PERSISTENT GAD-65 ANTIBODIES IN LONGSTANDING IDDM ARE NOT ASSOCIATED WITH RESIDUAL BETA-CELL FUNCTION, NEUROPATHY OR HLA-DR STATUS

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxyl ase (GAD) has been described in a substantial proportion of patients w ith insulin-dependent diabetes mellitus (IDDM) of long duration. The s ource of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cel ls and in the nervous system we investigated in the present study of t he largest number of well characterized patients with longstanding IDD M (n=105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-pep tide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of t he 105 individuals. One hundred healthy control subjects and 100 recen t onset IDDM patients were also studied for GAD 65 antibodies, GAD 65 antibodies were detected in a radioligand-binding-assay with recombina nt human GAD 65 and were present in 32% of the long-term diabetic pati ents, 82% of the recent onset IDDM patients and in 3% of the healthy c ontrol subjects. A preserved C-peptide response to i.v. glucagon (Hend riksen criteria) was observed in 23% of the long-term IDDM patients, A utonomic neuropathy and peripheral neuropathy was identified using cri teria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients, Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were si gnificantly less frequent in the long-term IDDM patients compared to r ecent onset IDDM (p<0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r=0.22, p<0.0 1). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particul ar HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persi stent autoimmunity directed to GAD 65 in longstanding IDDM, The stimul us for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.