Serological proteome analysis reveals new specific biases in the IgM and IgG autoantibody repertoires in autoimmune polyendocrine syndrome type 1

Abstract

Objective: Autoimmune polyendocrine syndrome type 1 (APS 1) is caused by mutations in the AIRE gene that induce intrathymic T-cell tolerance breakdown, which results in tissue-specific autoimmune diseases. Design: To evaluate the effect of a well-defined T-cell repertoire impairment on humoral self-reactive fingerprints, comparative serum self-IgG and self-IgM reactivities were analyzed using both one- and two-dimensional western blotting approaches against a broad spectrum of peripheral tissue antigens. Methods: Autoantibody patterns of APS 1 patients were compared with those of subjects affected by other autoimmune endocrinopathies (OAE) and healthy controls. Results: Using a Chi-square test, significant changes in the Ab repertoire were found when intergroup patterns were compared. A singular distortion of both serum self-IgG and self-IgM repertoires was noted in APS 1 patients. The molecular characterization of these antigenic targets was conducted using a proteomic approach. In this context, autoantibodies recognized more significantly either tissue-specific antigens, such as pancreatic amylase, pancreatic triacylglycerol lipase and pancreatic regenerating protein 1α, or widely distributed antigens, such as peroxiredoxin-2, heat shock cognate 71-kDa protein and aldose reductase. As expected, a well-defined self-reactive T-cell repertoire impairment, as described in APS 1 patients, affected the tissue-specific self-IgG repertoire. Interestingly, discriminant IgM reactivities targeting both tissue-specific and more widely expressed antigens were also specifically observed in APS 1 patients. Using recombinant targets, we observed that post translational modifications of these specific antigens impacted upon their recognition. Conclusions: The data suggest that T-cell-dependent but also T-cell-independent mechanisms are involved in the dynamic evolution of autoimmunity in APS 1.

• AIRE
• APS 1
• autoantibody repertoire
• post translational modifications
• T-dependent and T-independent mechanisms

Acknowledgements

We are particularly grateful to Prof. H. Lefebvre, Prof. J. M. Kuhn (Endocrinologie, Rouen), Prof. J. D. Lalau, Prof R. Desailloud (Endocrinologie, Amiens), Prof M. C. Vantyghem, Dr C. Cardot-Bauters (Endocrinologie, Lille), Dr J. Weil (Pédiatrie, Lille), Dr O. Verier-Mine (Endocrinologie, Valenciennes), Dr M. Lepage (Endocrinologie, Boulogne) and Dr B. Pigeon (Pédiatrie, Armentières) for their help with patient recruitment. We are indebted to Prof. F. Pattou, Prof. B. Carnaille, Dr L. Arnalsteen (Chirurgie viscérale et Endocrinienne, Lille), Prof. E. Leteurtre and Prof. X. Leroy (Anatomo-pathologie, Lille) for help in obtaining tissue extracts.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

This work was supported by a clinical and hospital research project grant (PHRC, EUDRACT: 2009-A00197-50 - PHRC NATIONAL).

Conceived and designed the experiments: SD, EP, DL, LP. Performed the experiments: EP, HK, AR, VLD, MB, SDB, PSW. Analyzed the data: SD, EP, DL. Contributed reagents/materials/analysis tools: EP, AR, JLW. Wrote the paper: SD, EP, DL, HK, JLW, LP.

Supplementary material available online

Supplementary Tables 1-2 and Supplementary Figures 1-2