IMMUNOGENETICS OF TYPE I DIABETES MELLITUS

Abstract

Type I (insulin-dependent) diabetes mellitus (IDDM), is generally considered to be an autoimmune disease based on: 1) the finding of numerous inflammatory cells in the islets of Langerhans at the onset of the disease; 2) the presence of circulating autoantibodies directed against the islet cells; and 3) the fact that immunosuppressive agents, such as cyclosporin A, are able to transiently block the course of the disease. Moreover, the observation that certain HLA class II alleles are associated with an increased risk for the disease, supports an autoimmune etiology for IDDM. In particular, the absence of aspartic acid in position 57 of the HLA-DQβ and the presence of arginine in position 52 of the DQα chain together, have been found to be strongly associated with IDDM in population studies. These heterodimers have been thought to play an important role in the pathogenesis of IDDM. In fact, the HLA class II molecule participates in a complex interaction between the processed foreign antigen and the T cell receptor (TCR) molecule, which starts the immune response. As the result of a stochastic rearrangement among variable (V), diversity (D), joining (J) and constant (C) gene segments encoding both α and β chains, the TCR may assume 1010 different configurations. If IDDM is provoked by a single antigen, a restricted set of T cell clones should emerge during the destruction of the insulin producing β cells. However, this phenomenon is difficult to study because T cells from the pancreas of patients with IDDM, at the onset of the disease, are required to characterize this process. We had the opportunity to study the pancreas of a newly diagnosed child with IDDM who unfortunately died of brain swelling during treatment of diabetic ketoacidosis. T cells from isolated islets were characterized based on their expression of different TCR Vβ regions. The presence of a remarkably restricted TCR Vβ repertoire of the T cells infiltrating the pancreatic islets of this patient strongly suggests the involvement of superanrigens in the etiology of IDDM