SIMILAR PEPTIDES FROM 2 BETA-CELL AUTOANTIGENS, PROINSULIN AND GLUTAMIC-ACID DECARBOXYLASE, STIMULATE T-CELLS OF INDIVIDUALS AT RISK FOR INSULIN-DEPENDENT DIABETES

Background: Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but n o molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-51 8) (G. Rudy, unpublished). In order to test the hypothesis that this r egion of similarity is implicated in the pathogenesis of IDDM, we assa yed T cell reactivity to these two peptides in subjects at risk for ID DM. Materials and Methods: subjects at risk for IDDM were islet cell a ntibody (ICA)-positive, first degree relatives of people with insulin- dependent diabetes. Peripheral blood mononuclear cells from 10 pairs o f at-risk and HLA-DR matched control subjects were tested in an in vit ro proliferation assay. Results: Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than contro ls (proinsulin; p < 0.008; GAD: p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost en tirely confined to the at-risk subjects. Conclusions: This is the firs t demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal pepti de region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecul ar basis for the conjoint autoantigenicity of proinsulin and GAD in ID DM.