INVERSE RELATION BETWEEN HUMORAL AND CELLULAR-IMMUNITY TO GLUTAMIC-ACID DECARBOXYLASE IN SUBJECTS AT RISK OF INSULIN-DEPENDENT DIABETES

Glutamic acid decarboxylase (GAD) in pancreatic beta cells is an autoa ntigen in insulin-dependent diabetes (IDD). We measured immunity to GA D in 31 first-degree relatives of IDD patients judged to be at risk of developing IDD themselves because of the presence of islet-cell antib odies. We found that in most of the subjects GAD autoimmunity was eith er predominantly humoral or predominantly cellular. High concentration s of circulating autoantibodies that precipitate native GAD activity w ere associated with low proliferation of peripheral-blood T cells to r ecombinant GAD; conversely, low concentrations of autoantibody to GAD were associated with high T-cell proliferation to GAD. Although T-cell proliferation was measured in the presence of autologous serum, GAD a utoantibodies did not have a blocking effect in vitro. This dichotomy of the immune response to GAD defined heterogeneity within at-risk rel atives and could have prognostic importance. We postulate that, if GAD is a pathogenetic autoantigen, sensitisation to beta-cell GAD is more likely to lead to IDD when the immune response deviates towards the e xpansion of autoreactive T cells rather than towards generation of aut oantibodies. This idea is consistent with evidence that beta-cell dest ruction is mediated by T cells and that high concentrations of GAD ant ibodies are associated with slower progression to clinical disease.