Mr. Perera and Ms Liu contributed equally to this work.
Insufficient Autoantigen Presentation and Failure of Tolerance in a Mouse Model of Rheumatoid Arthritis
Article first published online: 28 OCT 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 11, pages 2847–2856, November 2013
How to Cite
Perera, J., Liu, X., Zhou, Y., Joseph, N. E., Meng, L., Turner, J. R. and Huang, H. (2013), Insufficient Autoantigen Presentation and Failure of Tolerance in a Mouse Model of Rheumatoid Arthritis. Arthritis & Rheumatism, 65: 2847–2856. doi: 10.1002/art.38085
- Issue published online: 28 OCT 2013
- Article first published online: 28 OCT 2013
- Accepted manuscript online: 9 JUL 2013 02:33PM EST
- Manuscript Accepted: 2 JUL 2013
- Manuscript Received: 24 AUG 2012
- NIH (National Institute of Allergy and Infectious Diseases). Grant Numbers: R01-AI-087645, 2T32-AI-007090
In the K/BxN mouse model of rheumatoid arthritis, T cells reactive for the self antigen glucose-6-phosphate isomerase (GPI) escape negative selection even though GPI expression is ubiquitous. We sought to determine whether insufficient GPI presentation could account for the failure of negative selection and for the development of arthritis.
To increase the antigen presentation of GPI, we generated transgenic mice expressing a membrane-bound form of GPI (mGPI) and crossed them with K/BxN mice. A monoclonal antibody specific for the α-chain of the KRN T cell receptor was generated to examine the fate of GPI-specific T cells.
The mGPI-transgenic mice presented GPI more efficiently and showed a dramatic increase in negative selection and an inhibition of arthritis. Interestingly, thymic negative selection remained incomplete in these mice, and the escaped autoreactive T cells were anergic in the peripheral lymphoid organs, suggesting that enhanced antigen presentation also induces peripheral tolerance. Despite this apparent tolerance induction toward GPI, these mice developed a chronic wasting disease, characterized by colonic inflammation with epithelial dysplasia, as well as a dramatic reduction in Treg cells.
These data indicate that insufficient autoantigen expression or presentation results in defects of both central and peripheral tolerance in the K/BxN mice. Our findings also support the idea that insufficient autoantigen levels may underlie the development of autoimmunity.