HETEROGENEITY IN THE OCCURRENCE OF A SUBSET OF AUTOANTIBODIES TO GLUTAMIC-ACID DECARBOXYLASE IN AUTOIMMUNE POLYENDOCRINE PATIENTS WITH ISLET-CELL ANTIBODIES

Glutamic acid decarboxylase-65 (GAD-65) is a major target for autoanti bodies and autoreactive T cells in patients with insulin-dependent dia betes mellitus (IDDM). Autoantibodies to GAD are also found in patient s with stiff man syndrome (SMS) or polyendocrine autoimmunity (PE). Th e epitope specificities of autoantibodies to GAB in IDDM and SMS have been well documented, but the locations of autoantibody epitopes of GA D in PE patients have not been mapped. Thus, the properties of anti-GA D antibodies in PE patients (with or without diabetes) were investigat ed. The ability of PE serum antibodies to inhibit the binding of the m ouse monoclonal antibody, GAD-6, to native GAD in ELISA was determined . For PE patients without diabetes, levels of inhibition of GAD-6 bind ing ranged from 0% to almost 70% and were unrelated to the level of bi nding of serum antibodies to GAD (P = 0.351) or to the functional affi nities of these antibodies. This suggests differences in the epitope s pecificities of anti-GAD antibodies in different patients. Levels of i nhibition were also unrelated to clinical condition. SMS antibodies sh owed similar levels of inhibition of GAD-6 binding. Similar analysis w as applied to PE patients with diabetes and levels of inhibition of GA D-6 binding to GAD were determined. These ranged from 0% to 80%, and l evels of inhibition were similar in samples taken before or after diab etes onset. There was no significant difference between anti-GAD antib odies from PE patients with or without diabetes in the range of abilit ies to inhibit GAD-6 binding to GAD, although the highest levels of in hibition were given by sera from non-diabetic patients. This raises th e possibility of differential expression of subsets of anti-GAD antibo dies in progressive versus slow or non-progressive anti-islet autoimmu ne responses. Serum antibodies of PE and SMS patients did not inhibit the binding of antibodies specific for the extreme C-terminus of GAD, indicating that this is not the site of the epitopes for the patients' antibodies or for GAD-6.