CYTOPLASMIC ISLET-CELL ANTIBODIES RECOGNIZE DISTINCT ISLET ANTIGENS IN IDDM BUT NOT IN STIFF MAN SYNDROME

Cytoplasmic islet cell antibodies are well-established predictive mark ers of IDDM. Although target molecules of ICA have been suggested to b e gangliosides, human monoclonal ICA of the immunoglobulin G class (MI CA 1-6) produced from a patient with newly diagnosed IDDM recognized g lutamate decarboxylase as a target antigen. Here we analyzed the possi ble heterogeneity of target antigens of ICA by subtracting the GAD-spe cific ICA staining from total ICA staining of sera. This was achieved 1) by preabsorption of ICA_ sera with recombinant GAD65 and/or GAD67 e xpressed in a baculovirus system and 2) by ICA analysis of sera on mou se pancreas, as GAD antibodies do not stain mouse islets in the immuno fluorescence test. We show that 24 of 25 sera from newly diagnosed pat ients with IDDM recognize islet antigens besides GAD. In contrast, GAD was the only islet antigen recognized by ICA from 7 sera from patient s with stiff man syndrome. Two of these sera, however, recognized anti gens besides GAD in Purkinje cells. In patients with IDDM, non-GAD ICA were diverse. One group, found in 64% of the sera, stained human and mouse islets, whereas the other group of non-GAD ICA was human specifi c. Therefore, mouse islets distinguish two groups of non-GAD ICA and l ack additional target epitopes of ICA besides GAD. Longitudinal analys is of 6 sera from nondiabetic ICA+ individuals revealed that mouse-rea ctive ICA may appear closer to clinical onset of IDDM in some individu als. Mouse-reactive ICAs, however, remained absent in 36% of the patie nts at diagnosis of IDDM.