Rodríguez-Carrio Javier, Alperi-López Mercedes, López-Mejías Raquel, López Patricia, Ballina-García Francisco J, Abal Francisco, González-Gay Miguel Á, Suárez Ana
Area of Immunology, Department of Functional Biology, University of Oviedo, 33006 Asturias, Spain Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (IPLA-CSIC), 33300 Asturias, Spain.
Department of Rheumatology, Hospital Universitario Central de Asturias, 33011 Asturias, Spain.
Clin Sci (Lond). 2016 Nov 1;130(21):1889-99. doi: 10.1042/CS20160374. Epub 2016 Aug 12.
Traditional and non-traditional cardiovascular (CV) risk factors underlie CV disease occurrence in rheumatoid arthritis (RA). Recently, a functional impairment of high-density lipoprotein (HDL) has been observed. Although the actual players are unknown, anti-HDLs were associated with altered lipid profile, decreased paraoxonase 1 (PON1) activity and CV disease in RA. Therefore, we aimed to evaluate whether the presence of antibodies against PON1 may be involved in this scenario. IgG anti-PON1 antibodies were quantified by ELISA in serum samples from 212 RA patients, 175 healthy controls (HC) and 54 subjects with traditional CV risk factors (CVR). A subgroup of 13 RA patients was prospectively followed upon tumour necrosis factor-α (TNFα) blockade. Serum PON1 activity, nitric oxide (NO) and total antioxidant capacity (TAC) were measured. Interferon-γ (IFNγ), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule (sICAM) and TNFα serum levels were assessed by immunoassays. PON1 rs662 (Q > R) status was studied by reverse transcription (RT)-PCR. IgG anti-PON1 antibodies are increased in RA patients compared with HC (P<0.0001) and CVR subjects (P<0.001), even after correcting for total IgG levels. Although no associations with lipid profile were found, a positive correlation with Health Assessment Questionnaire (HAQ) was observed (r=0.215, P=0.004). Anti-PON1 antibodies were associated with PON1 activity, NO and TAC, a rs662-mediated gene-dosage effect being found. Similarly, anti-PON1 antibodies were associated with sICAM serum levels in univariate and multivariate models. Finally, these antibodies were not affected by TNFα blockade. Anti-PON1 antibodies can be responsible for PON1 impairment in RA patients, with a potential impact on biomarkers of oxidative status and endothelial activation. A gene-environment interaction of rs662 variants is supported.
传统和非传统心血管（CV）危险因素是类风湿关节炎（RA）中CV疾病发生的基础。最近，已观察到高密度脂蛋白（HDL）的功能受损。尽管实际机制尚不清楚，但抗HDL与RA患者脂质谱改变、对氧磷酶1（PON1）活性降低及CV疾病有关。因此，我们旨在评估抗PON1抗体的存在是否参与了这一情况。通过酶联免疫吸附测定（ELISA）对212例RA患者、175例健康对照（HC）和54例有传统CV危险因素（CVR）的受试者的血清样本中的IgG抗PON1抗体进行定量。对13例RA患者的亚组在肿瘤坏死因子-α（TNFα）阻断治疗后进行前瞻性随访。检测血清PON1活性、一氧化氮（NO）和总抗氧化能力（TAC）。通过免疫测定评估干扰素-γ（IFNγ）、白细胞介素8（IL-8）、单核细胞趋化蛋白1（MCP-1）、血管内皮生长因子（VEGF）、可溶性细胞间黏附分子（sICAM）和TNFα血清水平。通过逆转录（RT）-PCR研究PON1 rs662（Q > R）状态。与HC（P<0.0001）和CVR受试者（P<0.001）相比，RA患者的IgG抗PON1抗体增加，即使校正总IgG水平后也是如此。虽然未发现与脂质谱相关，但观察到与健康评估问卷（HAQ）呈正相关（r=0.215，P=0.004）。抗PON1抗体与PON1活性、NO和TAC相关，发现存在rs662介导的基因剂量效应。同样，在单变量和多变量模型中，抗PON1抗体与sICAM血清水平相关。最后，这些抗体不受TNFα阻断的影响。抗PON1抗体可能导致RA患者的PON1功能受损，对氧化状态和内皮激活的生物标志物有潜在影响。支持rs662变体的基因-环境相互作用。
