Humoral and cellular immune responses to proinsulin in adults with newly diagnosed type 1 diabetes

Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by immunity against pancreatic islet-derived proteins. The object of this study was to measure antibody and T-cell responses against proinsulin (PI), an islet-derived protein, and to map its dominant T-cell epitopes. Methods: Antibody responses to proinsulin, insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 and islet-cell antigen were measured in 116 newly diagnosed diabetic subjects aged 16 to 40 years. T-cell proliferative responses to proinsulin and proinsulin peptides were measured in 33 of these diabetic subjects and in 21 healthy control subjects. Results: 22% of diabetic subjects but no control subjects expressed antibodies to proinsulin. A strong correlation existed between antibody levels to proinsulin and insulin within diabetic subjects. Similar proportions of diabetic (12%) and healthy (9.5%) subjects displayed T-cell responses to proinsulin. There was no correlation between antibody and T-cell responses to proinsulin within subjects. Amino acid region 56 to 72 was identified as the major T-cell epitope of proinsulin, though significant responses to region 14 to 37 were also present. Conclusion: Elevated proinsulin autoantibodies in diabetic subjects confirm proinsulin is an important autoantigen in type 1 diabetes. Though elevated cellular immunity to proinsulin protein was not detected, two dominant T-cell epitopes of proinsulin were identified that span the C-peptide and insulin junctions. Immunity to proinsulin was lower than that reported for childhood-onset type 1 diabetes and we propose that, like insulin, proinsulin may be targeted less frequently in adulthood