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

Nicolas Vuilleumier; Panagiotis Antiochos; Pedro Marques-Vidal; Sabrina Pagano; Julien Virzi; Nathalie Satta; Oliver Hartley; Hubert Gaertner; Karim J Brandt; Fabienne Burger; Fabrizio Montecucco; Gerard Waeber; François Mach; Peter Vollenweider

doi:10.1002/cti2.1220

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

Clin Transl Immunology. 2020 Dec 14;9(12):e1220. doi: 10.1002/cti2.1220. eCollection 2020.

Authors

Nicolas Vuilleumier^{1

2}, Panagiotis Antiochos³, Pedro Marques-Vidal³, Sabrina Pagano^{1

2}, Julien Virzi¹, Nathalie Satta^{1

2}, Oliver Hartley⁴, Hubert Gaertner⁴, Karim J Brandt⁵, Fabienne Burger⁵, Fabrizio Montecucco^{6

7}, Gerard Waeber³, François Mach⁵, Peter Vollenweider³

Affiliations

¹ Division of Laboratory Medicine Diagnostics Department Geneva University Hospitals Geneva Switzerland.
² Department of Medicine Specialties Medical Faculty Geneva University Geneva Switzerland.
³ Department of Internal Medicine Lausanne University Hospital Lausanne Switzerland.
⁴ Department of Pathology and Immunology Faculty of Medicine University of Geneva Geneva Switzerland.
⁵ Division of Cardiology Foundation for Medical Researches Department of Medical Specialties University of Geneva Geneva Switzerland.
⁶ First Clinic of Internal Medicine Department of Internal Medicine University of Genoa Genoa Italy.
⁷ IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network Genoa Italy.

Abstract

Objectives: Autoantibodies against apolipoprotein A1 (anti-apoA1 IgGs) and its C-terminal region (cter apoA1) have emerged as an independent biomarker for cardiovascular disease. Cter apoA1 mimetic peptides were shown to reverse the deleterious anti-apoA1 IgG effects in vitro. We evaluated the association of anti-cter apoA1 IgGs with overall mortality in the general population and tested the ability of a cter apoA1 mimetic peptide to reverse the anti-apoA1 IgG-induced inflammatory response and mortality in vitro and in vivo, respectively.

Methods: Anti-cter apoA1 IgGs were measured in serum samples of 6386 participants of the CoLaus study of which 5220 were followed for a median duration of 5.6 years. The primary outcome was overall mortality. The peptide inhibitory concentration 50% (IC₅₀) was determined in vitro on HEK-Blue-4 and RAW cells. ApoE^-/- mice were exposed to 16 weeks of anti-apoA1IgG passive immunisation with and without peptide co-incubation.

Results: Anti-cter apoA1 IgGs were associated with higher interleukin 6 levels and independently predicted overall mortality; an increase of one standard deviation of anti-cter apoA1 IgG level was associated with an 18% increase in mortality risk (hazard ratio: 1.18, 95% confidence interval: 1.04-1.33; P = 0.009). The cterApoA1 analogue reversed the antibody-mediated inflammatory response with an IC₅₀ of 1 µm in vitro but did not rescue the significant anti-apoA1 IgG-induced mortality rate in vivo (69% vs. 23%, LogRank P = 0.02).

Conclusion: Anti-cter apoA1 IgG independently predicts overall mortality in the general population. Despite being effective in vitro, our cter apoA1 analogue did not reverse the anti-apoA1 IgG-induced mortality in mice. Our data suggest that these autoantibodies are not readily treatable through cognate peptide immunomodulation.

Keywords: ApoE−/− mice; CoLaus study; C‐terminal A1 peptide; anti‐apoA‐1 IgG; passive immunisation.