Insufficient Autoantigen Presentation and Failure of Tolerance in a Mouse Model of Rheumatoid Arthritis

Abstract

Objective 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 development of arthritis. Methods To increase the antigen presentation of GPI, we generated transgenic mice expressing a membrane-bound form of GPI (mGPI) and crossed them to the K/BxN mice. A monoclonal antibody specific for the alpha chain of the KRN TCR was generated to follow the fate of GPI-specific T cells. Results mGPI transgenic mice presented GPI more efficiently and showed a dramatic increase of 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 periphery, suggesting that enhanced antigen presentation also induces peripheral tolerance. Despite this apparent tolerance induction towards GPI, these mice did go on to develop a chronic wasting disease, characterized by colonic inflammation with epithelial dysplasia, as well as a dramatic reduction in Treg cells. Conclusion These data indicate that insufficient autoantigen expression or presentation results in defects of both central and peripheral tolerance in the K/BxN mice. It supports the idea that insufficient autoantigen levels may underlie the development of autoimmunity.

Follicular Helper T Cells in Systemic Lupus Erythematosus

“…In this mice, self-reactive CD4 + T cells escape clonal deletion in the thymus and appear in periphery. The primed self-reactive CD4 + T cells help B cells to produce pathologic antibodies ( 87 ). Tfh cells have been shown to contribute to the pathogenesis of lupus through ICOS–B7RP-1 pathway in NZB/NZW F1 mice ( 88 ).…”

Association BetweenAIREPolymorphisms rs870881(C>T), rs1003854(T>C) and Rheumatoid Arthritis Risk: A Hungarian Case-control Study

“…Quantitatively inappropriate presentation of self-antigens may decrease the effectiveness of central and peripheral tolerance, causing the survival and maturation of autoreactive thymocytes which leads to various autoimmune diseases, including RA. This effect has been confirmed for the glucose-6-phosphate isomerase self-antigen in the K/BxN mouse model of RA (15). Numerous studies describe the fundamental contribution to RA development of defective selection of autoimmune T cells and the resultant synovial infiltration of CD4 + type 1 T helper (Th) 1, Th2, Th17, and regulatory T cells (3,(16)(17)(18).…”

In vitro and ex vivo functional characterization of human HLA-DRB1∗04 restricted T cell receptors

“…The concept of specifically suppressing the response to a limited set of autoantigens, while leaving the rest of the immune system intact, should be compared to the current long-term, non-curative, broadly immunosuppressive treatments used for these patients. Multiple tolerance strategies have been suggested and proven in various pre-clinical model systems [ 41 , 42 , [45] , [46] , [47] , [48] ]. Often such strategies are based on providing the autoantigen in a context that induces tolerance (anergy, cell death, or T-reg induction of autoreactive clones), or modify the response in order to cause less tissue damage (e.g.…”