IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

J Clin Invest. 2008 Apr;118(4):1417-26. doi: 10.1172/JCI30065.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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

Substances

  • Adjuvants, Immunologic
  • Autoantibodies
  • Immunoglobulin G
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • STAT1 Transcription Factor
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9