IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet at Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
Clin Immunol. 2016 May;166-167:27-37. doi: 10.1016/j.clim.2016.04.007. Epub 2016 Apr 19.
Phosphorylcholine (PC) and malondialdehyde (MDA) are generated during lipid peroxidation and form adducts with proteins as albumin as studied herein. Atherosclerosis and cardiovascular disease (CVD) are increased in systemic lupus erythematosus (SLE). We here investigate the role and regulation of IgM antibodies against PC (anti-PC) and MDA (anti-MDA).
IgM anti-PC and anti-MDA in SLE patients (n=114) were compared with age- and sex-matched population-based controls (n=108). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded according to echogenicity (potentially vulnerability). Production of IgM anti-PC and anti-MDA by B cells was determined by ELISA and ELISPOT. The effect of anti-PC and anti-MDA on macrophage uptake of apoptotic cells and oxidative stress was studied by flow cytometry.
Above 66rd percentile together, IgM anti-PC and anti-MDA were striking protection markers for plaque prevalence and echolucency in SLE (OR: 0.08, CI: 0.01-0.46 and OR: 0.10, CI: 0.01-0.82), respectively, and risk markers for plaque prevalence when below 33rd percentile: OR: 3.79, CI: (1.10-13.00). In vitro, IgM anti-PC and anti-MDA were much higher when B cells were co-cultured with CD3 T cells. Anti-HLA-, anti-CD40 antibody or CD40 silencing abolished these effects. Uptake of apoptotic cells was increased by IgM anti-PC and anti-MDA. MDA induced increased oxidative stress, which was inhibited by IgM anti-MDA.
Unexpectedly, both IgM anti-MDA and IgM anti-PC are T-cell dependent and especially together, are strong protection markers for atherosclerosis in SLE. Underlying mechanisms include increased phagocytosis of apoptotic cells and decrease of oxidative stress.
在脂质过氧化过程中会产生磷酸胆碱（PC）和丙二醛（MDA），并与白蛋白等蛋白质形成加合物。系统性红斑狼疮（SLE）会增加动脉粥样硬化和心血管疾病（CVD）的风险。在此，我们研究了针对 PC（抗-PC）和 MDA（抗-MDA）的 IgM 抗体的作用和调节。
比较了 114 例 SLE 患者和 108 例年龄和性别匹配的基于人群的对照组的 IgM 抗-PC 和抗-MDA。通过 B 型超声测量颈总动脉内膜中层厚度（IMT）和斑块的发生情况。根据回声强度（潜在易损性）对斑块进行分级。通过 ELISA 和 ELISPOT 测定 B 细胞产生的 IgM 抗-PC 和抗-MDA。通过流式细胞术研究抗-PC 和抗-MDA 对巨噬细胞摄取凋亡细胞和氧化应激的影响。
IgM 抗-PC 和抗-MDA 超过第 66 百分位数时，在 SLE 中对斑块发生率和回声均有显著保护作用（OR：0.08，CI：0.01-0.46 和 OR：0.10，CI：0.01-0.82），低于第 33 百分位数时则为斑块发生率的风险标志物：OR：3.79，CI：（1.10-13.00）。体外，当 B 细胞与 CD3 T 细胞共培养时，IgM 抗-PC 和抗-MDA 的水平要高得多。抗-HLA-、抗-CD40 抗体或 CD40 沉默可消除这些作用。IgM 抗-PC 和抗-MDA 可增加对凋亡细胞的摄取。MDA 诱导的氧化应激增加，而 IgM 抗-MDA 可抑制氧化应激。
出乎意料的是，IgM 抗-MDA 和 IgM 抗-PC 均依赖于 T 细胞，尤其是两者同时存在时，是 SLE 动脉粥样硬化的强烈保护标志物。潜在机制包括增加对凋亡细胞的吞噬作用和减少氧化应激。
