Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

Abstract

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.

Prognostic and therapeutic considerations of antibodies against c‐ter apolipoprotein A‐1 in the general population

“…While likely to represent a specific class of antibodies, the inverse associations between anti-cter apoA1 IgG total and LDL cholesterol together with the positive correlations with proinflammatory parameters retrieved presently are globally similar to the ones reported with anti-apoA1 IgG on the same cohort. [3][4][5] Because the latter have been shown to mediate atherogenesis through sterile inflammation activation [12][13][14][15][16] and macrophage cellular cholesterol homeostasis disruption, 17,18 we would have expected such similar correlations to be associated with similar pathogenic mechanisms and therefore to similar associations with clinical outcomes, but it was not the case. Therefore, whether anti-cter apoA1 IgGs display different pathogenic mechanisms from anti-apoA1 IgGs, which underlie their distinct prognostic associations, deserves further investigation.…”

“…Among these, colchicine inhibits the same innate immune receptors as those that are activated by anti-apoA1 IgGs. 12,14,15,18,26 Because colchicine treatment has recently been shown to be highly effective at reducing incident ischemic CV events, 27 knowing whether anti-apoA1 or anticter apoA1 IgG seropositive individuals could represent a subgroup particularly prone to benefit from this treatment may represent an important field of investigation in the field of humoral autoimmunity against apoA1 in CVD.…”

“…Because other therapeutic means have been reported to neutralise anti‐apoA1 IgGs effects in vitro , such as intravenous immunoglobulins, L‐Type calcium channel blockers, and eplerenone, using an already existing means may represent a more appealing option than a mimetic peptide based‐approach. Among these, colchicine inhibits the same innate immune receptors as those that are activated by anti‐apoA1 IgGs 12,14,15,18,26 . Because colchicine treatment has recently been shown to be highly effective at reducing incident ischemic CV events, 27 knowing whether anti‐apoA1 or anti‐cter apoA1 IgG seropositive individuals could represent a subgroup particularly prone to benefit from this treatment may represent an important field of investigation in the field of humoral autoimmunity against apoA1 in CVD.…”

“…[2][3][4][5][6][7][8][9][10][11] Translational investigations showed that anti-apoA1 IgGs efficiently promote sterile inflammation, facilitate foam cell formation in vitro, and enhance the development of atherosclerosis and atherothrombosis in mice through specific innate immune receptors complexes and related signalling pathways. [12][13][14][15][16][17][18] In humans, the polyclonal anti-apoA1 IgG response has been shown to be preferentially oriented against the last alpha helix of the C-terminal part of apoA1 (amino acids: 241-266). 19 We previously showed that a corresponding mimetic peptide in a specified three-dimensional conformation could be used for both the detection of anti-c-terminus apoA1 IgG (anti-cter apoA1 IgG) and the neutralisation of deleterious anti-apoA1 IgG proinflammatory effects in vitro, including dampening of the anti-apoA1 IgG-induced inflammation 20 and related foam cell formation.…”

Auto-antibodies against apolipoprotein A-1 block cancer cells proliferation and induce apoptosis

“…In the field of cardiovascular diseases (CVD) sharing similar physiopathological pathways with cancer [7], several autoantibodies are involved as mediators of the disease [8]. Among these, autoantibodies directed against apolipoprotein A-1 (anti-apoA-1 IgGs), the main protein of high-density lipoprotein (HDL), have been shown to be actively implicated in the development of atherogenesis and atherosclerosic plaque vulnerability by activating macrophage-dependent inflammation, inducing foam cell formation, disturbing HDL-cholesterol homeostasis, and promoting a pro-arrhythmogenic effect [9][10][11][12]. Due to molecular mimicry between apoA-1 and the extra cellular parts of toll-like receptor 2 (TLR2) [9], anti-apoA-1 IgGs bind to TLR2 trough their Fab parts, inducing the constitution and activation of a TLR2/ TLR4/CD14 heterotrimer complex followed by nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and tyrosine protein kinase Src dependent pathways activation [9,13].…”