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Unique Epitopes of Glutamic Acid Decarboxylase Autoantibodies in Slowly Progressive Type 1 Diabetes

Third Department of Internal Medicine (T.K., S.T.), Yamanashi Medical University, Tamaho, Yamanashi 409-3898, Japan; Department of Endocrinology and Metabolism (M.O., K.N.), Toranomon Hospital, Tokyo, 105-8470, Japan; Okinaka Memorial Institute for Medical Research (M.O., K.N., T.M.), Tokyo 105-8470, Japan; and Department of Medicine (Å.L.), University of Washington, Seattle, Washington 98195-7710

Address all correspondence and requests for reprints to: Tetsuro Kobayashi, M.D., Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Yamanashi 409-3898, Japan. E-mail: tetsurou{at}yamanashi.ac.jp.

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 residing between amino acids 244–360 was identified in 17% (8 of 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 ß-cell failure in SPIDDM.

This work was supported, in part, by a grant from the Ministry of Education, Science, Sports and Culture, Japan.

Abbreviations: AIDDM, Acute onset type 1 (insulin-dependent) diabetes mellitus; AU, arbitrary units; GABA, -aminobutyric acid; GAD, glutamic acid decarboxylase; GAD65Ab, glutamic acid decarboxylase 65 autoantibodies; HLA, human lymphocyte antigen; IA-2Ab, insulinoma-associated protein 2/islet cell antigen 512 autoantibodies; NS, not significant; SDS, SD score; SMS, stiff-man syndrome; SPIDDM, slowly progressive type 1 (insulin-dependent) diabetes mellitus.

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