Studies on epitopes of glutamic acid decarboxylase 65 (GAD65) antibodies in type 1 diabetes

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Disease-specific epitope profiles of glutamic acid decarboxylase (GAD) 65 autoantibodies (GAD65Ab) were studied in slowly progressive type 1 (insulin-dependent) diabetes mellitus (SPIDDM) and acute onset type 1 (insulin-dependent) diabetes mellitus (AIDDM) using seven kinds of GAD65/67 chimeric molecules. Sera obtained from Japanese SPIDDM (n = 17) and AIDDM (n = 46) patients followed prospectively were analyzed by immunoprecipitation, ELISA and western blotting.GAD65Ab in all SPIDDM samples reacted specifically with an N-terminal linear epitope located on the membrane anchoring domain between amino acids 17-51 and C-terminal conformational epitope between amino acids 443-585 of GAD65. The binding of GAD65Ab with N-terminal 83 residues in SPIDDM inversely correlated with the period in which insulin was not required. GAD65Ab in AIDDM did not react with N-terminal epitope located between amino acids 1-83 irrespective of the titer of GAD65Ab. A novel epitope of GAD65Ab in AIDDM resided between amino acids 244-360 was identified in 17% (8/46) of patients whose age of onset was younger than other AIDDM patients.In conclusion, GADAb in SPIDDM has unique N-terminal linear epitopes that are located on the anchoring domain of GAD65 molecules. Association is suggested between GAD65Ab targeted to this region and slowly progressive β-cell failure in SPIDDM.