Antigenic determinants to GAD autoantibodies in patients with type 1 diabetes with and without autoimmune thyroid disease.

Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases. Most T1D patients' sera contain two distinct glutamic acid decarboxylase (GAD) antibody specificities, of which one targets an epitope region in the middle-third of GAD65 (amino acids 221-359) and the other targets the carboxy-third of GAD65 (amino acids 453-569). Using five chimeric GAD65/GAD67 proteins to maintain conformation-dependent epitopes of GAD65, we compared the humoral repertoire of antibodies from 127 T1D patients with and without autoimmune thyroid diseases (ATD). Thirty-one patients with T1D (24%) expressed antithyroid autoantibodies ATA and 22 patients (17%) had ATD in comparison to 6% of age-matched controls having ATA. GAD65-antibody-positive patients much more often (28% versus 5%, P < 0.0004) had ATD. Of 66 GAD65-autoantibody-positive T1D patients, 34 had autoantibodies reacting with both middle and carboxy epitopes. Autoantibodies of the other 32 reacted with middle, carboxy, or other epitopes but not with both middle- and carboxy-third. Those with GAD65 autoantibodies reacting with both middle- and carboxy-third had less ATD. Of 22 (23%) patients with ATD, 5 compared to 29 of 47 (62%) T1D patients without ATD had GAD65 autoantibodies reacting with both middle- and carboxy-third (relative risk = 0.2, P < 0.01). These results indicate that there are both similarities and differences in the humoral response to GAD65 in ATD and T1D, and expression of antibodies to middle- and carboxy-third at the same time is a feature specific to T1D.