期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 9, 页码 5543-5554出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.619817
关键词
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资金
- Canadian Institutes of Health Research (CIHR)/Institute of Musculoskeletal Health and Arthritis (IMHA)/Arthritis Society [MOP-42391]
- CIHR [MOP-67101, MOP-97916]
- CIHR/IMHA [MUS-67101]
- Japanese Ministry of Health, Labor and Welfare
- Arthritis Society/Canadian Arthritis Network
- Research Institute of the McGill University Health Centre
- Section of Nephrology, University of Illinois at Chicago
Systemic lupus erythematosus (SLE) is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous and molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting the apoptotic cell-binding protein beta(2)-glycoprotein I (beta(2)GPI). Notably, mice immunized with beta(2)GPI and LPS display a remarkably similar pattern of autoantibody emergence to that seen in human SLL. Here, we used this model to investigate whether epitope spread to SLE-related autoantibodies is associated with a unique or limited AAWI-specific T cell response. We ask whether MHC class II haplotype and its associated T cell epitope restriction impact epitope spread to SLE-related autoantibodies. We found that beta(2)GPI/LPS-immunized mice produced similar SLE-related autoantibody profiles regardless of their beta(2)GPI T cell epitope specificity or MHC class II haplotype. Although beta(2)GPI T cell epitope specificity was clearly determined by MHC class II haplotype, a number of different beta(2)GP IT cell epitopes were associated with epitope spread to SLE-related autoantibodies. Notably, one beta(2)GPI T cell epitope (peptide 23, NTGFYLNGADSAKCT) was also recognized by T cells from an HLA-DRB1*0403(+) autoimmune patient. These data suggest that the generation of a beta(2)GPI-reacfive T cell response is associated with epitope spread to SLE-related autoantibodies, independent of epitope specificity or MHC class II restriction. On the basis of these findings, we propose that factors enabling a beta(2)GPI-reactive T cell response may predispose individuals to the development of SLE-related autoantibodies independent of their MHC class II haplotype.
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