Opposing impact of B cell–intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation

SW Jackson, NE Scharping, NS Kolhatkar… - The Journal of …, 2014 - journals.aai.org
SW Jackson, NE Scharping, NS Kolhatkar, S Khim, MA Schwartz, QZ Li, KL Hudkins…
The Journal of Immunology, 2014journals.aai.org
Systemic lupus erythematosus is a multisystem autoimmune disease characterized by
autoantibodies targeting nucleic acid–associated 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 …
Abstract
Systemic lupus erythematosus is a multisystem autoimmune disease characterized by autoantibodies targeting nucleic acid–associated 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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