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

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 patho...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2008-04, Vol.118 (4), p.1417-1426
Main Authors: 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
Format: Article
Language:English
Subjects:
Acids
Adjuvants, Immunologic
Animals
Antigens
Autoantibodies - immunology
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Biomedical research
Connective tissue diseases
Gene expression
Gene Expression Profiling
Genes
Health aspects
Immunoglobulin G
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
Kidney Diseases - genetics
Kidney Diseases - metabolism
Kidney Diseases - pathology
Lupus
Mice
Mice, Inbred BALB C
Mice, Knockout
Pathogenesis
Physiological aspects
Plasmacytoma - genetics
Plasmacytoma - metabolism
Plasmacytoma - pathology
Protein Binding
Proteins
Signal transduction
STAT1 Transcription Factor - deficiency
STAT1 Transcription Factor - genetics
STAT1 Transcription Factor - metabolism
Toll-Like Receptor 7 - metabolism
Toll-Like Receptor 9 - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci30065