Insulin is obviously not the only islet peptide recognized by anti-islet–specific CD4+
T cells in the NOD mouse (15
) but is, to date, the only antigen that, upon deletion or alterations of its immunogenic properties, dramatically accelerates or prevents diabetes (6
). Reactivity of T cells to other islet antigens such as glutamic acid decarboxylase and the β cell–specific protein islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) (21
) has been described, and the precise identities of some targets remain to be determined. Nevertheless, we believe it is likely that specific properties of the insulin B chain, and the relatively simple, low-stringency TCR motif implicated in recognizing the B:9–23 sequence (Table ) in the context of appropriate MHC molecules, make this epitope a preferred target for immunomodulation. Although it is much easier to posit a primary autoantigenic epitope for disease activation in an animal model with a single class II MHC molecule (e.g., I-Ag7
), we suggest that the immunogenicity of insulin and its recognition by autoreactive T cells may in fact drive the high prevalence of type 1 diabetes in humans.
A remarkable dominance of MHC molecules underlies type 1 diabetes in humans, with the highest-risk class II genotype (DR3-DQ2:DR4-DQ8) making up one-third of individuals who develop the disease versus a population frequency of 2.4% in Denver, Colorado (22
). In addition, HLA molecules such as DQB1*0602 provide dominant protection from type 1 diabetes in multiple populations (23
). Nevertheless, there is a different disease risk for each MHC genotype, and though it is possible that only a single peptide epitope will relate to disease with multiple MHC genotypes, this contention remains to be evaluated experimentally. In a recent study of pancreatic lymph nodes from 3 individuals with diabetes, 2 had T cells with marked conservation of their TCRs that reacted with insulin A chain peptide A:1–15 (25
). We believe that further study of both the pancreatic lymph nodes and the islets of individuals who develop type 1 diabetes is essential, and if dominant TCRs and target autoantigens similar to those of the NOD mouse can be identified, it will greatly facilitate molecular understanding of the pathogenesis of type 1 diabetes.