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Cellular and molecular roles of β cell autoantigens, macrophages and T cells in the pathogenesis of autoimmune diabetes

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Abstract

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM) results from the destruction of insulin-producing pancreatic β cells by a progressive β cell-specific autoimmune process. The pathogenesis of autoimmune IDDM has been extensively studied for the past two decades using animal models such as the non-obese diabetic (NOD) mouse and the Bio-Breeding (BB) rat. However, the initial events that trigger the immune responses leading to the selective destruction of the β cells are poorly understood. It is thought that β cell auto-antigens are involved in the triggering of β cell-specific autoimmunity. Among a dozen putative β cell autoantigens, glutamic acid decarboxylase (GAD) has been proposed as perhaps the strongest candidate in both humans and the NOD mouse. In the NOD mouse, GAD, as compared with other β cell autoantigens, provokes the earliest T cell proliferative response. The suppression of GAD expression in the β cells results in the prevention of autoimmune diabetes in NOD mice. In addition, the major populations of cells infiltrating the islets during the early stage of insulitis in BB rats and NOD mice are macrophages and dendritic cells. The inactivation of macrophages in NOD mice results in the prevention of T cell mediated autoimmune diabetes. Macrophages are primary contributors to the creation of the immune environment conducive to the development and activation of β cell-specific Th1-type CD4+ T cells and CD8+ cytotoxic T cells that cause autoimmune diabetes in NOD mice. CD4+ and CD8+ T cells are both believed to be important for the destruction of β cells. These cells, as final effectors, can kill the insulin-producing β cells by the induction of apoptosis. In addition, CD8+ cytotoxic T cells release granzyme and cytolysin (perforin), which are also toxic to β cells. In this way, macrophages, CD4+ T cells and CD8+ T cells act synergistically to kill the β ceils in conjunction with β cell autoantigens and MHC class I and class II antigens, resulting in the onset of sautoimmune type I diabetes.

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Authors and Affiliations

  1. Dept. of Microbiology and Infectious Disease, Laboratory of Viral and Immunopatbogenesis of Diabetes, The University of Calgary, 3330 Hospital Drive N. W., T2N 4N1, Calgary, Alberta, Canada

    Ji-Won Yoon

  2. Julia McFarlane Diabetes Research Centre, Faculty of Medicine, The University of Calgary, 3330 Hospital Drive N. W., T2N 4N1, Calgary, Alberta, Canada

    Ji-Won Yoon & Hee-Sook Jun

  3. The Department of Endocrinology, College of Medicine, Ajou University, 5 Wonchon-Dong, Paldal-Gu, Suwon, Korea

    Ji-Won Yoon

  4. The Laboratory of Endocrinology, Institute for Medical Science, Ajou University, 5 Wonchon-Dong, Paldal-Gu, Suwon, Korea

    Ji-Won Yoon

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  1. Ji-Won Yoon
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  2. Hee-Sook Jun
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Correspondence to Ji-Won Yoon.

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Yoon, JW., Jun, HS. Cellular and molecular roles of β cell autoantigens, macrophages and T cells in the pathogenesis of autoimmune diabetes. Arch Pharm Res 22, 437–447 (1999). https://doi.org/10.1007/BF02979150

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