| Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. | |
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MedLine Citation:
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PMID: 19574451 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Dwight H Kono; M Katarina Haraldsson; Brian R Lawson; K Michael Pollard; Yi Ting Koh; Xin Du; Carrie N Arnold; Roberto Baccala; Gregg J Silverman; Bruce A Beutler; Argyrios N Theofilopoulos |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-07-02 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 106 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-22 Completed Date: 2009-08-25 Revised Date: 2010-09-27 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 12061-6 Citation Subset: IM |
Affiliation:
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Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. dkono@scripps.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Antinuclear / immunology* B-Lymphocytes / cytology, drug effects, immunology Dendritic Cells / cytology, drug effects, immunology Endosomes / drug effects, immunology* Immunoglobulin G / immunology Immunoglobulin M / immunology Lupus Erythematosus, Systemic / immunology*, pathology Lymphocyte Activation / drug effects Male Mice Mice, Inbred MRL lpr Mutation / genetics Nucleic Acids / pharmacology Picrates / pharmacology Rheumatoid Factor / immunology* Signal Transduction / drug effects, immunology* Survival Analysis T-Lymphocytes / cytology, drug effects, immunology Toll-Like Receptor 4 / immunology Toll-Like Receptors / immunology* |
| Grant Support | |
ID/Acronym/Agency:
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AI059777/AI/NIAID NIH HHS; AR053228/AR/NIAMS NIH HHS; AR31203/AR/NIAMS NIH HHS; AR39555/AR/NIAMS NIH HHS; AR42242/AR/NIAMS NIH HHS; ES07511/ES/NIEHS NIH HHS; GM67759/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Antinuclear; 0/Immunoglobulin G; 0/Immunoglobulin M; 0/Nucleic Acids; 0/Picrates; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; 0/Toll-Like Receptors; 88-89-1/picric acid; 9009-79-4/Rheumatoid Factor |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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