Abstract
IntroductionSystemic 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.MethodsWild-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.ResultsAutoantigen 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.ConclusionsOur 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.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of hightiter IgG autoantibodies directed against nuclear autoantigens
Autoantigen microarray profiling revealed that pristanetreated IFNAR2-/- mice lacked autoantibodies directed against components of the RNA-associated autoantigen complexes Smith antigen/ribonucleoprotein (Sm/RNP) and ribosomal phosphoprotein P0 (RiboP)
We have previously shown that the IFN-I signaling molecules IFN regulatory factor 9 (IRF9) and STAT1 are required for the production of IgG autoantibodies in the pristane model and mediate the IFN-I-inducible expression of TLR7 and TLR9 in B cells [32]
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of hightiter IgG autoantibodies directed against nuclear autoantigens. 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. ANA: anti-nuclear autoantibody; ELISA: enzyme-linked immunosorbent assay; FBS: fetal bovine serum; GAM-Ig: goat-anti-mouse-immunoglobulin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HRP: horseradish peroxidase; IFN-I: type I interferon; IFNAR: interferon-I receptor; IL-6: interleukin-6; IRF9: interferon regulatory factor 9; ODN: oligodeoxynucleotide; OVA: ovalbumin; PBS: phosphate-buffered saline; PDC: plasmacytoid dendritic cell; RiboP: ribosomal phosphoprotein P0; RNP: ribonucleoprotein; SAM: significance analysis of microarrays; SLE: systemic lupus erythematosus; Sm: Smith antigen; snRNP: small nuclear ribonucleoprotein; SOCS1: suppressor of cytokine signaling 1; ssDNA: single-stranded DNA; TAM: Tyro-3, Axl, and Mer; TLR: Toll-like receptor; WT: wild-type. TLRs control isotype switching to pathogenic IgG isotypes in SLE as MyD88-/- and TLR9-/- SLE mice lack autoantibodies of the IgG2a and IgG2b subclasses [19]
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