Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus

Dwight H. Kono, M. Katarina Haraldsson, Brian R. Lawson, K. Michael Pollard, Ting Koh Yi, Xin Du, Carrie N. Arnold, Roberto Baccala, Gregg J. Silverman, Bruce A. Beutler, Argyrios N. Theofilopoulos

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Using the Unc93b1 3d mutation that selectively abolishes nucleic acid-binding Toll-like receptor (TLR) (TLR3, -7, -9) signaling, we show these endosomal TLRs are required for optimal production of IgG autoAbs, IgM rheumatoid factor, and other clinical parameters of disease in 2 lupus strains, B6-Faslpr and BXSB. Strikingly, treatment with lipid A, an autoAb-inducing TLR4 agonist, could not overcome this requirement. The 3d mutation slightly reduced complete Freund's adjuvant (CFA)-mediated antigen presentation, but did not affect T-independent type 1 or alum-mediated T-dependent humoral responses or TLR-independent IFN production induced by cytoplasmic nucleic acids. These findings suggest that nucleic acid-sensing TLRs might act as an Achilles' heel in susceptible individuals by providing a critical pathway by which relative tolerance for nucleic acid-containing antigens is breached and systemic autoimmunity ensues. Importantly, this helps provide an explanation for the high frequency of anti-nucleic acid Abs in lupus-like systemic autoimmunity.

Original languageEnglish (US)
Pages (from-to)12061-12066
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number29
DOIs
StatePublished - Jul 21 2009

Keywords

  • Autoimmunity
  • Innate immunity
  • SLE
  • Unc93b1

ASJC Scopus subject areas

  • General

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    Kono, D. H., Haraldsson, M. K., Lawson, B. R., Pollard, K. M., Yi, T. K., Du, X., Arnold, C. N., Baccala, R., Silverman, G. J., Beutler, B. A., & Theofilopoulos, A. N. (2009). Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. Proceedings of the National Academy of Sciences of the United States of America, 106(29), 12061-12066. https://doi.org/10.1073/pnas.0905441106