Association between Antibodies to the MR 67,000 Isoform of Glutamate Decarboxylase (GAD) and Type 1 (Insulin-Dependent) Diabetes Mellitus with Coexisting Autoimmune Polyendocrine Syndrome Type II

Abstract

By using an immunoprecipitation assay, we analysed reactivity of autoantibodies to human recombinant GAD₆₅ and GAD₆₇ in sera from patients with autoimmune polyendocrine syndrome Type II (APS II) with and without Type 1 (insulin-dependent) diabetes mellitus (IDDM) compared to patients with organ-specific autoimmunity. Overall antibodies to GAD₆₅ were correlated with IDDM in all study groups, whereas GAD₆₇ antibodies were associated with IDDM when APS II coexists. Antibodies to GAD₆₅ and GAD₆₇ were detected in 13 (44.8%) and 7 (24.1%) out of 29 APS II patients with IDDM, but in only 4 (13.8%) and 2 (6.9%) out of 29 APS II patients without IDDM, respectively (p < 0.05). In short-standing IDDM (< 1 year), antibodies to GAD₆₇ were significantly more frequent in patients with APS II (5 of 9 [55.6%] subjects) compared to matched diabetic patients without coexisting polyendocrinopathy (1 of 18 [5.6%] subjects) (p < 0.02). The levels of GAD₆₅ (142 ± 90 AU) and GAD₆₇ antibodies (178 ± 95 AU) were significantly higher in patients with polyglandular disease than in patients with isolated IDDM (91 ± 85 AU and 93 ± 57 AU) (p < 0.02). Interestingly, all 11 GAD₆₇ antibody positive subjects also had GAD₆₅ antibodies (p < 0.0001), and in 10 of 11 anti-GAD₆₇ positive sera the GAD₆₇ antibodies could be blocked by either GAD₆₇ or GAD₆₅, suggesting the presence of cross-reactive autoantibodies. No correlation was observed between GAD antibodies and age, sex or any particular associated autoimmune disease, besides IDDM. GAD antibodies were present in only 1 of 6 (16.7%) patients with APS Type I, in 1 of 26 (3.9%) patients with autoimmune thyroid disease but in none of the patients with Addison's disease (n = 16), pernicious anaemia (n = 7) or normal controls (n = 50). Our data suggest distinct antibody specificities reactive to GAD isoforms in APS II and IDDM, which might reflect different mechanisms of autoimmune response in IDDM with coexisting autoimmune polyendocrine autoimmunity.

Key Words:

• Insulin-dependent diabetes mellitus
• autoimmune polyendocrine syndrome
• glutamic acid decarboxylase
• autoimmunity