Beta cell DNA damage response promotes islet inflammation in type 1 diabetes (original) (raw)
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Biology direct, 2007
Type 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet beta cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at the Idd9 diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in beta cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD beta cells is altered. TNFR2 lies within the candidate Idd9 interval and the diabetes-associated variant contains a mutation adjacent to the TRAF2 binding site. A component of diabetes susceptibility may therefore be determined by the target of the autoimmune response, and protective TNFR2 signaling in islets inhibit early cytokine-in...
DNA fragmentation is an early event in cytokine-induced islet beta-cell destruction
Diabetologia, 1994
The cytokines, interleukin 1, tumour necrosis factor, and interferon gamma are cytotoxic to islet beta cells, however, their mechanisms of beta-cell killing are not fully characterized. Since DNA damage is a mechanism of cytokine-induced cell death in some cell types, we sought evidence for cytotoxic effects of cytokincs at a nuclear level in islet beta cells by measuring DNA fragmentation in rat islets and islet beta-cell lines. The individual cytokines, interleukin 1 (10 U/ml), tumour recrosis factor (10 3 U/rnl) and interferon gamma (10 3 U/ml) inhibited insulin release from rat islets, but did not cause DNA fragmentation or destroy islet cells; by contrast, combination of the three cytokines induced DNA fragmentation and islet-cell death. Cytokine-induced DNA fragmemation preceded cell lysis in islet beta-cell lines (RINm5F, rat insulinoma cells; and NIT-l, NOD/Lt mouse transgenic beta cells), whereas in non-islet cell lines (GH-3, rat pituitary; and PC-12, rat adrenal) the cytokines induced cell lysis and no or late DNA fragmentation. Nicotinamide prevented both DNA fragmentation and destruction of RINm5F islet cells by the cytokines. These findings identify DNA as an early target of cytokine action in islet beta cells, and implicate DNA fragmentation as a mechanism of cytokine-induced beta-cell destruction. [Diabetologia (1994) 37: 733-738] Key words Islet beta cells, cytokines, interleukin l, tumour necrosis factor, interferon gamma, DNA damage. Infiltration of the pancreatic islets by immune/inflammatory cells (insulitis), followed by loss of the insulinproducing beta cells is the characteristic histologic feature of IDDM. It is not known, however, how islet beta-cell destruction may be mediated by the insulitis process. This may involve direct contacts between the infiltrating monocytic/lymphocytic cells (effectors) and islet beta cells (targets) and/or may result from the release of soluble mediators from the effector cells.
The pancreatic β cell and type 1 diabetes: innocent bystander or active participant?
Trends in endocrinology and metabolism: TEM, 2013
Type 1 diabetes mellitus (T1DM) is a chronic disease resulting from destruction of insulin-producing pancreatic β cells. Genetic and environmental factors contribute to T1DM onset. Use of high-throughput DNA sequencing has allowed geneticists to perform genome-wide association studies (GWAS) to identify novel gene loci associated with T1DM. Interestingly, >50% of these genes encode products that are expressed in β cells. These studies, coupled with emerging molecular evidence that β cells are impaired by gain-of-function or loss-of-function of these loci, suggest an active role for the β cell in eliciting its own demise. Although immune dysregulation plays a vital role in T1DM pathogenesis, understanding the mechanisms contributing to β cell failure may lead to new strategies to preserve or improve β cell function in patients with T1DM.
Islet‐Immune Interactions in Type 1 Diabetes: The Nexus of Beta Cell Destruction
Clinical & Experimental Immunology
Recent studies in Type 1 Diabetes (T1D) support an emerging model of disease pathogenesis that involves intrinsic β-cell fragility combined with defects in both innate and adaptive immune cell regulation. This combination of defects induces systematic changes leading to organ-level atrophy and dysfunction of both the endocrine and exocrine portions of the pancreas, ultimately culminating in insulin deficiency and β-cell destruction. In this review, we discuss the animal model data and human tissue studies that have informed our current understanding of the crosstalk that occurs between β-cells, the resident stroma, and immune cells that potentiate T1D. Specifically, we will review the cellular and molecular signatures emerging from studies on tissues derived from organ procurement programs, focusing on in situ defects occurring within the T1D islet microenvironment, many of which are not yet detectable by standard peripheral blood biomarkers. In addition to improved access to organ donor tissues, various methodological advances, including immune receptor repertoire sequencing and single-cell molecular profiling, are poised to improve our understanding of antigen-specific autoimmunity during disease development. Collectively, the knowledge gains from these studies at the isletimmune interface are enhancing our understanding of T1D heterogeneity, likely to be Accepted Article This article is protected by copyright. All rights reserved. an essential component for instructing future efforts to develop targeted interventions to restore immune tolerance and preserve β-cell mass and function.
Autoimmune islet destruction in spontaneous type 1 diabetes is not β-cell exclusive
Nature Medicine, 2003
, which express glial fibrillary acidic protein (GFAP) and S100β. pSC-autoreactive T-and B-cell responses arise in 3-to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable β-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100β prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8 + T-cell receptor gp double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and βcell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8 + /8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes
Arquivos Brasileiros de Endocrinologia & Metabologia, 2008
Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFkappa-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D.
Pathogenic mechanisms in type 1 diabetes: the islet is both target and driver of disease
The review of diabetic studies : RDS, 2012
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 molec...