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


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-Fas(lpr) 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.

SUBMITTER: Kono DH 

PROVIDER: S-EPMC2715524 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Kono Dwight H DH   Haraldsson M Katarina MK   Lawson Brian R BR   Pollard K Michael KM   Koh Yi Ting YT   Du Xin X   Arnold Carrie N CN   Baccala Roberto R   Silverman Gregg J GJ   Beutler Bruce A BA   Theofilopoulos Argyrios N AN  

Proceedings of the National Academy of Sciences of the United States of America 20090702 29


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-Fas(lpr) 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 ant  ...[more]

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