Intermolecular antigen spreading occurs during the preclinical period of human type 1 diabetes

Intra- and intermolecular spreading of T cell responses to autoantigens has been implicated in the pathogenesis of autoimmune diseases. Therefore, we questioned whether T cell responses from subjects identified as at-risk (po sitive for autoantibody reactivity to islet proteins) for the development o f type I diabetes, a cell-mediated autoimmune disease, would demonstrate in termolecular Ag spreading of T cell responses to islet cell proteins. Previ ously, we have demonstrated that by the time subjects develop type I diabet es, they have T cell responses to numerous islet proteins, whereas T cells from normal controls respond to a limited number of islet proteins. Initial testing of PBMC responses from 25 nondiabetic at-risk subjects demonstrate d that 16 of the 25 subjects have PBMC responses to islet proteins similar to controls. Fourteen of these 16 subjects were available for follow-up. El even of the 14 developed T cell responses to increasing numbers of islet pr oteins, and 6 of these subjects developed type I diabetes. In the nine subj ects who already demonstrated T cell Ag spreading at the initial visit, fou r were available for follow-up. Of these four, two had increases in T cell reactivity to islet proteins, while two maintained their initial levels of T cell reactivity. We also observed Ag spreading in autoantibody reactivity to islet proteins in nine of the 18 at-risk subjects available for follow- up. Our data strongly support the conclusion that intermolecular spreading of T cell and Ab responses to islet proteins occurs during the preclinical period of type I diabetes.