Cellular and Molecular Mechanisms for the Initiation and Progression of β Cell Destruction Resulting from the Collaboration Between Macrophages and T Cells

Abstract

Insulin-dependent diabetes mellitus (IDDM) is caused by the progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the pathogenesis of autoimmune IDDM has been extensively studied, the precise mechanisms involved in the initiation and progression of beta cell destruction remain unclear. Animal models used in the study of IDDM, such as the BioBreeding (BB) rat and the nonobese diabetic (NOD) mouse, have greatly enhanced our understanding of the pathogenic mechanisms involved in this disease. In these animals, macrophages and/or dendritic cells are the first cell types to infiltrate the pancreatic islets. Macrophages must be involved in the pathogenesis of IDDM early on, since inactivation of macrophages results in the near-complete prevention of insulitis and diabetes in both NOD mice and BB rats. The presentation of beta cell-specific autoantigens by macrophages and/or dendritic cells to CD4+ T helper cells, in association with MHC class II molecules, is considered the initial step in the development of autoimmune IDDM. The activated macrophages secrete IL-12, which stimulates Th1 type CD4+ T cells. The CD4+ T cells secrete IFN-gamma and IL-2. IFN-gamma activates other resting macrophages, which, in turn, release cytokines, such as IL-1beta, TNF-alpha, and free radicals, which are toxic to beta cells. During this process, IL-2 and other cytokines induce the migration of CD8+ peripheral T cells to the inflamed islets, perhaps by inducing the expression of a specific homing receptor. The precytotoxic CD8+ T cells that bear beta cell-specific autoantigen receptors differentiate into cytotoxic effector T cells upon recognition of the beta cell-specific peptide bound to MHC class I molecules in the presence of beta cell-specific CD4+ T helper cells. The cytotoxic CD8+ T cells then effect beta cell damage by releasing perforin and granzyme, and by Fas-mediated apoptosis. In this way, macrophages, CD4+ T cells, and CD8+ T cells synergistically destroy beta cells, resulting in the onset of autoimmune IDDM.

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…Induction of IL-15 mRNA has been previously reported in cyclophosphamide-induced insulits in NOD mice [62]. The expression of IL-15, IP-10 and MIP-3α in NOD islets (present data) occurs in parallel to infiltration by macrophages, dendritic cells, T helper and cytotoxic lymphocytes, and NK cells in NOD islets which is observed around 4 to 10 weeks [2]; from 10 to 12 weeks 80% of the NOD mice of our colony had intense insulitis [8]. T-cells are essential for the development of diabetes in both NOD mice and BB rats [2,3], and the increased expression of IP-10, IL-15 and MIP-3α by the islets might contribute to T-cell recruitment.…”

“…Rodent models of Type 1 diabetes, such as BioBreeding (BB) rats and non-obese diabetic (NOD) mice, are important tools for the study of Type 1 diabetes, since they share many features of the human disease [2,3]. In NOD mice, a non-destructive insulitis develops after weaning.…”

“…Antigen presenting cells such as macrophages and dendritic cells appear early, followed by CD4+ (T helper) and CD8+ (cytotoxic) T-cell and beta-cells [3]. This early insulitis is located around the islets and it becomes destructive when the mononuclear cells progressively invade the islets, leading to destruction of beta cells and hyperglycaemia around 22 weeks of age [2,3,4]. Although insulitis is evenly distributed between sexes, prevalence of diabetes is higher in females than in males [2,4,5].…”

“…This early insulitis is located around the islets and it becomes destructive when the mononuclear cells progressively invade the islets, leading to destruction of beta cells and hyperglycaemia around 22 weeks of age [2,3,4]. Although insulitis is evenly distributed between sexes, prevalence of diabetes is higher in females than in males [2,4,5]. The putative mediators of beta-cell death in NOD mice include cytokines, such as interleukin-1β (IL-1β) and interferon-γ (IFN-γ), perforin, free-radicals and FAS-ligand [3,6].…”

Antigen presentation of detergent-free glutamate decarboxylase (GAD65) is affected by human serum albumin as carrier protein

“…The smaller isoform of glutamate decarboxylase (GAD65) is implicated as a major contributing autoantigen in the pathogenesis of beta cell destruction [1,2]. Autoantibodies directed to GAD65 (GAD65Ab) are present in the majority of new onset T1D patients [3,4] and GAD65-specific T cells have been identified in T1D patients and in spontaneously diabetic NOD mice and BB rats (for review see [5,6] [9]. The establishment of a standard T cell assay remains critical for the understanding of GAD65 antigen uptake, processing and presentation.…”