J Clin Invest 2008,
PMID: 18340381
Thibault, Donna L; Chu, Alvina D; Graham, Kareem L; Balboni, Imelda; Lee, Lowen Y; Kohlmoos, Cassidy; Landrigan, Angela; Higgins, John P; Tibshirani, Robert; Utz, Paul J
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.
Diseases/Pathways annotated by Medline MESH: Kidney Diseases, Plasmacytoma
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Text Mining Data
TLR7 → STAT1: "
IRF9 and
STAT1 are
required for IgG autoantibody production and B cell expression of
TLR7 in mice
"
TLR7 → IRF9: "
IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice
"
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