Rajamohan A, Heit B, Cairns E, Barra L
Department of Microbiology and Immunology, The University of Western Ontario, London, ON, Canada.
Robarts Research Institute, London, ON, Canada.
Scand J Rheumatol. 2021 Sep;50(5):343-350. doi: 10.1080/03009742.2020.1867237. Epub 2021 Mar 6.
: Antibodies to citrullinated and homocitrullinated (also known as carbamylated) proteins, specific for rheumatoid arthritis (RA), are associated with cardiovascular disease (CVD). Immune complexes containing these proteins have been identified in the atherosclerotic plaque of CVD patients. In mice, homocitrullinated low-density lipoprotein (HomoCitLDL) promotes foam cell formation, which is critical in the pathogenesis of atherosclerosis. We aimed to investigate the atherogenic potential of HomoCitLDL and citrullinated low-density lipoprotein (CitLDL) in RA.: Human LDL was homocitrullinated in potassium cyanate and citrullinated by rabbit skeletal muscle peptidyl arginine deiminase-2. The modifications were confirmed by mass spectrometry. Primary human monoctyes from healthy subjects (N = 8) were differentiated to macrophages using macrophage colony-stimulating factor and incubated with modified LDL. Foam cells were visualized using Oil Red O staining. Serum from RA patients (N = 101) and controls (N = 32) was tested for immunoglobulin G antibodies to modified LDL using enzyme-linked immunosorbent assay.: HomoCitLDL and CitLDL strongly induced foam cell production (> 90%) versus unmodified LDL (11%) (p < 0.0001). The characteristics of the RA subjects were: 73% females, median age 60 [interquartile range (IQR) 17] years and disease duration 7.5 (IQR 13) years; 11% had a prior major cardiovascular event, 66% were ever smokers, 32% had hypertension, 33% dyslipidaemia, and 14% diabetes. Antibodies to HomoCitLDL were detected in 18% of RA patients; they were significantly associated with dyslipidaemia [odds ratio (OR) 3.86; 95% confidence interval (CI) 1.22, 12.17] and antibodies to other homocitrullinated antigens (OR 10.61; 95% CI 1.31, 86.11).: HomoCitLDL and CitLDL have atherogenic properties in vitro. Antibody responses to HomoCitLDL, but not CitLDL, were detected in RA patients.
对瓜氨酸化和高瓜氨酸化（也称为氨甲酰化）蛋白的抗体，对类风湿性关节炎（RA）具有特异性，与心血管疾病（CVD）相关。在CVD患者的动脉粥样硬化斑块中已鉴定出含有这些蛋白的免疫复合物。在小鼠中，高瓜氨酸化低密度脂蛋白（HomoCitLDL）促进泡沫细胞形成，这在动脉粥样硬化的发病机制中至关重要。我们旨在研究HomoCitLDL和瓜氨酸化低密度脂蛋白（CitLDL）在RA中的致动脉粥样硬化潜力。
人低密度脂蛋白在氰酸钾中进行高瓜氨酸化，并通过兔骨骼肌肽基精氨酸脱亚氨酶-2进行瓜氨酸化。通过质谱法确认修饰。使用巨噬细胞集落刺激因子将来自健康受试者（N = 8）的原代人单核细胞分化为巨噬细胞，并与修饰的低密度脂蛋白一起孵育。使用油红O染色观察泡沫细胞。使用酶联免疫吸附测定法检测RA患者（N = 101）和对照组（N = 32）血清中针对修饰低密度脂蛋白的免疫球蛋白G抗体。
与未修饰的低密度脂蛋白（11%）相比，HomoCitLDL和CitLDL强烈诱导泡沫细胞产生（>90%）（p<0.0001）。RA受试者的特征为：73%为女性，中位年龄60岁[四分位间距（IQR）17岁]，病程7.5年（IQR 13年）；11%曾有过重大心血管事件，66%曾经吸烟，32%患有高血压，33%患有血脂异常，14%患有糖尿病。18%的RA患者检测到针对HomoCitLDL的抗体；它们与血脂异常显著相关[比值比（OR）3.86；95%置信区间（CI）1.22，12.17]以及与其他高瓜氨酸化抗原的抗体（OR 10.61；95%CI 1.31，86.11）。
HomoCitLDL和CitLDL在体外具有致动脉粥样硬化特性。在RA患者中检测到针对HomoCitLDL而非CitLDL的抗体反应。
