Atherosclerosis is a chronic inflammatory disease leading to cardiovascular diseases responsible for a high level of morbidity and mortality worldwide. Increasing evidence tends to hold that humoral and cellular immune responses are a key component of human atherosclerosis development. Since the last decade, auto-antibodies have been identified as active mediators of cardiovascular disease, some presenting protective effects whereas others act as proatherogenic factors. This review presents an overview of the most relevant auto-antibodies with regards to their respective cardiovascular prognostic value in acute coronary syndrome, stroke and other cardiomyopathies, and their potential pathophysiologic implication in atherogenesis. Insights in the mechanisms of action of auto-antibodies show that they commonly modulate the innate immune system towards a pro- or anti-inflammatory response and/or affect the regulation of basal heart rate. The increased understanding of the auto-antibodies functional properties has led to the development of new therapeutic approaches targeting the innate immune system or the epitope-binding site. Some of these auto-antibodies have been reported to be independent prognostic factors of poor disease outcome. In addition to conventional risk factors, these autoantibodies could be helpful biomarkers to increase the sensitivity and specificity of the cardiovascular stratification tools.

Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5–15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD). Methods: Anti-ApoA-1 IgG and lipid profiles were measured on 29 FH and 25 healthy children. The impact of anti-ApoA-1 IgG on key CH regulators (SREBP2, HMGCR, LDL-R, ABCA1, and miR-33a) and foam cell formation detected by Oil Red O staining were assessed using human monocyte-derived macrophages. PD experiments were performed using a validated THP-1 macrophage model. Results: Prevalence of high anti-ApoA-1 IgG levels (seropositivity) was about 38% in both study groups. FH children seropositive for anti-ApoA-1 IgG had significant lower total cholesterol LDL and miR-33a levels than those who were seronegative. On macrophages, anti-ApoA-1 IgG induced foam cell formation in a toll-like receptor (TLR) 2/4-dependent manner, accompanied by NF-kB- and AP1-dependent increases of SREBP-2, LDL-R, and HMGCR. Despite increased ABCA1 and decreased mature miR-33a expression, the increased ACAT activity decreased membrane free cholesterol, functionally culminating to PD inhibition. Conclusions: Anti-ApoA-1 IgG seropositivity is frequent in children, unrelated to FH, and paradoxically associated with a favorable lipid profile. In vitro, anti-ApoA-1 IgG induced foam cell formation through a complex interplay between innate immune receptors and key cholesterol homeostasis regulators, functionally impairing the PD cholesterol efflux capacity of macrophages.

Background: Autoimmune diseases are closely associated with cardiovascular diseases (CVD). Over the last decades, the comprehension of atherosclerosis, the principal initiator of CVD, evolved from a lipidcentered disease to a predominant inflammatory and immune response-driven disease displaying features of autoimmunity against a broad range of auto-antigens, including lipoproteins. Among them, high density lipoproteins (HDL) are important actors of cholesterol transport and bear several anti-atherogenic properties, raising a growing interest as therapeutic targets to decrease atherosclerosis and CVD burden, with nevertheless rather disappointing results so far. Reflecting HDL composition complexity, autoimmune responses and autoantibodies against various HDL components have been reported.Results: In this review, we addressed the important complexity of humoral autoimmunity towards HDL and particularly how this autoimmune response could help improving our understanding of HDL biological implication in atherosclerosis and CVD. We also discussed several issues related to specific HDL autoantibody subclasses characteristics, including etiology, prognosis and pathological mechanisms according to Rose criteria.Conclusion: Finally, we addressed the possible clinical value of using these antibodies not only as potential biomarkers of atherogenesis and CVD, but also as a factor potentially mitigating the benefit of HDL-raising therapies.

// Nathalie Satta1^,2, Rémy Weppe1^,2, Sabrina Pagano1^,2, Miguel Frias1^,2, Catherine Juillard1^,2 and Nicolas Vuilleumier1^,2 1 Division of Laboratory Medicine, Department of Diagnostic, Geneva University Hospitals, Geneva, Switzerland 2 Department of Medicine, Medical Faculty, Geneva University, Geneva, Switzerland Correspondence to: Nathalie Satta, email: nathalie.satta@unige.ch Keywords: anti-apoA-1 antibodies; apoptose; cell proliferation; oxidative stress Received: July 03, 2020 Accepted: October 27, 2020 Published: November 17, 2020 Copyright: © 2020 Satta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Auto-antibodies against apoA-1 (anti-apoA-1 IgGs) have been identified as important actors of atherosclerosis development through pro-inflammatory and pro-atherogenic properties and to also induce apoptosis in tumoral neuronal and lymphocyte derived cell lines through unknown mechanisms. The purpose of this study was to explore the cellular pathways involved in tumoral cell survival modulated by anti-apoA-1 antibodies. We observed that anti-apoA-1 antibodies induce growth arrest (in G2/M phase) and cell apoptosis through caspase 3 activation, accompanied by a selective p53 phosphorylation on serine 15. RNA sequencing indicated that anti-apoA-1 IgGs affect the expression of more than 950 genes belonging to five major groups of genes and respectively involved in i) cell proliferation inhibition, ii) p53 stabilisation and regulation, iii) apoptosis regulation, iv) inflammation regulation, and v) oxidative stress. In conclusion, anti-apoA-1 antibodies seem to have a role in blocking tumoral cell proliferation and survival, by activating a major tumor suppressor protein and by modulating the inflammatory and oxidative stress response. Further investigations are needed to explore a possible anti-cancer therapeutic approach of these antibodies in very specific and circumscribed conditions.