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Updated: Nov 27, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies
Cristina Lorenzo1, Pilar Delgado1,2, Christian E Busse3
1B Lymphocyte Biology Lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Insights
Researchers identified autoantibodies targeting ALDH4A1 in atherosclerosis. These antibodies may serve as biomarkers and offer therapeutic potential for cardiovascular disease (CVD) by protecting against plaque formation.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Proteomics
Background:
- Cardiovascular disease (CVD) is a leading global cause of death, primarily due to myocardial infarction and stroke.
- Atherosclerosis, an inflammatory disease, underlies most CVD events and can be asymptomatic for extended periods.
- The role of autoantibodies and their triggers in atherosclerosis remains poorly understood, highlighting a need for new diagnostic and therapeutic strategies.
Purpose of the Study:
- To investigate the atherosclerosis-associated antibody repertoire using high-throughput single-cell analysis.
- To identify specific autoantigens targeted by antibodies in atherosclerosis.
- To evaluate the potential of identified autoantibodies as biomarkers and therapeutic agents for CVD.
Main Methods:
- High-throughput single-cell analysis of antibody gene sequencing from over 1,700 B cells in atherogenic and control mice.
- Deep proteomics analysis to identify autoantigen targets of expanded B cell clones.
- In vivo studies involving antibody infusion in Ldlr-/- mice to assess effects on plaque formation and lipid levels.
Main Results:
- Fifty-six antibodies from in-vivo-expanded B cell clones were identified in the context of atherosclerosis.
- One-third of these antibodies showed reactivity against atherosclerotic plaques, indicating diverse lesion-associated autoantigens.
- ALDH4A1 was identified as a target antigen; its circulating levels were elevated in atherosclerosis, and anti-ALDH4A1 antibodies (A12) delayed plaque progression and improved lipid profiles in mice.
Conclusions:
- Atherosclerosis involves a significant autoantibody response targeting various plaque antigens, including ALDH4A1.
- ALDH4A1 shows potential as a biomarker for atherosclerosis due to altered distribution and increased circulating levels.
- Anti-ALDH4A1 antibodies demonstrate protective effects against atherosclerosis progression, suggesting therapeutic potential for cardiovascular disease.
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.
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