Prognostic and therapeutic considerations of antibodies against c‐ter apolipoprotein A‐1 in the general population. Issue 12 (14th December 2020)

• Record Type: Journal Article
• Authors: Vuilleumier, Nicolas; Antiochos, Panagiotis; Marques‐Vidal, Pedro; Pagano, Sabrina; Virzi, Julien; Satta, Nathalie; Hartley, Oliver; Gaertner, Hubert; Brandt, Karim J; Burger, Fabienne; Montecucco, Fabrizio; Waeber, Gerard; Mach, François; Vollenweider, Peter
• Is Part Of: Clinical & translational immunology. Volume 9:Issue 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-14
• Subjects: anti‐apoA‐1 IgG -- ApoE−/− mice -- CoLaus study -- C‐terminal A1 peptide -- passive immunisation; Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1002/cti2.1220
• Languages: English
• ISSNs: 2050-0068

Abstract

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. Abstract : Autoantibodies against apolipoprotein A1 (anti‐apoA1 IgGs) have emerged as an independent cardiovascular risk factor in different settings including in the general population and seem to be preferentially oriented against the its C‐terminal region (cterA1) in humans. In this translational work, we extend previous knowledge in the field by demonstrating for the first time that anti‐cterA1 IgGs are independently predictive of premature mortality in a large general population sample of 5220 individuals. Furthermore, we also report that, despite being effective in vitro, our cterA1 analogue did not reverse the significant anti‐apoA1 IgG‐induced mortality in mice.