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  • Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation.

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

Journal of immunology (Baltimore, Md. : 1950) (2014-04-09)
Shaun W Jackson, Nicole E Scharping, Nikita S Kolhatkar, Socheath Khim, Marc A Schwartz, Quan-Zhen Li, Kelly L Hudkins, Charles E Alpers, Denny Liggitt, David J Rawlings
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ribonucleic acid from torula yeast, core, Type II-C
Sigma-Aldrich
Ribonucleic acid from torula yeast, Type VI
Sigma-Aldrich
Ribonucleic acid from baker′s yeast (S. cerevisiae)
Sigma-Aldrich
Ribonucleic acid diethylaminoethanol salt, Type IX
Ribonucleic acid, European Pharmacopoeia (EP) Reference Standard