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Open Access Research article

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 Thibault12*, Kareem L Graham1, Lowen Y Lee1, Imelda Balboni13, Paul J Hertzog4 and Paul J Utz1

Author Affiliations

1 Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive, CCSR 2250, Stanford, CA, 94305, USA

2 Current address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

3 Department of Pediatrics, Division of Pediatric Rheumatology, Stanford University School of Medicine, 300 Pasteur Drive, Boswell Building A085, Stanford, CA, 94305, USA

4 Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia

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Arthritis Research & Therapy 2009, 11:R112  doi:10.1186/ar2771

Published: 22 July 2009

Abstract

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-α.

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.