C-Reactive Protein Inhibits Plasmacytoid Dendritic Cell Interferon Responses to Autoantibody Immune Complexes
C-Reactive Protein Inhibits Plasmacytoid Dendritic Cell Interferon Responses to Autoantibody Immune Complexes
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DOI：
10.1002/art.37968
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发表时间：
2013-07-01
影响因子：
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通讯作者：
Du Clos, Terry W.
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文献类型：
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作者：
Mold, Carolyn;Du Clos, Terry W.
ObjectiveC 反应蛋白 (CRP) 是一种血清模式识别分子，可与凋亡细胞、核蛋白自身抗原和 Fc 受体 (FcR) 结合。在系统性红斑狼疮 (SLE) 中，含有核蛋白自身抗原的免疫复合物 (IC) 会激活浆细胞样树突状细胞 (PDC) 产生 I 型干扰素 (IFN)，从而促进疾病发病机制。自身抗体 IC 被 PDC 通过 IIa 型 FcR 摄取到内涵体中，其中核酸成分激活 Toll 样受体 7 (TLR-7) 或 TLR-9。本研究的目的是探讨 CRP 对 PDC 和单核细胞对核蛋白自身抗原和 IC 反应的影响。方法从健康志愿者中分离外周血单核细胞 (PBMC)、纯化的单核细胞和 PDC，并用含有凋亡细胞、小核 RNP (snRNP) 或 DNA 的自身抗体 IC 刺激，或直接用 TLR-7 和 TLR-9 激动剂刺激。通过酶联免疫吸附测定和多重测定分析上清液的干扰素和细胞因子水平。对小核RNP进行荧光标记，并通过流式细胞术和共聚焦显微镜测量CRP对自身抗体snRNP复合物的结合、摄取和细胞内定位的影响。结果与自身抗原结合的CRP不会在PBMCs或PDCs中诱导IFN，而与自身抗体形成的复合物则会诱导IFN。值得注意的是，CRP 抑制 IFN 对抗 U1 RNP-snRNP 复合物和抗 DNA-DNA 复合物的反应，但不抑制对其他 TLR-7 和 TLR-9 激动剂的反应。 CRP直接抑制PDC IFN释放，促进PDC分化，并增加PDC和单核细胞中自身抗原的晚期内体定位。结论CRP是I型IFN对SLE IC反应的调节剂。 CRP 增加了晚期内体中 IC 的细胞内加工，这与细胞内 TLR 激活后 I 型 IFN 的合成减少有关。
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.