Autoimmune responses to the beta cell autoantigen, insulin, and the INS VNTR-IDDM2 locus

Type 1 diabetes is associated with autoimmunity to insulin. Genetic suscept ibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 loc us which may regulate the expression of insulin in pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a ge netic susceptibility conferred by the INS VNTR-IDDM2 locus, peripheral bloo d T cell proliferation to human insulin and insulin autoantibodies (IAA) wa s measured in patients with new onset type 1 diabetes and control subjects. IAA were detected in 21 of 53 patients and in none of 25 control subjects, while T cell responses were low (stimulation index range 0.4-7.2) and simi lar in both groups. Both antibody and T cell responses were higher in young er subjects and IAA were more prevalent in patients with the HLA-DR4 allele . No relationship was observed between humoral and cellular responses to in sulin. No association was found between the INS VNTR-IDDM2-susceptible alle le and insulin autoimmunity. Increased T cell responses and IAA were found in patients with either the diabetes-susceptible or the diabetes-protective INS VNTR-IDDM2 locus genotypes, and increased T cell responses were also f ound in control subjects with either susceptible or protective INS VNTR-IDD M2 locus genotypes. This study confirms that primary T cell proliferative r esponses to insulin are low and detectable also in control subjects. The de tection of T cell proliferation and autoantibodies to insulin in subjects w ith and without the protective INS VNTR-IDDM2 locus genotypes does not supp ort the hypothesis of an allele-specific capacity for tolerance induction w hich could determine a susceptibility to develop autoimmunity against the i nsulin protein and subsequently diabetes.