Lood Christian, Gullstrand Birgitta, Truedsson Lennart, Olin Anders I, Alm Gunnar V, Rönnblom Lars, Sturfelt Gunnar, Eloranta Maija-Leena, Bengtsson Anders A
Lund University Hospital and Lund University, Lund, Sweden.
Arthritis Rheum. 2009 Oct;60(10):3081-90. doi: 10.1002/art.24852.
C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFNalpha).
Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFNalpha production was determined by an immunoassay.
C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNalpha production induced by ICs and CpG DNA but increased PDC IFNalpha production induced by HSV. The regulatory role of C1q was not specific for IFNalpha but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins.
Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.
C1q缺乏是已知的系统性红斑狼疮（SLE）发病最强的危险因素，因为几乎所有遗传性C1q缺乏的人都会患此病。低C1q血清浓度也是SLE病情活动期的典型表现，这强调了C1q参与SLE的发病机制。最近的研究表明，C1q对Toll样受体诱导的细胞因子产生具有调节作用。因此，我们进行了这项研究，以调查C1q是否能调节α干扰素（IFNα）的产生。
用3种已知的干扰素诱导刺激物刺激外周血单个核细胞（PBMC）和浆细胞样树突状细胞（PDC），并与生理浓度的C1q一起培养。通过免疫测定法测定IFNα的产生。
C1q显著抑制由含RNA免疫复合物（IC）、单纯疱疹病毒（HSV）和CpG DNA诱导的PBMC的IFNα产生。C1q也抑制由IC和CpG DNA诱导的PDC的IFNα产生，但增加由HSV诱导的PDC的IFNα产生。C1q的调节作用并非特异性针对IFNα，对白介素-6（IL-6）、IL-8和肿瘤坏死因子α也有调节作用。我们通过表面等离子体共振相互作用分析和流式细胞术证明了C1q与PDC的结合，并且还证明了细胞内两种C1q结合蛋白的检测。
我们的研究结果有助于理解为什么C1q缺乏是SLE如此强的危险因素，并为SLE患者中I型干扰素系统上调提供了解释。
