HLA-ASSOCIATED HETEROGENEITY OF THE HUMORAL RESPONSE TO ISLET ANTIGENS IN INSULIN-DEPENDENT DIABETES

Insulin-dependent diabetes mellitus (IDDM) is associated with suscepti bility HLA class II alleles. Islet cell antibodies (ICA), detected by indirect immunofluorescence on pancreas sections, represent the best m arker of the disease. Autoantibodies to glutamic acid decarboxylase (G ADA), one major islet antigen, do not totally account for ICA reactivi ty, suggesting heterogeneity of the anti-islet humoral response. In 97 patients with IDDM we have correlated ICA heterogeneity with clinical markers and DR and Do alleles. ICA were found in 81% of the patients, and in 33% the serum blocked the binding to islet cells of reference sera with a granular fluorescence pattern. GADA were found in 62% of c ases. Patients with high GADA titers and blocking sera were older at o nset and less often had a family history of IDDM, suggesting that thes e antibodies might be a marker of slow progression to IDDM. ICAs were not associated with particular HLA DR or Do alleles. Conversely, GADA were less frequent than ICA in DR4 subjects but not in the other group s. Moreover, among DR4 non-DR3 patients, GADA were found almost exclus ively in DRB1(star)0401 patients but not in other DR4 subtypes. There was an association of GADA with Do alleles but it was secondary to lin kage disequilibrium between DR and Do loci. In conclusion, the heterog eneity of the humoral response in IDDM is controlled by HLA class II g enes and correlates with clinical heterogeneity. (C) 1995 Academic Pre ss Limited