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 β cells. Although the pathogenesis of autoimmune IDDM has been extensively studied, the precise mechanisms involved in the initiation and progression of β 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 β 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 Thl type CD4+ T cells. The CD4+ T cells secrete IFN-γ and IL-2. IFN-γ activates other resting macrophages, which, in turn, release cytokines, such as 1L-1 β, TNF-α, and free radicals, which are toxic to β 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 β cell-specific autoantigen receptors differentiate into cytotoxic effector T cells upon recognition of the β cell-specific peptide bound to MHC class I molecules in the presence of β cell-specific CD4+ T helper cells. The cytotoxic CD8+ T cells then effect β 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 β cells, resulting in the onset of autoimmune IDDM.