Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 118, Issue 4, Pages 1417-1426Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI30065
Keywords
-
Categories
Funding
- NHLBI NIH HHS [N01-HV-28183, N01HV28183] Funding Source: Medline
- NIAID NIH HHS [AI-10663-02, R01 AI051614, AI40093, AI051614, F31 AI010663, T32 AI007290, N01AI40093] Funding Source: Medline
- NIAMS NIH HHS [5 T32 AR050942, T32 AR050942] Funding Source: Medline
Ask authors/readers for more resources
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 autoandbodies 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available