will guide the design and evaluation of parallel studies in patients.
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Affiliation(s)
- Xueyang Zou
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Shuang Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yi Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Xiaoya Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Rongchao Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yi Li
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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Zhu X, Bian F, Zhao Y, Qin Y, Sun X, Zhou L. Combined therapy of adenovirus vector mediated IGF-1 gene with anti-CD20 mAbs exerts potential beneficial role on type 1 diabetes in nonobese diabetic mice. Life Sci 2021:119853. [PMID: 34331973 DOI: 10.1016/j.lfs.2021.119853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/13/2021] [Accepted: 07/19/2021] [Indexed: 11/27/2022]
Abstract
AIMS To assess the protective effects of combined treatment with anti-CD20 monoclonal antibody (mAb) and adenovirus mediated mouse insulin-like growth factor 1 (Adv-mIGF-1) gene on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice at early stage. METHODS To simultaneously restore the proportion of Th cells and block the interaction of B cells, NOD model mice were assigned to four groups which received PBS, Adv-mIGF-1 gene and anti-CD20 mAbs alone or combination, respectively. After 16 weeks of therapeutic intervention, blood samples and pancreatic tissues of mice were measured via the methods of ELISA, RT-PCR, western blotting, H&E staining, TUNEL and immunohistochemistry assays. KEY FINDINGS Chronic combination intervention with Adv-mIGF-1 gene and anti-CD20 mAbs reduced the T1D-related morbidity, promoted the secretion of insulin, controlled the blood glucose levels (BGLs) and alleviated insulitis of experimental mice. In addition, current combination intervention also protected the pancreatic β cells via suppressing the expression of Fas and TNF-α, inhibiting Caspase-3/8 related apoptotic pathway, and activating the Bcl-2-related antiapoptotic pathway. Furthermore, current combination therapy also increased the expression levels of PDX-1 and CK-19 genes, and finally accelerated the proliferation and differentiation of pancreatic β-cells. In addition, combination therapy could also ameliorate the pathological characteristics of diabetic nephropathy in NOD mice. CONCLUSION Combination treatment with Adv-mIGF-1 gene and anti-CD20 mAbs may exert a potential beneficial role on T1D in NOD mice.
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Affiliation(s)
- Xiaoxiao Zhu
- Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, Guangdong Province, PR China
| | - Fei Bian
- Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, Guangdong Province, PR China
| | - Yuchen Zhao
- Department of Mathematics, University of California, Los Angeles, Los Angeles 90095, CA, USA
| | - Yanyan Qin
- Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, Guangdong Province, PR China
| | - Xiang Sun
- Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, Guangdong Province, PR China
| | - Lanlan Zhou
- Department of Medical College, Shenzhen Polytechnic, Shenzhen 518055, Guangdong Province, PR China.
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Targeting immunosuppressor cells with nanoparticles in autoimmunity: How far have we come to? Cell Immunol 2021; 368:104412. [PMID: 34340162 DOI: 10.1016/j.cellimm.2021.104412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/24/2022]
Abstract
Autoimmunity is the assault of immune response towards self-antigens, resulting to inflammation and tissue injury. It is staged into three phases and caused by malfunction of immune tolerance. In our body, immune tolerance is synchronized by several immunosuppressor cells such as regulatory T cells and B cells as well as myeloid-derived suppressor cells, which are prominently dysregulated in autoimmunity. Hence, targeting these cell populations serve as a significant potential in the therapy of autoimmunity. Nanotechnology with its advantageous properties is shown to be a remarkable tool as drug delivery system in this field. This review focused on the development of therapeutics in autoimmune diseases utilizing various nanoparticles formulation based on two targeting approaches in autoimmunity, passive and active targeting. Lastly, this review outlined the approved present nanomedicines as well as in clinical evaluations and issues regarding the lack of translation of these nanomedicines into the market, despite the abundant of positive experimental observations.
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30
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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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31
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Battaglia M, Buckner JH, Levings MK, Richardson SJ, Wong FS, Tree TI. Identifying the 'Achilles heel' of type 1 diabetes. Clin Exp Immunol 2021; 204:167-178. [PMID: 33368173 DOI: 10.1111/cei.13570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/22/2022] Open
Abstract
When Thetis dipped her son Achilles into the River Styx to make him immortal, she held him by the heel, which was not submerged, and thus created a weak spot that proved deadly for Achilles. Millennia later, Achilles heel is part of today's lexicon meaning an area of weakness or a vulnerable spot that causes failure. Also implied is that an Achilles heel is often missed, forgotten or under-appreciated until it is under attack, and then failure is fatal. Paris killed Achilles with an arrow 'guided by the Gods'. Understanding the pathogenesis of type 1 diabetes (T1D) in order to direct therapy for prevention and treatment is a major goal of research into T1D. At the International Congress of the Immunology of Diabetes Society, 2018, five leading experts were asked to present the case for a particular cell/element that could represent 'the Achilles heel of T1D'. These included neutrophils, B cells, CD8+ T cells, regulatory CD4+ T cells, and enteroviruses, all of which have been proposed to play an important role in the pathogenesis of type 1 diabetes. Did a single entity emerge as 'the' Achilles heel of T1D? The arguments are summarized here, to make this case.
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Affiliation(s)
- M Battaglia
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, Italy
| | - J H Buckner
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - M K Levings
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - S J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - F S Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - T I Tree
- Department of Immunobiology, School of Immunology and Microbial Sciences (SIMS), King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
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32
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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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Leadbetter EA, Karlsson MCI. Invariant natural killer T cells balance B cell immunity. Immunol Rev 2021; 299:93-107. [PMID: 33438287 DOI: 10.1111/imr.12938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/21/2020] [Accepted: 12/04/2020] [Indexed: 12/21/2022]
Abstract
Invariant natural killer T (iNKT) cells mediate rapid immune responses which bridge the gap between innate and adaptive responses to pathogens while also providing key regulation to maintain immune homeostasis. Both types of important iNKT immune responses are mediated through interactions with innate and adaptive B cells. As such, iNKT cells sit at the decision-making fulcrum between regulating inflammatory or autoreactive B cells and supporting protective or regulatory B cell populations. iNKT cells interpret the signals in their environment to set the tone for subsequent adaptive responses, with outcomes ranging from getting licensed to maintain homeostasis as an iNKT regulatory cell (iNKTreg ) or being activated to become an iNKT follicular helper (iNKTFH ) cell supporting pathogen-specific effector B cells. Here we review iNKT and B cell cooperation across the spectrum of immune outcomes, including during allergy and autoimmune disease, tumor surveillance and immunotherapy, or pathogen defense and vaccine responses. Because of their key role as influencers, iNKT cells provide a valuable target for therapeutic interventions. Understanding the nature of the interactions between iNKT and B cells will enable the development of clinical interventions to strategically target regulatory iNKT and B cell populations or inflammatory ones, depending on the circumstance.
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Affiliation(s)
- Elizabeth A Leadbetter
- Department of Microbiology, Immunology and Molecular Genetics, UT Health San Antonio, San Antonio, TX, USA
| | - Mikael C I Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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Hu W, Song X, Yu H, Sun J, Wang H, Zhao Y. Clinical Translational Potentials of Stem Cell-Derived Extracellular Vesicles in Type 1 Diabetes. Front Endocrinol (Lausanne) 2021; 12:682145. [PMID: 35095751 PMCID: PMC8789747 DOI: 10.3389/fendo.2021.682145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 12/06/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes (T1D) is an organ-specific disease characterized by the deficiency of insulin caused by the autoimmune destruction of pancreatic islet β cells. Stem cell-based therapies play essential roles in immunomodulation and tissue regeneration, both of which hold great promise for treating many autoimmune dysfunctions. However, their clinical translational potential has been limited by ethical issues and cell transplant rejections. Exosomes are small extracellular vesicles (EVs) released by almost all types of cells, performing a variety of cell functions through the delivery of their molecular contents such as proteins, DNAs, and RNAs. Increasing evidence suggests that stem cell-derived EVs exhibit similar functions as their parent cells, which may represent novel therapeutic agents for the treatment of autoimmune diseases including T1D. In this review, we summarize the current research progresses of stem cell-derived EVs for the treatment of T1D.
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Affiliation(s)
- Wei Hu
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Xiang Song
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Haibo Yu
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Jingyu Sun
- Department of Chemistry and Chemistry Biology, Stevens Institute of Technology, Hoboken, NJ, United States
| | - Hongjun Wang
- Department of Chemistry and Chemistry Biology, Stevens Institute of Technology, Hoboken, NJ, United States
| | - Yong Zhao
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
- Throne Biotechnologies Inc., Paramus, NJ, United States
- *Correspondence: Yong Zhao,
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Xiao Y, Deng C, Zhou Z. The Multiple Roles of B Lymphocytes in the Onset and Treatment of Type 1 Diabetes: Interactions between B Lymphocytes and T Cells. J Diabetes Res 2021; 2021:6581213. [PMID: 34778464 PMCID: PMC8580688 DOI: 10.1155/2021/6581213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 10/21/2021] [Indexed: 01/10/2023] Open
Abstract
Although type 1 diabetes is thought to be an organ-specific autoimmune disease, mediated by effective CD4+ and CD8+ T cells, it has recently become clear that B cells participate in the initiation and progress of this disease. Indeed, B cell deletion can prevent or reverse autoimmune diabetes in nonobese diabetic mice and even result in partially remaining β cell function in patients with new-onset type 1 diabetes. This review summarizes the dual role of B cells in this process not only of pathogenic effect but also of immunoregulatory function in type 1 diabetes. We focus on the impact that B cells have on regulating the activation, proliferation, and cytokine production of self-reactive T cells along with regulatory T cells, with the aim of providing a better understanding of the interactions between T and B cells in immunopathogenesis and improving the efficacy of interventions for clinical practice.
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Affiliation(s)
- Yangfan Xiao
- Clinical Nursing Teaching and Research Section, Department of Anesthesiology, and Anesthesia Medical Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Chao Deng
- National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, and Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, and Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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Abstract
PURPOSE OF REVIEW Although type 1 diabetes (T1D) is characterized by destruction of the pancreatic beta cells by self-reactive T cells, it has become increasingly evident that B cells also play a major role in disease development, likely functioning as antigen-presenting cells. Here we review the biology of islet antigen-reactive B cells and their participation in autoimmune diabetes. RECENT FINDINGS Relative to late onset, individuals who develop T1D at an early age display increased accumulation of insulin-reactive B cells in islets. This B-cell signature is also associated with rapid progression of disease and responsiveness to B-cell depletion therapy. Also suggestive of B-cell participation in disease is loss of anergy in high-affinity insulin-reactive B cells. Importantly, loss of anergy is seen in patient's healthy first-degree relatives carrying certain T1D risk alleles, suggesting a role early in disease development. SUMMARY Recent studies indicate that islet-reactive B cells may play a pathogenic role very early in T1D development in young patients, and suggest utility of therapies that target these cells.
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Affiliation(s)
- Mia J. Smith
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - John C. Cambier
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO
| | - Peter A. Gottlieb
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
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Altered Regulatory B Cell Subsets in Children with Type 1 Diabetes Mellitus. J Immunol Res 2020; 2020:8935694. [PMID: 32775471 PMCID: PMC7391103 DOI: 10.1155/2020/8935694] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/24/2020] [Accepted: 07/04/2020] [Indexed: 12/12/2022] Open
Abstract
B regulatory cells (Breg) refer to characteristic subsets of B cells that generally exert anti-inflammatory functions and maintain peripheral tolerance mainly through their ability to secrete interleukin-10 (IL10). Dysregulation in the function of Breg cells was reported in several autoimmune diseases. However, the relation between Breg and children with type 1 diabetes (T1D) is poorly understood. Thus, this study is aimed at determining whether Breg cells play a role in T1D in children or not, so we hypothesized that an altered phenotype of B cell subsets is associated with T1D in children. Children with T1D (n = 29) and control children with normal blood glucose levels (n = 14) were recruited. The percentages of different circulating IL10-producing Breg subsets, including B10, immature transitional, and plasmablasts were determined using flow cytometry analysis. Furthermore, the association between different IL10-producing B cells and patient parameters was investigated. The percentage of circulating IL10+CD24hiCD27+ (B10) and IL10+CD24hiCD38hi (immature transitional) subsets of Breg cells was significantly lower in T1D patients than in healthy controls. Moreover, these cells were also negatively correlated with fasting blood glucose and HbA1c levels. Breg cells did not correlate with autoantibody levels in the serum. These findings suggest that certain Breg subsets are numerically deficient in children with T1D. This alteration in frequency is associated with deficient islet function and glycemia. These findings suggest that Breg cells may be involved in the loss of auto-tolerance and consequent destruction of pancreatic cells and could, therefore, be a potential target for immunotherapy.
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Combination therapy with anti-CD20 mAb and IL-10 gene to reverse type 1 diabetes by attenuating pancreatitis and inhibiting apoptosis in NOD mice. Life Sci 2020; 256:117985. [PMID: 32562692 DOI: 10.1016/j.lfs.2020.117985] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/14/2020] [Accepted: 06/15/2020] [Indexed: 01/12/2023]
Abstract
AIMS To assess the combination therapy of anti-CD20 mabs and adenovirus-mediated interleukin-10 (IL-10) gene delivery on the prevention of type 1 diabetes (T1D) in non-obese diabetes (NOD) mice. MAIN METHODS In present study, we simultaneously blocked the B cell interactions and recovered the Th cell subset proportion by using through anti-CD20 Mab and adenovirus-mediated gene delivery of IL-10, respectively. After 9 consecutive days of combination therapy, various measurements, including hematoxylin-eosin staining (HE), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay (TUNEL), immunohistochemistry, ELISA, PCR and western blot were applied to further assess the efficacy. KEY FINDINGS The results suggested that the combination intervention reduced the T1D-associated morbidity of NOD mice, promote insulin secretion, control blood glucose and ease pancreatitis. Moreover, the combination therapy might play a protective role in pancreatic β cells by suppressing the expression of TNF-α and Fas, blocking the Caspase-8 and Caspase-3 apoptotic pathways and activating the Bcl-2 anti-apoptotic pathway. Finally, the combination intervention may up-regulate the gene expression of CK-19 and PDX-1 and further accelerate the differentiation and proliferation of pancreatic β cells. SIGNIFICANCE Therefore, the combination intervention with anti-CD20 mabs and the IL-10 gene plays a role in the prevention of T1D to some extent in NOD mice.
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Camilo DS, Pradella F, Paulino MF, Baracat ECE, Marini SH, Guerra G, Pavin EJ, Parisi C, Longhini ALF, Marques SB, Guariento EG, Lieber SR, Macedo CF, Gama E Silva L, Farias AS, Santos LMB, Volpini WMG. Partial remission in Brazilian children and adolescents with type 1 diabetes. Association with a haplotype of class II human leukocyte antigen and synthesis of autoantibodies. Pediatr Diabetes 2020; 21:606-614. [PMID: 32078220 DOI: 10.1111/pedi.12999] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 01/26/2020] [Accepted: 02/04/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Characterization of partial remission using the insulin dose-adjusted HbA1c (IDAA1c) ≤ 9 definition in a multiethnic Brazilian population of children and adolescents with type 1 diabetes (T1D), in addition with the determination of both Class II HLA genotype and autoantibodies. METHODS We analyzed the prevalence of partial remission in 51 new-onset T1D patients with a median time follow-up of 13 months from diagnosis. For this study, anti-GAD65, anti-IA2 and HLA class II genotyping were considered. RESULTS Partial remission occurred in 41.2% of T1D patients until 3 months after diagnosis, mainly in those aged 5-15 years. We have demonstrated a significant increase in the haplotypes of class II HLA DRB1*0301-DQB1*0201 in children and adolescents with a partial remission phase of the disease (42.9% vs 21.7% in non-remitters, P = .0291). This haplotype was also associated with the reduction of anti-IA2 antibodies production. Homozygote DRB1*03-DQB1*0201/DRB1*03-DQB1*0201 children had the lowest prevalence of IA-2A antibodies (P = .0402). However, this association does not correlate with the time of the remission phase. CONCLUSION Although the number of patients studied was reduced, our data suggested that the association between genetics and decrease in antibody production to certain islet auto-antigen may contribute, at least in part, to the remission phase of T1D.
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Affiliation(s)
- Daniela S Camilo
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil
| | - Fernando Pradella
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil
| | | | - Emilio C E Baracat
- Departament of Pediatrics, Campinas University UNICAMP, Campinas, Brazil
| | - Sofia H Marini
- Departament of Pediatrics, Campinas University UNICAMP, Campinas, Brazil
| | - Gil Guerra
- Departament of Pediatrics, Campinas University UNICAMP, Campinas, Brazil
| | - Elizabeth J Pavin
- Endocrinology Diabetes Service of the Clinical Hospital, Campinas University UNICAMP, Campinas, Brazil
| | - Candida Parisi
- Endocrinology Diabetes Service of the Clinical Hospital, Campinas University UNICAMP, Campinas, Brazil
| | - Ana Leda F Longhini
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil
| | - Silvia B Marques
- HLA Laboratory, Blood Center, Campinas University UNICAMP, Campinas, Brazil
| | | | - Sofia R Lieber
- HLA Laboratory, Blood Center, Campinas University UNICAMP, Campinas, Brazil
| | | | - Letícia Gama E Silva
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil
| | - Alessandro S Farias
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil.,National Institute for Science and Technology-Neuroimmunomodulation (INCT-NIM), CNPq, Brasília, Brazil
| | - Leonilda M B Santos
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil.,National Institute for Science and Technology-Neuroimmunomodulation (INCT-NIM), CNPq, Brasília, Brazil
| | - Walkyria M G Volpini
- Neuroimmunology Unit, Biology Institut, Campinas University UNICAMP, Campinas, Brazil
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Le Bagge S, Fotheringham AK, Leung SS, Forbes JM. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med Res Rev 2020; 40:1200-1219. [PMID: 32112452 DOI: 10.1002/med.21654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.
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Affiliation(s)
- Selena Le Bagge
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Amelia K Fotheringham
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Sherman S Leung
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Josephine M Forbes
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Mater Clinical School, The University of Queensland, Brisbane, Queensland, Australia
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Wang Y, Qin Y, Wang X, Zhang L, Wang J, Xu X, Chen H, Hsu HT, Zhang M. Decrease in the proportion of CD24 hi CD38 hi B cells and impairment of their regulatory capacity in type 1 diabetes patients. Clin Exp Immunol 2020; 200:22-32. [PMID: 31849037 DOI: 10.1111/cei.13408] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2019] [Indexed: 01/11/2023] Open
Abstract
B10 cells restore immune balance by producing interleukin (IL)-10. Impaired B10 cell responses are related to numerous autoimmune diseases. However, the function of B10 cells in type 1 diabetes (T1D) patients is controversial. We hypothesized that there are numerical and functional defects of B10 cells in T1D. Sixty-two patients with T1D and 74 healthy volunteers were included in our study. We showed that B10 cells in human peripheral blood belong to a CD24hi CD38hi B cell subpopulation. CD24hi CD38hi B cells from healthy individuals possessed regulatory capacity, suppressed interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-17A production and promoted IL-4 production and forkhead box protein 3 (FoxP3) expression in CD4+ T cells through an IL-10-dependent mechanism. Compared to healthy controls, B10 cell percentages in T1D were significantly lower (5·6 ± 3·5 versus 6·9 ± 3·3%; P < 0·05), produced less IL-10 (15·4 ± 4·3 versus 29·0 ± 4·5%; P < 0·001) and lacked regulatory capacity. In addition, Pearson's correlation analysis showed that the frequency of circulating B10 cells was negatively correlated with the frequency of CD4+ IFN-γ+ and CD4+ TNF-α+ T cells (r = -0·248 and r = -0·283, P = 0·008 and P = 0·017, respectively), positively correlating with the frequency of CD4+ CD25+ FoxP3+ T cells (r = 0·247, P = 0·001). These data offer direct proof that there is a deficiency of circulating CD24hi CD38hi B cells in peripheral blood of patients with T1D, which participate in the T1D immune imbalance involved in the development of T1D.
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Affiliation(s)
- Y Wang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Pediatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Y Qin
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - X Wang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - L Zhang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - J Wang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - X Xu
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - H Chen
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - H-T Hsu
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - M Zhang
- Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
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Chen K, Xue Q, Liu F, Liu L, Yu C, Bian G, Zhang K, Fang C, Song J, Ju G, Wang J. B lymphocytes expressing high levels of PD-L1 are key regulators of diabetes development in non-obese diabetic mice. Mol Immunol 2019; 114:289-298. [DOI: 10.1016/j.molimm.2019.07.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 07/24/2019] [Accepted: 07/27/2019] [Indexed: 01/13/2023]
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Laule CF, Odean EJ, Wing CR, Root KM, Towner KJ, Hamm CM, Gilbert JS, Fleming SD, Regal JF. Role of B1 and B2 lymphocytes in placental ischemia-induced hypertension. Am J Physiol Heart Circ Physiol 2019; 317:H732-H742. [PMID: 31397167 DOI: 10.1152/ajpheart.00132.2019] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Preeclampsia is a prevalent pregnancy complication characterized by new-onset maternal hypertension and inflammation, with placental ischemia as the initiating event. Studies of others have provided evidence for the importance of lymphocytes in placental ischemia-induced hypertension; however, the contributions of B1 versus B2 lymphocytes are unknown. We hypothesized that peritoneal B1 lymphocytes are important for placental ischemia-induced hypertension. As an initial test of this hypothesis, the effect of anti-CD20 depletion on both B-cell populations was determined in a reduced utero-placental perfusion pressure (RUPP) model of preeclampsia. Anti-murine CD20 monoclonal antibody (5 mg/kg, Clone 5D2) or corresponding mu IgG2a isotype control was administered intraperitoneally to timed pregnant Sprague-Dawley rats on gestation day (GD)10 and 13. RUPP or sham control surgeries were performed on GD14, and mean arterial pressure (MAP) was measured on GD19 from a carotid catheter. As anticipated, RUPP surgery increased MAP and heart rate and decreased mean fetal and placental weight. However, anti-CD20 treatment did not affect these responses. On GD19, B-cell populations were enumerated in the blood, peritoneal cavity, spleen, and placenta with flow cytometry. B1 and B2 cells were not significantly increased following RUPP. Anti-CD20 depleted B1 and B2 cells in peritoneum and circulation but depleted only B2 lymphocytes in spleen and placenta, with no effect on circulating or peritoneal IgM. Overall, these data do not exclude a role for antibodies produced by B cells before depletion but indicate the presence of B lymphocytes in the last trimester of pregnancy is not critical for placental ischemia-induced hypertension.NEW & NOTEWORTHY The adaptive and innate immune systems are implicated in hypertension, including the pregnancy-specific hypertensive condition preeclampsia. However, the mechanism of immune system dysfunction leading to pregnancy-induced hypertension is unresolved. In contrast to previous reports, this study reveals that the presence of classic B2 lymphocytes and peritoneal and circulating B1 lymphocytes is not required for development of hypertension following third trimester placental ischemia in a rat model of pregnancy-induced hypertension.
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Affiliation(s)
- Connor F Laule
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | - Evan J Odean
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | - Cameron R Wing
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | - Kate M Root
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | - Kendra J Towner
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | - Cassandra M Hamm
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | - Jeffrey S Gilbert
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
| | | | - Jean F Regal
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth Campus, Duluth, Minnesota
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Role of complement in diabetes. Mol Immunol 2019; 114:270-277. [PMID: 31400630 DOI: 10.1016/j.molimm.2019.07.031] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 02/07/2023]
Abstract
Accumulating evidence suggests a role for the complement system in the pathogenesis of diabetes and the vascular complications that characterise this condition. Complement proteins contribute to the development of type 1 diabetes (T1D) by enhancing the underlying organ-specific autoimmune processes. Complement upregulation and activation is also an important feature of insulin resistance and the development of type 2 diabetes (T2D). Moreover, animal and human studies indicate that complement proteins are involved in the pathogenic mechanisms leading to diabetic microvascular and macrovascular complications. The adverse vascular effects of complement appear to be related to enhancement of the inflammatory process and the predisposition to a thrombotic environment, eventually leading to vascular occlusion. Complement proteins have been considered as therapeutic targets to prevent or treat vascular disease but studies have been mainly conducted in animal models, while human work has been both limited and inconclusive so far. Further studies are needed to understand the potential role of complement proteins as therapeutic targets for reversal of the pathological processes leading to T1D and T2D and for the prevention/treatment of diabetic vascular complications.
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Egia-Mendikute L, Arpa B, Rosell-Mases E, Corral-Pujol M, Carrascal J, Carrillo J, Mora C, Chapman H, Panosa A, Vives-Pi M, Stratmann T, Serreze D, Verdaguer J. B-Lymphocyte Phenotype Determines T-Lymphocyte Subset Differentiation in Autoimmune Diabetes. Front Immunol 2019; 10:1732. [PMID: 31428087 PMCID: PMC6689997 DOI: 10.3389/fimmu.2019.01732] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 07/09/2019] [Indexed: 11/17/2022] Open
Abstract
Previous studies indicate that B-lymphocytes play a key role activating diabetogenic T-lymphocytes during the development of autoimmune diabetes. Recently, two transgenic NOD mouse models were generated: the NOD-PerIg and the 116C-NOD mice. In NOD-PerIg mice, B-lymphocytes acquire an activated proliferative phenotype and support accelerated autoimmune diabetes development. In contrast, in 116C-NOD mice, B-lymphocytes display an anergic-like phenotype delaying autoimmune diabetes onset and decreasing disease incidence. The present study further evaluates the T- and B-lymphocyte phenotype in both models. In islet-infiltrating B-lymphocytes (IIBLs) from 116C-NOD mice, the expression of H2-Kd and H2-Ag7 is decreased, whereas that of BAFF, BAFF-R, and TACI is increased. In contrast, IIBLs from NOD-PerIg show an increase in CD86 and FAS expression. In addition, islet-infiltrating T-lymphocytes (IITLs) from NOD-PerIg mice exhibit an increase in PD-1 expression. Moreover, proliferation assays indicate a high capacity of B-lymphocytes from NOD-PerIg mice to secrete high amounts of cytokines and induce T-lymphocyte activation compared to 116C B-lymphocytes. This functional variability between 116C and PerIg B-lymphocytes ultimately results in differences in the ability to shape T-lymphocyte phenotype. These results support the role of B-lymphocytes as key regulators of T-lymphocytes in autoimmune diabetes and provide essential information on the phenotypic characteristics of the T- and B-lymphocytes involved in the autoimmune response in autoimmune diabetes.
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Affiliation(s)
- Leire Egia-Mendikute
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Berta Arpa
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Estela Rosell-Mases
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Marta Corral-Pujol
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Jorge Carrascal
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Jorge Carrillo
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | - Conchi Mora
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain
| | | | - Anaïs Panosa
- Microscopy and Flow Cytometry Facility, IRBLleida, Universitat de Lleida, Lleida, Spain
| | - Marta Vives-Pi
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Barcelona, Spain.,CIBER of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Thomas Stratmann
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - David Serreze
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Joan Verdaguer
- Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, IRBLleida, University of Lleida, Lleida, Spain.,CIBER of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid, Spain
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46
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Wiede F, Brodnicki TC, Goh PK, Leong YA, Jones GW, Yu D, Baxter AG, Jones SA, Kay TWH, Tiganis T. T-Cell-Specific PTPN2 Deficiency in NOD Mice Accelerates the Development of Type 1 Diabetes and Autoimmune Comorbidities. Diabetes 2019; 68:1251-1266. [PMID: 30936146 DOI: 10.2337/db18-1362] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 03/17/2019] [Indexed: 11/13/2022]
Abstract
Genome-wide association studies have identified PTPN2 as an important non-MHC gene for autoimmunity. Single nucleotide polymorphisms that reduce PTPN2 expression have been linked with the development of various autoimmune disorders, including type 1 diabetes. The tyrosine phosphatase PTPN2 attenuates T-cell receptor and cytokine signaling in T cells to maintain peripheral tolerance, but the extent to which PTPN2 deficiency in T cells might influence type 1 diabetes onset remains unclear. NOD mice develop spontaneous autoimmune type 1 diabetes similar to that seen in humans. In this study, T-cell PTPN2 deficiency in NOD mice markedly accelerated the onset and increased the incidence of type 1 diabetes as well as that of other disorders, including colitis and Sjögren syndrome. Although PTPN2 deficiency in CD8+ T cells alone was able to drive the destruction of pancreatic β-cells and the onset of diabetes, T-cell-specific PTPN2 deficiency was also accompanied by increased CD4+ T-helper type 1 differentiation and T-follicular-helper cell polarization and increased the abundance of B cells in pancreatic islets as seen in human type 1 diabetes. These findings causally link PTPN2 deficiency in T cells with the development of type 1 diabetes and associated autoimmune comorbidities.
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Affiliation(s)
- Florian Wiede
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Thomas C Brodnicki
- St. Vincent's Institute, Fitzroy, Victoria, Australia
- Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
| | - Pei Kee Goh
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Yew A Leong
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Gareth W Jones
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, U.K
- Systems Immunity University Research Institute, Cardiff University, Cardiff, U.K
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, U.K
| | - Di Yu
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Alan G Baxter
- Comparative Genomics Centre, James Cook University, Townsville, Queensland, Australia
| | - Simon A Jones
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, U.K
- Systems Immunity University Research Institute, Cardiff University, Cardiff, U.K
| | - Thomas W H Kay
- St. Vincent's Institute, Fitzroy, Victoria, Australia
- Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
| | - Tony Tiganis
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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47
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Montanari E, Gonelle-Gispert C, Seebach JD, Knoll MF, Bottino R, Bühler LH. Immunological aspects of allogeneic pancreatic islet transplantation: a comparison between mouse and human. Transpl Int 2019; 32:903-912. [PMID: 31033036 DOI: 10.1111/tri.13445] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/29/2018] [Accepted: 04/23/2019] [Indexed: 11/30/2022]
Abstract
Pancreatic islet allotransplantation is a treatment for patients with severe forms of type 1 diabetes. As long-term graft function and survival are not yet optimal, additional studies are warranted in order to continue improving transplant outcomes. The mechanisms of islet graft loss and tolerance induction are often studied in murine diabetes models. Despite numerous islet transplantation studies successfully performed over recent years, translation from experimental mouse models to human clinical application remains elusive. This review aims at critically discussing the strengths and limitations of current mouse models of diabetes and experimental islet transplantation. In particular, we will analyze the causes leading to diabetes and compare the immunological mechanisms responsible for rejection between mouse and human. A better understanding of the experimental mouse models should facilitate translation to human clinical application.
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Affiliation(s)
- Elisa Montanari
- Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Carmen Gonelle-Gispert
- Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Jörg D Seebach
- Division of Immunology and Allergy, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Michael F Knoll
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rita Bottino
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, USA
| | - Leo H Bühler
- Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
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48
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Getahun A, Cambier JC. Non-Antibody-Secreting Functions of B Cells and Their Contribution to Autoimmune Disease. Annu Rev Cell Dev Biol 2019; 35:337-356. [PMID: 30883216 DOI: 10.1146/annurev-cellbio-100617-062518] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
B cells play multiple important roles in the pathophysiology of autoimmune disease. Beyond producing pathogenic autoantibodies, B cells can act as antigen-presenting cells and producers of cytokines, including both proinflammatory and anti-inflammatory cytokines. Here we review our current understanding of the non-antibody-secreting roles that B cells may play during development of autoimmunity, as learned primarily from reductionist preclinical models. Attention is also given to concepts emerging from clinical studies using B cell depletion therapy, which shed light on the roles of these mechanisms in human autoimmune disease.
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Affiliation(s)
- Andrew Getahun
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA; .,Department of Biomedical Research, National Jewish Health, Denver, Colorado 80206, USA
| | - John C Cambier
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA; .,Department of Biomedical Research, National Jewish Health, Denver, Colorado 80206, USA
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49
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Abstract
The clinical onset of type 1 diabetes is characterized by the destruction of the insulin-producing β cells of the pancreas and is caused by autoantigen-induced inflammation (insulitis) of the islets of Langerhans. The current standard of care for type 1 diabetes mellitus patients allows for management of the disease with exogenous insulin, but patients eventually succumb to many chronic complications such as limb amputation, blindness, and kidney failure. New therapeutic approaches now on the horizon are looking beyond glycemic management and are evaluating new strategies from protecting and regenerating endogenous islets to treating the underlying autoimmunity through selective modulation of key immune cell populations. Currently, there are no effective treatments for the autoimmunity that causes the disease, and strategies that aim to delay or prevent the onset of the disease will play an important role in the future of diabetes research. In this review, we summarize many of the key efforts underway that utilize molecular approaches to selectively modulate this disease and look at new therapeutic paradigms that can transform clinical treatment.
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Affiliation(s)
- Daniel Sheehy
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Sean Quinnell
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Arturo J. Vegas
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
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50
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Lees JR. Targeting antigen presentation in autoimmunity. Cell Immunol 2018; 339:4-9. [PMID: 30554782 DOI: 10.1016/j.cellimm.2018.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/06/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
Abstract
Autoimmune diseases are heterogeneous group of disorders that together represent an enormous societal and medical problem. CD4+ T cells have critical roles in the initiation and pathogenesis of autoimmune disease. As such, modulation of T cell activity has proven to have significant therapeutic effects in multiple autoimmune settings. T cell activation is a complex process with multiple potential therapeutic targets, many of which have been successfully utilized to treat human disease. Current pharmacological treatment largely targets T cell intrinsic activities as a means of treating various autoimmune disorders. Here I review extant and potential therapeutic approaches that instead specifically target antigen presentation to CD4+ T cells as a critical checkpoint in autoimmune responses. In addition, the contribution of antigen modulation components in current therapeutic approaches is considered along with the impact of new antigen targeted treatment modalities. Finally, potential challenges are considered in the context of the potential for antigen specific targeting of the antigen presentation process.
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Affiliation(s)
- Jason R Lees
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
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