title: C-reactive protein inhibits plasmacytoid dendritic cell interferon responses to autoantibody immune complexes.
abstract: OBJECTIVE
  C-reactive protein (CRP) is a serum pattern recognition molecule that binds to apoptotic cells and nucleoprotein autoantigens and Fcγ receptors (FcγR). In systemic lupus erythematosus (SLE), immune complexes (ICs) containing nucleoprotein autoantigens activate plasmacytoid dendritic cells (PDCs) to produce type I interferon (IFN), which contributes to disease pathogenesis. Autoantibody ICs are taken up by PDCs through FcγR type IIa into endosomes, where the nucleic acid components activate Toll-like receptor 7 (TLR-7) or TLR-9. The objective of this study was to investigate the effect of CRP on PDC and monocyte responses to nucleoprotein autoantigens and ICs.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs), purified monocytes, and PDCs were isolated from healthy volunteers and stimulated with autoantibody ICs containing apoptotic cells, small nuclear RNPs (snRNPs), or DNA, or directly with TLR-7 and TLR-9 agonists. Supernatants were analyzed for IFNα and cytokine levels by enzyme-linked immunosorbent assay and multiplex assay. Small nuclear RNPs were fluorescence-labeled, and the effect of CRP on binding, uptake, and intracellular localization of autoantibody snRNP complexes was measured by flow cytometry and confocal microscopy.
  
  
  RESULTS
  CRP bound to autoantigen did not induce IFNα in PBMCs or PDCs, whereas complexes formed with autoantibody did. Significantly, CRP inhibited the IFNα response to both anti-U1 RNP-snRNP complexes and anti-DNA-DNA complexes, but not to other TLR-7 and TLR-9 agonists. CRP directly inhibited PDC IFNα release, promoted PDC differentiation, and increased late endosome localization of autoantigen in PDCs and monocytes.
  
  
  CONCLUSIONS
  CRP is a regulator of the type I IFN response to SLE ICs. CRP increased the intracellular processing of ICs in late endosomes, which is associated with decreased synthesis of type I IFN after intracellular TLR activation.
authors.affiliation: University of New Mexico Health Sciences Center, Albuquerque, NM, USA. CMold@salud.unm.edu
authors.forename: Carolyn
authors.initials: C
authors.lastname: Mold
authors.forename: Terry W Du
authors.initials: TW
authors.lastname: Clos
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology*; D002097:C-Reactive Protein / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology; D020298:U937 Cells
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D016207:Cytokines; D007370:Interferon Type I; D016898:Interferon-alpha; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D002097:C-Reactive Protein