Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus.
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.
Kono
Dwight H
DH
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. dkono@scripps.edu
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
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D011992:Endosomes / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009154:Mutation / Q000235:genetics; D009696:Nucleic Acids / Q000494:pharmacology; D010851:Picrates / Q000494:pharmacology; D012217:Rheumatoid Factor / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009696:Nucleic Acids; D010851:Picrates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D012217:Rheumatoid Factor; C005858:picric acid