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

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.

• 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
• Journal: Diabetologia (Diabetologia) Vol. 48 Issue 5 Pg. 922-30 (May 2005) ISSN: 0012-186X [Print] Germany
• PMID: 15834701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Autoantibodies
• Epitopes
• HLA Antigens
• Immunoglobulin Fab Fragments
• Isoenzymes
• Glutamate Decarboxylase
• glutamate decarboxylase 2

Topics

• Adolescent
• Autoantibodies (blood)
• Child
• Diabetes Mellitus, Type 1 (epidemiology, immunology)
• Epitopes (analysis)
• Female
• Genotype
• Glutamate Decarboxylase (immunology)
• HLA Antigens
• Humans
• Immunoglobulin Fab Fragments (immunology)
• Isoenzymes (immunology)
• Major Histocompatibility Complex
• Male
• Risk Factors