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ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies
Nature ( IF 64.8 ) Pub Date : 2020-12-02 , DOI: 10.1038/s41586-020-2993-2
Cristina Lorenzo 1 , Pilar Delgado 1, 2 , Christian E Busse 3 , Alejandro Sanz-Bravo 1 , Inmaculada Martos-Folgado 1 , Elena Bonzon-Kulichenko 4, 5 , Alessia Ferrarini 4 , Ileana B Gonzalez-Valdes 4 , Sonia M Mur 1 , Raquel Roldán-Montero 6 , Diego Martinez-Lopez 6 , Jose L Martin-Ventura 5, 6 , Jesús Vázquez 4, 5 , Hedda Wardemann 3 , Almudena R Ramiro 1
Affiliation  

Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies 1 , 2 , and there is a connection between atherosclerosis and autoimmunity 3 . However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood 3 – 5 . Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr −/− and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr −/− mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD. An autoantibody found in a mouse model of atherosclerosis recognizses ALDH4A1, and infusion of the antibody delays plaque formation in mice.

中文翻译:

ALDH4A1 是一种由保护性抗体靶向的动脉粥样硬化自身抗原

心血管疾病 (CVD) 是世界上导致死亡的主要原因,大多数与 CVD 相关的死亡是由心肌梗塞或中风引起的。血栓形成和心血管事件的主要根本原因是动脉粥样硬化,这是一种可以长时间保持无症状的炎症性疾病。该领域迫切需要治疗和诊断选择。动脉粥样硬化斑块含有自身抗体 1、2,动脉粥样硬化和自身免疫之间存在联系 3。然而,动脉粥样硬化期间免疫原性触发和自身抗体反应的影响尚不清楚 3 – 5 。在这里,我们对动脉粥样硬化相关的抗体库进行了高通量单细胞分析。1个以上的抗体基因测序,来自致动脉粥样硬化 Ldlr -/- 和对照小鼠的 700 个 B 细胞鉴定了 56 种抗体,这些抗体由动脉粥样硬化背景下的 B 淋巴细胞的体内扩增克隆表达。三分之一的扩增抗体与动脉粥样硬化斑块发生反应,表明病变中的各种抗原可以触发抗体反应。深度蛋白质组学分析发现 ALDH4A1(一种参与脯氨酸代谢的线粒体脱氢酶)是这些自身抗体之一 A12 的靶抗原。ALDH4A1 分布在动脉粥样硬化期间发生改变,并且在患有动脉粥样硬化的小鼠和人类中循环 ALDH4A1 增加,支持 ALDH4A1 作为疾病生物标志物的潜在用途。将 A12 抗体注入 Ldlr -/- 小鼠可延迟斑块形成并降低循环游离胆固醇和低密度脂蛋白,表明抗 ALDH4A1 抗体可以防止动脉粥样硬化进展,并且可能在 CVD 中具有治疗潜力。在动脉粥样硬化小鼠模型中发现的一种自身抗体可识别 ALDH4A1,并且抗体的输注延迟了小鼠斑块的形成。
更新日期:2020-12-02
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