Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-06, Vol.107 (22), p.10154-10159
• Main Authors: Savitsky, David A, Yanai, Hideyuki, Tamura, Tomohiko, Taniguchi, Tadatsugu, Honda, Kenya
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigens; Arthritis; Arthritis, Experimental - immunology; Autoantibodies; Autoantibodies - biosynthesis; Autoantibodies - genetics; Autoimmune diseases; B lymphocytes; B-Lymphocytes - immunology; Biological Sciences; Cells; Disease Models, Animal; Female; Gene expression regulation; Humans; Immune system; Immunity, Innate; Immunoglobulin G - biosynthesis; Immunoglobulin G - genetics; Interferon; Interferon Regulatory Factors - deficiency; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Lupus; Lupus Erythematosus, Systemic - etiology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pathogenesis; Polyclonal antibodies; Rodents; Secretion; Systemic lupus erythematosus; Toll-Like Receptor 9 - metabolism; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005599107

Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Toll-like receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in Irf5⁻/⁻ mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the γ2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.