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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4525-4532
Number of pages8
JournalJournal of Immunology
Volume192
Issue number10
DOIs
StatePublished - May 15 2014

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Autoantibodies
B-Lymphocytes
Inflammation
Systemic Lupus Erythematosus
RNA
DNA
Autoantigens
Glomerulonephritis
Antigen-Antibody Complex
Autoimmunity
Nucleic Acids
Autoimmune Diseases

ASJC Scopus subject areas

  • Immunology

Cite this

Jackson, S. W., Scharping, N. E., Kolhatkar, N. S., Khim, S., Schwartz, M. A., Li, Q. Z., ... Rawlings, D. J. (2014). Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. Journal of Immunology, 192(10), 4525-4532. https://doi.org/10.4049/jimmunol.1400098

Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. / Jackson, Shaun W.; Scharping, Nicole E.; Kolhatkar, Nikita S.; Khim, Socheath; Schwartz, Marc A.; Li, Quan Zhen; Hudkins, Kelly L.; Alpers, Charles E.; Liggitt, Denny; Rawlings, David J.

In: Journal of Immunology, Vol. 192, No. 10, 15.05.2014, p. 4525-4532.

Research output: Contribution to journalArticle

Jackson, SW, Scharping, NE, Kolhatkar, NS, Khim, S, Schwartz, MA, Li, QZ, Hudkins, KL, Alpers, CE, Liggitt, D & Rawlings, DJ 2014, 'Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation', Journal of Immunology, vol. 192, no. 10, pp. 4525-4532. https://doi.org/10.4049/jimmunol.1400098
Jackson, Shaun W. ; Scharping, Nicole E. ; Kolhatkar, Nikita S. ; Khim, Socheath ; Schwartz, Marc A. ; Li, Quan Zhen ; Hudkins, Kelly L. ; Alpers, Charles E. ; Liggitt, Denny ; Rawlings, David J. / Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. In: Journal of Immunology. 2014 ; Vol. 192, No. 10. pp. 4525-4532.
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