Insulin (auto)antibodies from human IDDM cross-react with retroviral antigen p73

In NOD mice, endogenous retroviruses including intracisternal type A particles (IAP) are expressed in the pancreatic beta cells. Furthermore, in these mice, insulin autoantibodies (IAA) cross-react with retroviral protein p73 (the IAP gag gene product), suggesting molecular mimicry between insulin and p73. We therefore investigated whether IAA and insulin antibodies (IA) associated with human IDDM cross-reacted with p73. Fifty IAA positive sera from 30 newly diagnosed IDDM before insulin therapy and 20 non-diabetic first degree relatives of IDDM and 27 IA positive sera from insulin treated IDDM, initially defined as IAA or IA positive by radioimmunoassay, were evaluated. Binding to insulin and to p73 of these sera were analysed by ELISA. Approximately 65% of sera which bound insulin by ELISA also bound p73. Only one sample negative for insulin binding was positive for p73 binding. Preabsorption with either insulin or p73 inhibited binding to both insulin and p73. However, preabsorption with mouse hemoglobin had no effect on their binding. Repeat measurement of binding to insulin and p73 in 10 non-diabetic first degree relatives of IDDM over an average of 16.6 months showed that each individual's reactivity to insulin and to p73 was relatively stable over time. Furthermore, in different individuals, binding to p73 and to insulin was closely correlated over time. In addition, 75 healthy teenagers (IAA negative by RIA) were used as normal controls in this study. p73 binding was found in only two (2.7%) of the 75 subjects. These results indicate that approximately 65% of ELISA (+) IAA and IA subjects have antibodies which recognize both insulin and p73, suggesting that IAA and IA from some subjects recognize an epitope shared between human insulin and the murine gag gene product. This raises the possibility that for some subjects who are IAA positive, the immunizing antigen may be antigenically similar to p73, rather than insulin, and that endogenous retroviruses may be involved in human IDDM.