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-α 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.
Donna L. Thibault, Alvina D. Chu, Kareem L. Graham, Imelda Balboni, Lowen Y. Lee, Cassidy Kohlmoos, Angela Landrigan, John P. Higgins, Robert Tibshirani, Paul J. Utz
Serum Ig isotype levels in pristane-treated mice.