The Immune Response to Insulin in Man: Interaction of HLA Alloantigens and the Development of the Immune Response

In both mice and guinea pigs, the immunologic response to insulin has been demonstrated to be under immune response (Ir) gene control. In the present study, we have attempted to identify Ir genes to insulin in man by correlating HLA allotype with immunologic response to insulin. Three groups of patients were studied: (1) 117 diabetic patients with a history of exaggerated immunologic response to insulin (insulin allergy, resistance, or systemic reactions); (2) 95 insulin-taking diabetics without clinically significant immune response; and (3) 109 nondiabetic controls. Determination of HLA alloantigen frequencies in the “insulin allergic” population and the nonallergic diabetics revealed only modest increases of HLA-Bw44 (29% versus 16%, P < 0.05) and -DR7 (28% versus 15%, P < 0.05). Studies of linkage disequilibrium, however, revealed interesting associations involving HLA-A2, -Bw44, and -DR7 in the diabetic with insulin allergy that were not present in the nonallergic diabetic. Combinations of any two or all three of these antigens were observed in 39% of diabetics with insulin allergy but in only 3% of nonallergic diabetics. An intermediate frequency (23%) was observed in the normal population. Thus, if an individual with any combination of HLA-A2, -Bw44, and -DR7 develops diabetes and receives insulin therapy, there is over a 90% probability he will exhibit a clinically significant immune reaction to insulin (calculated relative risk = 20.6). These data suggest that in man, as in the mouse, the immune response to insulin is under genetic control, but this may involve interactions of several genes in the major histocompatibility (MHC) complex, or a locus in linkage with these genes that is not measured by current techniques.