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

Arthritis Res Ther. 2009;11(4):R112. doi: 10.1186/ar2771. Epub 2009 Jul 22.

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autoantibodies / biosynthesis
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • Autoantigens / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Immunoprecipitation
  • Interleukin-6
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Nucleic Acids / immunology
  • Protein Array Analysis
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / immunology*
  • Receptor, Interferon alpha-beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptors / biosynthesis
  • Toll-Like Receptors / immunology*

Substances

  • Autoantibodies
  • Autoantigens
  • Ifnar2 protein, mouse
  • Interleukin-6
  • Nucleic Acids
  • Toll-Like Receptors
  • Receptor, Interferon alpha-beta