小柯机器人

ALDH4A1是动脉粥样硬化靶向抗原
2020-12-04 13:33

西班牙国家心血管研究中心(CNIC)Almudena R. Ramiro研究组取得最新进展。他们揭示ALDH4A1是一种由保护性抗体靶向的动脉粥样硬化自身抗原。这一研究成果发表在2020年12月2日出版的《自然》杂志上。

他们进行了动脉粥样硬化相关抗体库的高通量单细胞分析。来自动脉粥样硬化Ldlr-/-和对照小鼠的1,700多个B细胞的抗体基因测序确定了在动脉粥样硬化背景下,B淋巴细胞的体内扩增克隆表达的56种抗体。三分之一的扩增抗体对动脉粥样硬化斑具有反应性,表明病变中的各种抗原可触发抗体反应。深度蛋白质组学分析确定,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。

在动脉粥样硬化期间,ALDH4A1的分布发生了变化,在患有动脉粥样硬化的小鼠和人类中,循环中的ALDH4A1增加,这支持了ALDH4A1作为疾病生物标记物的潜在用途。向Ldlr-/-小鼠中输注A12抗体可延迟斑块形成并减少循环中的游离胆固醇和LDL,这表明抗ALDH4A1抗体可预防动脉粥样硬化进展,并可能在心血管疾病(CVD)中具有治疗潜力。

研究人员表示,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原因是动脉粥样硬化,这是一种炎症性疾病,可以长期保持无症状。在这一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,并且动脉粥样硬化与自身免疫之间存在联系。然而,动脉粥样硬化过程中的免疫原性触发和自身抗体反应的影响尚不清楚。

附:英文原文

Title: ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies

Author: Cristina Lorenzo, Pilar Delgado, Christian E. Busse, Alejandro Sanz-Bravo, Inmaculada Martos-Folgado, Elena Bonzon-Kulichenko, Alessia Ferrarini, Ileana B. Gonzalez-Valdes, Sonia M. Mur, Raquel Roldn-Montero, Diego Martinez-Lopez, Jose L. Martin-Ventura, Jess Vzquez, Hedda Wardemann, Almudena R. Ramiro

Issue&Volume: 2020-12-02

Abstract: 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 autoantibodies1,2, and there is a connection between atherosclerosis and autoimmunity3. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood3,4,5. 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.

DOI: 10.1038/s41586-020-2993-2

Source: https://www.nature.com/articles/s41586-020-2993-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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