Immune reactivity to glutamic acid decarboxylase 65 in stiff-man syndrome and type 1 diabetes mellitus

Background The immune response to an isoform of glutamic acid decarboxylase (GAD), GAD65, is associated with two clinically distinct diseases, stiff-m an syndrome (SMS) and type 1 (insulin-dependent) diabetes mellitus. We soug ht to identify differences in the cellular and humoral immune responses to GAD in these two diseases. Methods We compared T-cell responses in 14 SMS patients with axial disease and 17 patients with type 1 diabetes. Findings Peripheral blood T cells of eight SMS patients recognised differen t immunodominant epitopes of GAD65 compared with T cells from 17 patients w ith type 1 diabetes. GAD regions 81-171 and 313-403 induced a dominant T-ce ll response in six of eight patients with SMS but in only one of 17 patient s with type 1 diabetes (p=0.001). No SMS patients responded dominantly to G AD fragments 161-243 and 473-555 compared with ten patients with type 1 dia betes (p=0.008). GAD antibodies were detected in 11 of 14 SMS patients (sev en with diabetes) and 11 of 17 patients with type 1 diabetes; IgG1 was domi nant in both groups. SMS patients, however, were more likely than patients with diabetes to have isotypes other than IgG1 (p=0.03), in particular, IgG 4 or IgE isotypes, which were not detected in patients with type 1 diabetes (p=0.012). Interpretation Our findings indicate differences between patients with SMS and type 1 diabetes in cellular (epitope recognition) and humoral (isotype pattern) responses to GAD65. Thus the same autoantigen can elicit distinct immune responses in patients with SMS, even when associated with diabetes, compared with patients with type 1 diabetes.