Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 10, Pages 4525-4532Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1400098
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Funding
- National Institutes of Health [R01HL075453, R01AI084457, R01AI071163, 5T32AR007108, K12HD043376]
- Cancer Research Institute Pre-doctoral Training Grants
- Rheumatology Research Foundation Scientist Development Award
- Arnold Lee Smith Endowed Professorship for Research Faculty Development
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Systemic lupus erythematosus is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acidassociated Ags. The endosomal TLRs TLR7 and TLR9 are critical for generation of Abs targeting RNA-or DNA-associated Ags, respectively. In murine lupus models, deletion of TLR7 limits autoimmune inflammation, whereas deletion of TLR9 exacerbates disease. Whether B cell or myeloid TLR7/TLR9 signaling is responsible for these effects has not been fully addressed. In this study, we use a chimeric strategy to evaluate the effect of B cell-intrinsic deletion of TLR7 versus TLR9 in parallel lupus models. We demonstrate that B cell-intrinsic TLR7 deletion prevents RNA-associated Ab formation, decreases production of class-switched Abs targeting nonnuclear Ags, and limits systemic autoimmunity. In contrast, B cell-intrinsic TLR9 deletion results in decreased DNA-reactive Ab, but increased Abs targeting a broad range of systemic autoantigens. Further, we demonstrate that B cell-intrinsic TLR9 deletion results in increased systemic inflammation and immune complex glomerulonephritis, despite intact TLR signaling within the myeloid compartment. These data stress the critical importance of dysregulated B cell-intrinsic TLR signaling in the pathogenesis of systemic lupus erythematosus.
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