TY - JOUR
T1 - Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation
AU - Jackson, Shaun W.
AU - Scharping, Nicole E.
AU - Kolhatkar, Nikita S.
AU - Khim, Socheath
AU - Schwartz, Marc A.
AU - Li, Quan Zhen
AU - Hudkins, Kelly L.
AU - Alpers, Charles E.
AU - Liggitt, Denny
AU - Rawlings, David J.
PY - 2014/5/15
Y1 - 2014/5/15
N2 - 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.
AB - 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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U2 - 10.4049/jimmunol.1400098
DO - 10.4049/jimmunol.1400098
M3 - Article
C2 - 24711620
AN - SCOPUS:84901282428
SN - 0022-1767
VL - 192
SP - 4525
EP - 4532
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -