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Diabetologia
Published in: Diabetologia 5/2005

01-05-2005 | Article

Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes

Authors: M. Schlosser, J. P. Banga, A. M. Madec, K. A. Binder, M. Strebelow, I. Rjasanowski, R. Wassmuth, L. K. Gilliam, D. Luo, C. S. Hampe

Published in: Diabetologia | Issue 5/2005

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Abstract

Aims/hypothesis

Progression to type 1 diabetes is associated with intramolecular epitope spreading to disease-specific antibody epitopes located in the middle region of glutamic acid decarboxylase 65 (GAD65).

Methods

The relationship between intramolecular epitope spreading of autoantibodies specific to GAD65 in relation to the risk of developing type 1 diabetes was tested in 22 high-risk individuals and 38 low-risk individuals. We determined the conformational epitopes in this longitudinal study by means of competition experiments using recombinant Fab of four GAD65-specific monoclonal antibodies.

Results

Sera from high-risk children in the preclinical stage recognise a specific combination of GAD65 antibody epitopes located in the middle and the C-terminus of GAD65. High risk of progressing to disease is associated with the emergence of antibodies specific for conformational epitopes at the N-terminus and the middle region. Binding to already established antibody epitopes located in the middle and at the N-terminus increases and shows a significant relation (p=0.005) with HLA, which confers risk of developing diabetes.

Conclusions/interpretation

In type 1 diabetes, GAD65 antibodies are initially generated against the middle and C-terminal regions of GAD65. In genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading towards epitopes on the N-terminus and further epitopes located in the middle. These findings clearly demonstrate that the GAD65 autoantibody response in the preclinical stage of type 1 diabetes is dynamic and related to the HLA genotypes that confer risk of diabetes. GAD65-specific Fab should prove useful in predicting progression from islet autoimmunity to clinical onset of type 1 diabetes.
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Metadata
Title
Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes
Authors
M. Schlosser
J. P. Banga
A. M. Madec
K. A. Binder
M. Strebelow
I. Rjasanowski
R. Wassmuth
L. K. Gilliam
D. Luo
C. S. Hampe
Publication date
01-05-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-1719-1

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