caa a22 4500 475772962 CHVBK 20180406123622.0 cr unu---uuuuu 170329e20000201xx s 000 0 eng 10.1007/s001250050031 doi (NATIONALLICENCE)springer-10.1007/s001250050031 Epitope spreading and a varying but not disease-specific GAD65 antibody response in Type I diabetes [Elektronische Daten] [P. Söhnlein, M. Müller, K. Syren, U. Hartmann, B. O. Böhm, H. M. Meinck, M. Knip, H. K. Akerblom, W. Richter] Aims/hypothesis. The aim of this study was to analyse the conformational and linear epitope profiles of glutamic acid decarboxylase antibody (GAD65-ab)-positive sera to find disease-specific epitope profiles and to study, whether GAD65-ab epitope recognition changes or spreads during the prediabetic period and, thus, can provide markers to differentiate early from later stages of progression to diabetes.¶Methods. Sera from subjects before (n = 21), at onset (n = 44), or at increased risk of Type I (insulin-dependent) diabetes mellitus (n = 20) and from patients with stiff-man syndrome (SMS, n = 18) or polyendocrine autoimmune syndrome (PAS, n = 21) were analysed for conformational and linear GAD65 epitope recognition by an immunohistochemical blocking test based on human monoclonal GAD65-ab (MICA 1-10) and western blotting of a GAD65 epitope-cDNA-library.¶Results. A redundant reactivity of many GAD65-ab positive sera to three major conformational (EP-1, EP-2, EP-3) and two dominant linear epitope clusters (amino acid 1-124 and 535-585) was observed in diabetes, polyendocrine autoimmune syndrome and stiff-man syndrome and no disease-specific epitopes or epitope-profiles were detected. Epitope recognition broadened with higher titres and with the vulnerability of patients to acquire additional autoimmune diseases apart from diabetes. Low GAD65-ab serum titres ( < 1200 arbitrary units) and EP-1 recognition in the absence of EP-2 binding characterised the early immune response. Changing epitope profiles combined stable recognition of EP-1 with gain or loss of reactivity to C-terminal epitopes during follow-up.¶Conclusion/interpretation. A maturing autoantibody response, which could spread from EP-1-recognition to other regions of GAD65, resulted in titre-related rather than disease-specific epitope profiles which were not sufficient to predict whether GAD65-ab positive subjects will progress to Type I diabetes, autoimmune polyendocrine syndrome or stiff-man syndrome. [Diabetologia (2000) 43: 210-217] Springer-Verlag Berlin Heidelberg, 2000 Keywords Glutamate decarboxylase, autoantibodies, epitope-specificity, Type I diabetes, polyendocrine autoimmune syndrome, stiff-man syndrome, prediabetes nationallicence Söhnlein P. Dept of Orthopaedic Surgery University of Heidelberg, Germany, DE aut Müller M. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut Syren K. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut Hartmann U. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut Böhm B. O. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut Meinck H. M. Department of Clinical Neurology, University of Heidelberg, Germany, DE aut Knip M. Medical School University of Tampere and Deptartment of Paediatrics, Tampere University Hospital, Tampere, Finland, FI aut Akerblom H. K. Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, FI aut Richter W. Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, FI aut https://doi.org/10.1007/s001250050031 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250050031 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Söhnlein P. Dept of Orthopaedic Surgery University of Heidelberg, Germany, DE aut NATIONALLICENCE 700 1- Müller M. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut NATIONALLICENCE 700 1- Syren K. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut NATIONALLICENCE 700 1- Hartmann U. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut NATIONALLICENCE 700 1- Böhm B. O. Department of Internal Medicine 1, University of Ulm, Ulm, Germany, DE aut NATIONALLICENCE 700 1- Meinck H. M. Department of Clinical Neurology, University of Heidelberg, Germany, DE aut NATIONALLICENCE 700 1- Knip M. Medical School University of Tampere and Deptartment of Paediatrics, Tampere University Hospital, Tampere, Finland, FI aut NATIONALLICENCE 700 1- Akerblom H. K. Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, FI aut NATIONALLICENCE 700 1- Richter W. Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, FI aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer