Merched Aksam J, Daret Danièle, Li Lan, Franzl Nathalie, Sauvage-Merched Maria
Department of Pharmaceutical Sciences, and INSERM U1053, University of Bordeaux, Bordeaux, France Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA.
FASEB J. 2016 Jun;30(6):2123-34. doi: 10.1096/fj.201500131. Epub 2016 Feb 18.
Higher cardiovascular morbidity in patients with a wide range of autoimmune diseases highlights the importance of autoimmunity in promoting atherosclerosis. Our purpose was to investigate the mechanisms of accelerated atherosclerosis and identified vascular autoantigens targeted by autoimmunity. We created a mouse model of autoimmunity-associated atherosclerosis by transplanting bone marrow from FcγRIIB knockout (FcRIIB(-/-)) mice into LDL receptor knockout mice. We characterized the cellular and molecular mechanisms of atherogenesis and identified specific aortic autoantigens using serologic proteomic studies. En face lesion area analysis showed more aggressive atherosclerosis in autoimmune mice compared with control mice (0.64 ± 0.12 vs 0.32 ± 0.05 mm(2); P < 0.05, respectively). At the cellular level, FcRIIB(-/-) macrophages showed significant reduction (46-72%) in phagocytic capabilities. Proteomic analysis revealed circulating autoantibodies in autoimmune mice that targeted 25 atherosclerotic lesion proteins, including essential components of adhesion complex, cytoskeleton, and extracellular matrix, and proteins involved in critical functions and pathways. Microscopic examination of atherosclerotic plaques revealed essential colocalization of autoantibodies with endothelial cells, their adherence to basement membranes, the internal elastica lamina, and necrotic cores. The new vascular autoimmunosome may be a useful target for diagnostic and immunotherapeutic interventions in autoimmunity-associated diseases that have accelerated atherosclerosis.-Merched, A. J., Daret, D., Li, L., Franzl, N., Sauvage-Merched, M. Specific autoantigens in experimental autoimmunity-associated atherosclerosis.
多种自身免疫性疾病患者较高的心血管发病率凸显了自身免疫在促进动脉粥样硬化中的重要性。我们的目的是研究动脉粥样硬化加速的机制，并确定自身免疫所靶向的血管自身抗原。我们通过将FcγRIIB基因敲除（FcRIIB(-/-)）小鼠的骨髓移植到低密度脂蛋白受体基因敲除小鼠中，创建了自身免疫相关动脉粥样硬化的小鼠模型。我们对动脉粥样硬化形成的细胞和分子机制进行了表征，并使用血清学蛋白质组学研究确定了特定的主动脉自身抗原。正面病变面积分析显示，与对照小鼠相比，自身免疫小鼠的动脉粥样硬化更严重（分别为0.64 ± 0.12 vs 0.32 ± 0.05 mm(2)；P < 0.05）。在细胞水平上，FcRIIB(-/-)巨噬细胞的吞噬能力显著降低（46 - 72%）。蛋白质组学分析显示，自身免疫小鼠体内存在循环自身抗体，这些抗体靶向25种动脉粥样硬化病变蛋白，包括黏附复合物、细胞骨架和细胞外基质的重要成分，以及参与关键功能和信号通路的蛋白。对动脉粥样硬化斑块的显微镜检查显示，自身抗体与内皮细胞基本共定位，它们附着于基底膜、内弹性膜和坏死核心。新的血管自身免疫小体可能是自身免疫相关疾病中动脉粥样硬化加速的诊断和免疫治疗干预的有用靶点。- 默切德，A. J.，达雷，D.，李，L.，弗兰兹尔，N.，索瓦热 - 默切德，M. 实验性自身免疫相关动脉粥样硬化中的特异性自身抗原。
