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

DH Kono, MK Haraldsson… - Proceedings of the …, 2009 - National Acad Sciences
DH Kono, MK Haraldsson, BR Lawson, KM Pollard, YT Koh, X Du, CN Arnold, R Baccala
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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 …
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.
National Acad Sciences