Статья

Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus

Donna L ThibaultDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305, USA. [email protected]Kareem L. GrahamDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive, CCSR 2250, Stanford, CA, 94305, USALowen Y. LeeDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive, CCSR 2250, Stanford, CA, 94305, USAImelda BalboniDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive, CCSR 2250, Stanford, CA, 94305, USAPaul J. HertzogCentre for Functional Genomics and Human Disease, Monash Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria, 3168, AustraliaPaul J. UtzDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive, CCSR 2250, Stanford, CA, 94305, USA

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Аннотация

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of high-titer IgG autoantibodies directed against nuclear autoantigens. Type I interferon (IFN-I) has been shown to play a pathogenic role in this disease. In the current study, we characterized the role of the IFNAR2 chain of the type I IFN (IFN-I) receptor in the targeting of nucleic acid-associated autoantigens and in B-cell expression of the nucleic acid-sensing Toll-like receptors (TLRs), TLR7 and TLR9, in the pristane model of lupus. METHODS: Wild-type (WT) and IFNAR2-/- mice were treated with pristane and monitored for proteinuria on a monthly basis. Autoantibody production was determined by autoantigen microarrays and confirmed using enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation. Serum immunoglobulin isotype levels, as well as B-cell cytokine production in vitro, were quantified by ELISA. B-cell proliferation was measured by thymidine incorporation assay. RESULTS: Autoantigen microarray profiling revealed that pristane-treated IFNAR2-/- mice lacked autoantibodies directed against components of the RNA-associated autoantigen complexes Smith antigen/ribonucleoprotein (Sm/RNP) and ribosomal phosphoprotein P0 (RiboP). The level of IgG anti-single-stranded DNA and anti-histone autoantibodies in pristane-treated IFNAR2-/- mice was decreased compared to pristane-treated WT mice. TLR7 expression and activation by a TLR7 agonist were dramatically reduced in B cells from IFNAR2-/- mice. IFNAR2-/- B cells failed to upregulate TLR7 as well as TLR9 expression in response to IFN-I, and effector responses to TLR7 and TLR9 agonists were significantly decreased as compared to B cells from WT mice following treatment with IFN-alpha. CONCLUSIONS: Our studies provide a critical link between the IFN-I pathway and the regulation of TLR-specific B-cell responses in a murine model of SLE.

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Идентификаторы

DOI: 10.1186/ar2771

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Цитирований: 2Использованных источников: 0

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