C-Reactive Protein Inhibits Plasmacytoid Dendritic Cell Interferon Responses to Autoantibody Immune Complexes

ObjectiveC-reactive protein (CRP) is a serum pattern recognition molecule that binds to apoptotic cells and nucleoprotein autoantigens and Fc receptors (FcR). 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 FcR 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. MethodsPeripheral 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 IFN 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. ResultsCRP bound to autoantigen did not induce IFN in PBMCs or PDCs, whereas complexes formed with autoantibody did. Significantly, CRP inhibited the IFN 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 IFN release, promoted PDC differentiation, and increased late endosome localization of autoantigen in PDCs and monocytes. ConclusionCRP 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.