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Reduced display of conformational epitopes in the N-terminal truncated GAD65 isoform : relevance for people with stiff person syndrome or DQ8/8-positive Type 1 diabetes mellitus

Author:
  • C. S. Hampe
  • J. R. Radtke
  • A. Wester
  • A. Carlsson
  • E. Cedervall
  • B. Jönsson
  • S. A. Ivarsson
  • H. Elding Larsson
  • K. Larsson
  • B. Lindberg
  • J. Neiderud
  • O. Rolandsson
  • Lernmark
Publishing year: 2018
Language: English
Publication/Series: Diabetic Medicine
Document type: Journal article
Publisher: Wiley-Blackwell

Abstract english

Aims: To investigate whether the N-terminal truncated glutamic acid decarboxylase 65 (GAD65) isoform is as well recognized by people with stiff person syndrome as it is by people with Type 1 diabetes, and whether conformational GAD65 antibody epitopes are displayed properly by the isoform. Methods: GAD65 antibody-positive healthy individuals (n=13), people with stiff-person syndrome (n=15) and children with new-onset Type 1 diabetes (n=654) were analysed to determine binding to full-length GAD65 and the N-terminal truncated GAD65 isoform in each of these settings. GAD65 autoantibody epitope specificity was correlated with binding ratios of full-length GAD65/N-terminal truncated GAD65. Results: The N-terminal truncated GAD65 isoform was significantly less recognized in GAD65Ab-positive people with stiff-person syndrome (P=0.002) and in healthy individuals (P=0.0001) than in people with Type 1 diabetes. Moreover, at least two specific conformational GAD65Ab epitopes were not, or were only partially, presented by the N-terminal truncated GAD65 isoform compared to full-length GAD65. Finally, an N-terminal conformational GAD65Ab epitope was significantly less recognized in DQ8/8 positive individuals with Type 1 diabetes (P=0.02). Conclusions: In people with stiff person syndrome preferred binding to the full-length GAD65 isoform over the N-terminal truncated molecule was observed. This binding characteristic is probably attributable to reduced presentation of two conformational epitopes by the N-terminal truncated molecule. These findings support the notion of disease-specific GAD65Ab epitope specificities and emphasize the need to evaluate the applicability of novel assays for different medical conditions.

Keywords

  • Endocrinology and Diabetes

Other

Epub
  • PediatricCeliaki/Diabetes
  • Paediatric Endocrinology
  • Diabetes and Celiac Unit
  • ISSN: 0742-3071
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

+46 40 39 19 01

+46 70 616 47 79

60:11:015

Jan Waldenströms gata 35, Malmö

33

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00