ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies

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 Roldán-Montero, Diego Martinez-Lopez, Jose L. Martin-Ventura, Jesús Vázquez, Hedda Wardemann and Almudena R. Ramiro ()
Additional contact information
Cristina Lorenzo: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Pilar Delgado: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Christian E. Busse: German Cancer Research Center
Alejandro Sanz-Bravo: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Inmaculada Martos-Folgado: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Elena Bonzon-Kulichenko: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Alessia Ferrarini: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Ileana B. Gonzalez-Valdes: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Sonia M. Mur: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Raquel Roldán-Montero: IIS-Fundación Jiménez Díaz-Universidad Autónoma
Diego Martinez-Lopez: IIS-Fundación Jiménez Díaz-Universidad Autónoma
Jose L. Martin-Ventura: CIBER de Enfermedades Cardiovasculares (CIBERCV)
Jesús Vázquez: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Hedda Wardemann: German Cancer Research Center
Almudena R. Ramiro: Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature, 2021, vol. 589, issue 7841, 287-292

Abstract: 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 understood3–5. 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.

Date: 2021
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DOI: 10.1038/s41586-020-2993-2

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