Diabetologia

, Volume 43, Issue 2, pp 210–217

Epitope spreading and a varying but not disease-specific GAD65 antibody response in Type I diabetes

  • P. Söhnlein
  • M. Müller
  • K. Syren
  • U. Hartmann
  • B. O. Böhm
  • H. M. Meinck
  • M. Knip
  • H. K. Akerblom
  • W. Richter
  • The Childhood Diabetes in Finland Study Group
Article

DOI: 10.1007/s001250050031

Cite this article as:
Söhnlein, P., Müller, M., Syren, K. et al. Diabetologia (2000) 43: 210. doi:10.1007/s001250050031

Abstract

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]

Keywords Glutamate decarboxylase, autoantibodies, epitope-specificity, Type I diabetes, polyendocrine autoimmune syndrome, stiff-man syndrome, prediabetes.
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Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • P. Söhnlein
    • 1
  • M. Müller
    • 2
  • K. Syren
    • 2
  • U. Hartmann
    • 2
  • B. O. Böhm
    • 2
  • H. M. Meinck
    • 3
  • M. Knip
    • 4
  • H. K. Akerblom
    • 5
  • W. Richter
    • 5
  • The Childhood Diabetes in Finland Study Group
  1. 1. Dept of Orthopaedic Surgery University of Heidelberg, GermanyDE
  2. 2. Department of Internal Medicine 1, University of Ulm, Ulm, GermanyDE
  3. 3. Department of Clinical Neurology, University of Heidelberg, GermanyDE
  4. 4. Medical School University of Tampere and Deptartment of Paediatrics, Tampere University Hospital, Tampere, FinlandFI
  5. 5. Hospital for Children and Adolescents, University of Helsinki, Helsinki, FinlandFI