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Recognition of Glutamic Acid Decarboxylase (GAD) by Autoantibodies from Different GAD Antibody-Positive Phenotypes¹

Department of Medicine (C.S.H., L.P.H., L.B., Å.L.), University of Washington, Seattle, Washington 98195; Department of Woman and Child Health (E.Ö., B.P.) and Department of Molecular Medicine, Clinical Genetics (I.K.), Karolinska Institute, 171 76 Stockholm, Sweden; Department of Public Health and Clinical Medicine (O.R.), Umeå University, 901 87 Umeå, Sweden; and Department of Medicine (M.L.-O., C.T.), University Hospital, 221 00 Lund, Sweden

Address correspondence and requests for reprints to: Christiane S. Hampe, Department of Medicine, Box 357710, University of Washington, Seattle, Washington 98195. E-mail:champe{at}u.washington.edu

Autoantibodies against the smaller isoform of glutamic acid decarboxylase (GAD) are markers for Type 1 diabetes. GAD65 autoantibody (GAD65Ab)-positive individuals in the general population are, however, mostly at low risk of developing Type 1 diabetes, suggesting that GAD65Ab phenotypes may be associated with different underlying pathogenic processes. The aim of this study was to test the hypothesis that Type 1 diabetes patients (n = 243; group I), GAD65Ab-positive healthy individuals (n = 28; group II), and healthy first-degree relatives of Type 1 diabetes patients (n = 41; group III) have antibody phenotypes that recognize different GAD65 epitopes. Sera from groups I–III were tested for their binding to GAD65 and GAD67, as well as six different GAD65/67 fusion proteins. Regardless of group, sera reactive to both GAD65 and GAD67 showed broader epitope reactivity than GAD65-specific sera. Furthermore, Type 1 diabetes patients showed a more restricted epitope binding than healthy individuals and first-degree relatives, demonstrating significantly less binding to the N-terminal part of GAD65 and to GAD67. Our analysis demonstrates that the N-terminal part is essential for full antibody binding to GAD65, in particular, to the middle epitope. It is suggested that Type 1 diabetes is associated with restricted GAD65Ab epitope specificity.

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