B cell-directed therapies in type 1 diabetes

Mariño, Eliana; Silveira, Pablo A.; Stolp, Jessica; Grey, Shane T.

doi:10.1016/j.it.2011.03.006

Cited by 47 publications

(38 citation statements)

References 74 publications

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“…These observations suggested that targeting B cells prevented a late pathogenic event, such as CD8 + T cell–mediated β-cell destruction, and raised the possibility of a direct link between B cells and activation of self-reactive CD8 + T cells (23). B-cell depletion delays diabetes in man (24), indicating B cells as therapeutic targets for the treatment of type 1 diabetes (18); however, the mechanisms of action by which B-cell reduction effects diabetes progression are unclear. This background led us to investigate whether there was a requirement for B cells in the activation, expansion, and effector development of pathogenic CD8 + T cells and the subsequent transition to overt diabetes in the nonobese diabetic (NOD) model of spontaneous diabetes.…”

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confidence: 99%

B-Cell Cross-Presentation of Autologous Antigen Precipitates Diabetes

et al. 2012

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For autoimmune conditions like type 1 diabetes to progress, self-reactive CD8+ T cells would need to interact with peptide–antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion. However, the mechanisms by which autoantigen is cross-presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8+ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B+interferon-γ+lysosomal-associated membrane protein 1+ effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8+ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cell–dependent, interleukin-21–expressing Vβ4+CD4+ T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8+ T cells.

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B-Cell Cross-Presentation of Autologous Antigen Precipitates Diabetes

et al. 2012

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“…Although T lymphocytes are primarily the effectors, studies have indicated that B cells may play a vital role in the pathogenesis of autoimmune diseases. In NOD mice, the contribution of B cells was clearly demonstrated by the remarkable reduction in insulitis and diabetes incidence after B cell depletion using anti-IgM antibodies at birth or in NOD mice genetically deficient in B cells (Silveira and Grey 2006; Mariño, et al 2011). By using the same animal model, studies have shown that B cells function as islet antigen–presenting cells for autoreactive T cells and produce antibodies which are directly pathogenic.…”

Section: Discussionmentioning

confidence: 99%

RNase L contributes to experimentally induced type 1 diabetes onset in mice

Zeng¹,

Yi²,

Zipris³

et al. 2014

Journal of Endocrinology

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The cause of type I diabetes continues to be a focus of investigation. Studies have revealed that interferon (IFN)-α in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type I diabetes. However, how IFN-α contributes to the onset of type I diabetes is obscure. In this study, we found that 2-5A dependent RNase L (RNase L), an IFN-α-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type I diabetes. By using RNase L deficient, rat insulin promoter (RIP)-B7.1 transgenic mice which are more vulnerable to environmental harmful factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin (STZ), a drug which can artificially induce type I-like diabetes in experimental animals. Immunohistochemical staining showed that the population of infiltrated CD8+ T-cells was remarkably reduced in the islets of RNase L deficient mice, suggesting that RNase L may contribute to type I diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas in induced conditions. Our findings provide new insight into the molecular mechanism underlying β-cells destruction and may suggest novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.

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“…For decades, the predominant dogma was that autoantibodies possessed no known etiological role in the disease and, simply put, were thought to represent the "smoke of the fire" in the pancreas and not the fire itself. However, recent studies in animal models of T1D purporting a crucial role for B-lymphocytes in disease development have opened the door for a previously unappreciated role for autoantibodies in the presentation of self-antigens to the cytotoxic T cells responsible for b-cell destruction (Mariño et al 2011). This concept has also drawn support in human T1D studies in which therapeutic benefits were seen, over the short term, in recent-onset T1D patients treated with the B-lymphocyte-depleting agent anti-CD20 (rituximab) (Pescovitz et al 2009).…”

Section: Pathogenesis and Natural History Of T1dmentioning

confidence: 99%