B Cells in Autoimmune Diabetes

Wong, F. Susan; Liu, Wen

doi:10.1900/rds.2005.2.121

Cited by 42 publications

(41 citation statements)

References 96 publications

(120 reference statements)

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“…These findings have recently been confirmed using the PPI [15][16][17][18][19][20][21][22][23][24] clone and an additional HLA-A2-restricted PPI clone, PPI [3][4][5][6][7][8][9][10][11] [106]. These clones killed beta-cells by requiring a direct interaction via MHC class I and utilizing perforin and granzymes.…”

Section: Effector Mechanisms Utilized By Human Auto-reactive Ctlsmentioning

confidence: 83%

“…Recent studies have clarified this and demonstrated that diabetes cannot be transferred by antibody or B cells alone [10]. Instead, B cells contribute primarily as antigenpresenting cells [10][11][12]. Using a series of transgenic and mutant mice with increased B cell activation, Silva et al demonstrated that B cells act to enhance the accumulation and function of isletreactive CD4 + T cells promoting diabetes development [10].…”

Section: Abbreviationsmentioning

confidence: 99%

“…Recent X-ray crystallography revealed the interaction between HLA-A2/PPI [15][16][17][18][19][20][21][22][23] peptide/TCR [55]. Most attempts to define CD8 + T cell responses have focused on HLA A2, but recently an HLA A24-restricted epitope derived from proinsulin, PPI [3][4][5][6][7][8][9][10][11] , has been identified using a similar peptide elution approach [56].…”

Section: Antigen Specificity Of Autoreactive T Cells In Human Typementioning

confidence: 99%

“…It has been suggested that B cells present antigens to both CD4 + and CD8 + T cells, although it is unclear whether this occurs within the islet environment or just within the PLN [10][11][12]. B cells have also been shown to promote the survival of autoreactive CTLs within islets.…”

Section: Antigen Presentation Within the Islet Environmentmentioning

confidence: 99%

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Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

et al. 2012

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Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4 + T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8 + T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.

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Section: Effector Mechanisms Utilized By Human Auto-reactive Ctlsmentioning

confidence: 83%

Section: Abbreviationsmentioning

confidence: 99%

Section: Antigen Specificity Of Autoreactive T Cells In Human Typementioning

confidence: 99%

Section: Antigen Presentation Within the Islet Environmentmentioning

confidence: 99%

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Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

et al. 2012

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“…However, other cells of the immune system also play a relevant role in the development of the disease. In this regard, it is believed that B lymphocytes may act both as APCs for autoreactive T lymphocytes and/or as producers of autoantibodies against several ␤ cell autoantigens (5,6).…”

mentioning

confidence: 99%

Peripherin Is a Relevant Neuroendocrine Autoantigen Recognized by Islet-Infiltrating B Lymphocytes

Puertas

Carrillo

Pastor

et al. 2007

The Journal of Immunology

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Most of our knowledge of the antigenic repertoire of autoreactive B lymphocytes in type 1 diabetes (T1D) comes from studies on the antigenic specificity of both circulating islet-reactive autoantibodies and peripheral B lymphocyte hybridomas generated from human blood or rodent spleen. In a recent study, we generated hybridoma cell lines of infiltrating B lymphocytes from different mouse strains developing insulitis, but with different degrees of susceptibility to T1D, to characterize the antigenic specificity of islet-infiltrating B lymphocytes during progression of the disease. We found that many hybridomas produced mAbs restricted to the peripheral nervous system (PNS), thus indicating an active B lymphocyte response against PNS elements in the pancreatic islet during disease development. The aim of this study was to identify the autoantigen recognized by these anti-PNS mAbs. Our results showed that peripherin is the autoantigen recognized by all anti-PNS mAbs, and, therefore, a relevant neuroendocrine autoantigen targeted by islet-infiltrating B lymphocytes. Moreover, we discovered that the immune dominant epitope of this B lymphocyte immune response is found at the C-terminal end of Per58 and Per61 isoforms. In conclusion, our study strongly suggests that peripherin is a major autoantigen targeted during T1D development and poses a new question on why peripherin-specific B lymphocytes are mainly attracted to the islet during disease.

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B‐1 cells produce insulin and abrogate experimental streptozotocin‐induced diabetes

et al. 2015

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The participation of B-1 cells in a murine model of spontaneous diabetes has been recently reported. Here, we describe the role of B-1 cells in streptozotocin (STZ) induced diabetes in mice. We demonstrated that XID (B-1 cell-deficient) mice are more susceptible to STZ treatment than WT mice, as evidenced by their higher blood glucose level in response to STZ. Unexpectedly, the XID mice that were i.p. transferred with purified B-1 cells, either before or after the STZ treatment, did not develop diabetes. These cell transfers provided long-lasting protection for the XID mice against STZ-induced diabetes, suggesting that B-1 cells play an important role in the experimental diabetes pathobiology. We also showed that B-1 cell culture supernatants were able to regulate the blood glucose level of the diabetic XID mice, and we identified insulin-producing cells when B-1 cells were differentiated in B-1 cell-derived phagocyte in vitro. These findings provide a novel role for B-1 cells in metabolic processes, presenting a new mechanism to explain the pathogenesis of diabetes and a possible therapeutical target. Keywords: B-1 cells r Experimental diabetes r Insulin r Streptozotocin r XID mice IntroductionType-1 diabetes is an organ-specific autoimmune disease in which T cells mediate the destruction of pancreatic β cells. The role played by T cells in the pathogenesis of diabetes has been extensively investigated. In 1996, Serreze et al. published the first study providing evidence that B lymphocytes play an important role in the development of diabetes [1]. Since then, the possible but controversial role of B cells in the outcome and evolution of this disease has been suggested in the literature. Although some authors have proposed the involvement of B cells in the development of autoimmune diabetes [2,3], others have suggested that B cells may not be necessary for the initiation of the autoimmune process [4].Correspondence: Prof. Mario Mariano e-mail: mariomu@uol.com.brThe different populations of B cells, denominated B-1 and B-2 cells, have been characterized in mice. B-1 cells differ from conventional B cells (B-2 cells) in their ontogeny, anatomical distribution, surface markers, antibody subtype production, selfrenewing ability, and the activity and localization of their precursors during adulthood [5,6]. B-1 cells are further subdivided into two subpopulations, B-1a and B-1b, based on the presence or absence of the CD5 molecule on their membrane, respectively [7,8], and are responsible for the secretion of "natural" antibodies that recognize polymeric antigens of high molecular weight [9,10]. B-1a cells produce autoreactive antibodies, suggesting the participation of these cells in autoimmune diseases in both humans and murine experimental models [11]. We have previously demonstrated that B-1 cells migrate toward a nonspecific inflammatory focus and that they are able to differentiate into mononuclear phagocytes (B-1 cell derived C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. ...

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B Cells in Autoimmune Diabetes

Cited by 42 publications

References 96 publications

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

Peripherin Is a Relevant Neuroendocrine Autoantigen Recognized by Islet-Infiltrating B Lymphocytes

B‐1 cells produce insulin and abrogate experimental streptozotocin‐induced diabetes

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