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Review
. 2014 May 26;6(5):314-26.
doi: 10.4330/wjc.v6.i5.314.

Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity

Nicolas Vuilleumier  1 , Fabrizio Montecucco  1 , Oliver Hartley  1
Affiliations
Review

Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity

Nicolas Vuilleumier et al. World J Cardiol. .

Abstract

Immune-driven inflammation plays an important part in atherogenesis and is therefore believed to be key to the development of cardiovascular disease (CVD), which is currently the leading cause of death in the Western world. By fulfilling some of the Koch postulates, atherogenesis has even been proposed to be considered as an autoimmune disease, raising the hope that CVD could be prevented by immunomodulation. Nevertheless, the role of the immune system and autoimmune reactions in atherosclerosis appear to be a double edged-sword, with both pro-atherogenic and anti-atherogenic attributes. Hence, if immunomodulation is to become a therapeutic option for atherosclerosis and CVD, it will be crucial to correctly identify patients who might benefit from targeted suppression of deleterious autoimmune responses. This could be achieved, for example, by the detection of disease-associated autoantibodies. In this work, we will review the currently available clinical, in vitro, and animal studies dedicated to autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG), the major proteic fraction of high density lipoprotein. Current clinical studies indicate that high levels of anti-apoA-1 IgG are associated with a worse cardiovascular prognosis. In addition, in vitro and animal studies indicate a pro-inflammatory and pro-atherogenic role, supporting the hypothesis that these autoantibodies may play a direct causal role in CVD, and furthermore that they could potentially represent a therapeutic target for CVD in the future.

Keywords: Apolipoprotein A-1; Atherosclerosis; Autoantibodies; Autoimmunity; Biomarkers; Cardiovascular disease.

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Figures

Figure 1
Figure 1
Deaths by cause in Europe for the latest available year, and by gender. Adapted from European Heart Network (www.ehnheart.org). CVD: cardiovascular disease.
Figure 2
Figure 2
Annual evolution of publications on cardiac biomarkers since 2000. This graphic represents the number of publications per year indexed and retrieved in Pubmed between 2000 and 2012 when the key words “cardiovascular biomarkers” are entered. Entry date: 22nd of January 2014.
Figure 3
Figure 3
Autoantibodies against apolipoprotein A-1 IgG elicit a pro-inflammatory response through Toll-like receptor 2/CD14 complex on human macrophages. Autoantibodies against apolipoprotein A-1 (anti-apoA-1) IgG specifically bind to Toll-like receptor (TLR)2 due to conformational homology between apoA-1 and TLR2. In the presence of CD14, the binding of anti-apoA-1 IgG to TLR2 induces a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent production of pro-inflammatory cytokines. MMP-9: Matrix-metalloproteinases; IL-8: Interleukin-8.
Figure 4
Figure 4
Current understanding of the mechanism by which autoantibodies against apolipoprotein A-1 IgG elicit chronotropic responses in nenonatal rat cardiomyocytes. Stimulation of the mineralocorticoid receptor (MR), either by aldosterone or oxidized glucocorticoids, induces the downstream activation of PI3K, which in turn activates L-type calcium channels. Anti-apoA-1 IgG has been shown to sensitize the L-type calcium channel in a protein kinase A (PKA)-dependent manner. The PI3K and PKA activated pathways alone are not sufficient to induce an increase in basal contraction rate, when simultaneously activated L-type calcium channels are activated, leading to an increase in intracellular Ca2+. This signal is amplified by the Na+/Ca2+ exchanger, leading to an increase of the prepotential slope of the cells, which ultimately translates into an increased contraction rate.
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