RRC ID 5462
Author Thibault DL, Chu AD, Graham KL, Balboni I, Lee LY, Kohlmoos C, Landrigan A, Higgins JP, Tibshirani R, Utz PJ.
Title IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice.
Journal J. Clin. Invest.
Abstract A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.
Volume 118(4)
Pages 1417-26
Published 2008-4
DOI 10.1172/JCI30065
PMID 18340381
PMC PMC2267033
MeSH Adjuvants, Immunologic Animals Autoantibodies / immunology* B-Lymphocytes / immunology* B-Lymphocytes / metabolism* Gene Expression Profiling Immunoglobulin G / biosynthesis Immunoglobulin G / classification Immunoglobulin G / immunology* Interferon-Stimulated Gene Factor 3, gamma Subunit / deficiency Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism* Kidney Diseases / genetics Kidney Diseases / metabolism Kidney Diseases / pathology Mice Mice, Inbred BALB C Mice, Knockout Plasmacytoma / genetics Plasmacytoma / metabolism Plasmacytoma / pathology Protein Binding STAT1 Transcription Factor / deficiency STAT1 Transcription Factor / genetics STAT1 Transcription Factor / metabolism* Toll-Like Receptor 7 / metabolism* Toll-Like Receptor 9 / metabolism
IF 13.251
Times Cited 52