THE RELATIONSHIP BETWEEN HUMORAL AND CELLULAR-IMMUNITY TO IA-2 IN IDDM

Autoantibodies to the neuroendocrine protein insulinoma-associated pro tein 2 (IA-2), a member of the tyrosine phosphatase family, have been observed in individuals with or at increased risk for IDDM. Because th is disease is thought to result from a T-cell-mediated autoimmune dest ruction of the insulin-producing pancreatic beta-cells, we analyzed hu moral and cellular immune reactivity to this autoantigen to further de fine its role in the pathogenesis of IDDM. Peripheral blood mononuclea r cells (PBMC) from individuals with newly diagnosed IDDM or at varyin g levels of risk for the disease were stimulated in vitro with the ent ire 42-kDa internal domain of IA-2 (amino acids 603-979), a series of control antigens (glutathionine-S-transferase, tetanus toroid, Candida albicans, mumps, bovine serum albumin), and a mitogen (phytohemagglut inin). The frequency and mean stimulation index of PBMC proliferation against IA-2 was significantly higher in newly diagnosed IDDM subjects (14 of 33 [42%]; 3.8 +/- 4.5 at 10 mu g/ml) and autoantibody-positive relatives at increased risk for IDDM (6 of 9 [66%]; 3.9 +/- 3.2) comp ared with autoantibody-negative relatives (1 of 15 [7%]; 1.8 +/- 1.0) or healthy control subjects (1 of 12 [8%]; 1.5 +/- 1.0). The frequenci es of cellular immune reactivities to all other antigens were remarkab ly similar between each subject group. Sera from 58% of the newly diag nosed IDDM patients tested mere IA-2 autoantibody positive. Despite in vestigations suggesting an inverse association between humoral and cel lular immune reactivities against islet-cell-associated autoantigens, no such relationship was observed (r(s) = 0.18, P = 0.39) with respect to IA-2. These studies support the autoantigenic nature of IA-2 in ID DM and suggest the inclusion of cellular immune responses as an adjunc t marker for the disease.