Abstract
Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity. Autoantibodies to numerous 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 phospholipid-binding proteins, particularly β2-glycoprotein I. Notably, mice immunized with β2-glycoprotein I and lipopolysaccharide develop a strong T cell response to β2-glycoprotein I that is associated with autoantibody production and renal disease, similar to that seen in human SLE. Here we hypothesized that mice with murine systemic lupus erythematosus, whether induced or spontaneous, should have T cells that recognize β2-glycoprotein I. We evaluated the response of splenic T cells from mice with induced (C57BL/6 and C3H/HeN) and spontaneous (MRL/lpr) systemic lupus erythematosus to peptides spanning the entire sequence of human β2GPI. We found that mice with induced and spontaneous systemic lupus erythematosus recognize a common T cell epitope (peptide 31; LYRDTAVFECLPQHAMFG) in domain III of β2-glycoprotein I. β2GPI-reactive CD4+ T cells from the two models differed primarily in cytokine production: T cells from mice with induced SLE expressed IFN-γ, while T cells from MRL/lpr mice expressed both IL-17 and IFN-γ, indicating that IL-17-expressing T cells are not necessary for generating a β2GPI-reactive T cell response. These data suggest that the generation of a β2-glycoprotein I-reactive T cell response is shared by both induced and spontaneous models of systemic lupus erythematosus and that this T cell response may mediate epitope spread to autoantibodies in both models.
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Acknowledgements
This study has been funded in part by operating grants from the Canadian Institutes of Health Research (CIHR; MOP-67101 and MOP-97916; J.R.) and funding from the Department of Medicine of McGill University, the Research Institute of the McGill University Health Centre, the Division of Rheumatology of McGill University, and the Arthritis Society of Canada (Rheumatic Disease Unit grant). D.S. is the recipient of a studentship from the FRQS and a Merit Fellowship from the Department of Microbiology and Immunology. J.S.L. is supported by institutional funds from Dr. José A. Arruda and the Section of Nephrology, University of Illinois at Chicago. The authors are grateful to Dr. Salman Qureshi for providing the C3H/HeN mice used in this study, and to Annie Beauchamp for her expertise and technical assistance with the mice.
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Salem, D., Subang, R., Kuwana, M. et al. T cells from induced and spontaneous models of SLE recognize a common T cell epitope on β2-glycoprotein I. Cell Mol Immunol 16, 685–693 (2019). https://doi.org/10.1038/s41423-018-0013-3
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DOI: https://doi.org/10.1038/s41423-018-0013-3
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