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Auto-antibodies against atherosclerosis

Paper commented by the ESC WG on Cellular Biology of the Heart



Atherosclerotic diseases are a global, major public health problem, contributing importantly to a wide range of cardiovascular phenotypes[1]. Although immune dysregulation and inflammatory burden are known to greatly participate in many cardiovascular diseases[2-4], the precise mechanisms by which immunity modulates atherosclerosis are only partially understood. With respect to adaptive immunity, B cells and their final product, antibodies, have been detected in atherosclerotic plaques[5]. Different studies have suggested both a protective or a detrimental role of B cells and antibodies in atherosclerotic plaque formation[6, 7]. However, the antigenic targets of B cells response in atherosclerosis remain elusive.
In the paper of the month, Lorenzo et al.[8], performed an unbiased, high-throughput single-cell analysis of the antibody repertoire associated with atherosclerosis. In search of novel antibody-antigen pair that might contribute to atherosclerosis development, these authors identified a previously unrecognized auto-antibody – A12 – which is enriched in human and murine atherosclerotic plaques. Going forward, using mass spectrometry, they were able to identify in the aldehyde dehydrogenase 4 family member A1 (ALDH4A1) – a mitochondrial dehydrogenase – the antigen specifically recognized by the antibody A12. Strikingly, serial intravenous injections of A12 antibody in atherosclerotic mice, were able to significantly reduce the extent of atherosclerotic plaques and to ameliorate the circulating lipid profile of the mice.
This investigation provides several novel findings that greatly contribute to increase our knowledge of the pathophysiology of the atherosclerosis. First, the identification of an auto-antibody able to slow the progression of atherosclerotic plaque formation has, per se, great therapeutic implications. Second, as the antibody against ALDH4A1 was also increased in the plasma of human subjects and was associated with the presence of atherosclerosis independently of traditional risk factors, the A12 antibody can be considered as potential biomarker and diagnostic tool in atherosclerosis subjects. Finally, the use of an unbiased discovery approach will probably lead to other antigen-antibody pairs involved in the atherosclerosis process.
As with all the good studies, many questions arise from this investigation. What is the biological role(s) of ALDH4A1 in atherosclerotic plaque formation? What are the effects of A12 on ALDH4A1 functions? As ALDH4A1 is a mitochondrial enzyme, what are the potential implications of autoantibodies regulating metabolic function in atherosclerosis? Interestingly, despite being smaller in size, atherosclerotic plaques in A12-treated mice did not shown differences in cellular and fibrotic composition compared to control group, suggesting that the effects of A12 on plaque development might go beyond the regulation of its qualitative properties.
In conclusion, Lorenzo et al.[8], identified a novel antigen-antibody pair strongly implicated in the development of atherosclerosis with potential diagnostic and therapeutic implications in atherosclerotic diseases. Their findings open a novel field of investigation involving antigen-antibody complexes as novel players in the pathogenesis of atherosclerosis.

References


1. Hansson, G.K., Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 2005. 352(16): p. 1685-95.
2. Schiattarella, G.G., D. Rodolico, and J.A. Hill, Metabolic Inflammation in Heart Failure with Preserved Ejection Fraction. Cardiovasc Res, 2020.
3. Schiattarella, G.G., V. Sequeira, and P. Ameri, Distinctive patterns of inflammation across the heart failure syndrome. Heart Fail Rev, 2020.
4. Gistera, A. and G.K. Hansson, The immunology of atherosclerosis. Nat Rev Nephrol, 2017. 13(6): p. 368-380.
5. Sage, A.P., et al., The role of B cells in atherosclerosis. Nat Rev Cardiol, 2019. 16(3): p. 180-196.
6. Ait-Oufella, H., et al., B cell depletion reduces the development of atherosclerosis in mice. J Exp Med, 2010. 207(8): p. 1579-87.
7. Caligiuri, G., et al., Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest, 2002. 109(6): p. 745-53.
8. Lorenzo, C., et al., ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies. Nature, 2020.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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