1. B Cell αv Integrins Regulate TLR-Driven Autoimmunity
- Author
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Quan Z. Li, Lauren Kadavy, Sara Sagadiev, Emily Gilbertson, Mei Yan, Mridu Acharya, Adam Lacy-Hulbert, Jessica A. Hamerman, Fiona Raso, and Lynda M. Stuart
- Subjects
Genetically modified mouse ,Immunology ,Autoimmunity ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Lymphocyte Activation ,Immune Regulation ,Immunomodulation ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans ,Lupus Erythematosus, Systemic ,B cell ,Cells, Cultured ,Autoantibodies ,B-Lymphocytes ,Membrane Glycoproteins ,Autoantibody ,RNA ,Integrin alphaV ,Cell biology ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Toll-Like Receptor 7 ,Immunoglobulin G ,Regulatory Pathway ,DNA ,030215 immunology - Abstract
Systemic lupus erythematosus (SLE) is defined by loss of B cell tolerance, resulting in production of autoantibodies against nucleic acids and other cellular Ags. Aberrant activation of TLRs by self-derived RNA and DNA is strongly associated with SLE in patients and in mouse models, but the mechanism by which TLR signaling to self-ligands is regulated remains poorly understood. In this study, we show that αv integrin plays a critical role in regulating B cell TLR signaling to self-antigens in mice. We show that deletion of αv from B cells accelerates autoantibody production and autoimmune kidney disease in the Tlr7.1 transgenic mouse model of SLE. Increased autoimmunity was associated with specific expansion of transitional B cells, extrafollicular IgG2c-producing plasma cells, and activation of CD4 and CD8 T cells. Our data show that αv-mediated regulation of TLR signaling in B cells is critical for preventing autoimmunity and indicate that loss of αv promotes escape from tolerance. Thus, we identify a new regulatory pathway in autoimmunity and elucidate upstream signals that adjust B cell activation to prevent development of autoimmunity in a mouse model.
- Published
- 2020