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

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.

Autoantibodies against apolipoprotein A‐1 after COVID‐19 predict symptoms persistence

“…The third and probably most important finding of this study resides in the demonstration that the COVID‐19‐induced AAA1 IgG response displays a substantial prognostic accuracy for the persistence of respiratory symptoms after SARS‐CoV‐2 infection. Although suspected due to the worse and independent prognostic value ascribed to these autoantibodies in other settings 22 , 23 , 24 , 25 , 40 , 43 and to the fact that autoantibodies against‐G‐coupled receptors sharing similar functional properties with AAA1 IgGs were associated with long COVID‐19 symptoms, 27 such hypothesis remained to be formally demonstrated in the context of COVID‐19. Our convergent results derived from LRM, ROC curve and logistic regression analyses concur to indicate that AAA1 IgG seropositivity at any time point studied independently predicted the persistence of respiratory symptoms at 12 months.…”

SARS‐CoV‐2 infection as a trigger of humoral response against apolipoprotein A‐1

“…This sequence is part of the leucine‐rich repeats (LRR) ectodomain of TLR2, known to be key for proper pathogen‐associated or damage‐associated molecular pattern recognition and TLR2’s function. 37 The anti‐apoA‐1 IgGs engagement of this region due to sequence homology with apoA‐1 20 has been reported to mediate their pro‐inflammatory/pro‐atherogenic response, 18 , 19 , 20 , 34 , 38 and the present correlations retrieved between anti‐apoA‐1 IgG, anti‐SARS‐CoV‐2 serologies and pro‐inflammatory cytokines on the case‐control cohort would have lend further weight to the molecular mimicry hypothesis proposed to explain the occurrence of other cross‐reacting pathogenic antibodies in COVID‐19. 39 , 40 However, by failing to clearly demonstrate any cross‐reactivity between the different antigens and antibodies of interest, our experimental approach did not support the molecular mimicry hypothesis to explain the occurrence of COVID‐19‐induced anti‐apoA‐1 IgG response and its intricate relationship with anti‐SARS‐CoV‐2 serologies.…”

SARS-CoV2- infection as a trigger of humoral response against apolipoprotein A-1

“…This sequence is part of the leucine reach repeats (LRR) ectodomain of TLR2, known to be key for proper pathogen-associated or damage-associated molecular pattern recognition and TLR2’s function (39). The engagement of this region by anti-apoA-1 IgGs due to sequence homology with apoA-1 (20) is believed to mediate their pro-atherogenic response (18-20, 31), affecting myocardial necrosis and mice survival through specific signaling pathways (18-20, 40). Taken together, these results indicate that these two SARS-CoV-2 epitopes previously identified as potential T cell and B cell epitopes (13, 14, 15, 41), share linear sequence homologies with host antigens playing key roles in inflammation and lipid homeostasis regulation, and that the COVID-19-induced humoral response may elicit pathogenic antibodies potentially cross-reacting with numerous autoantigens due to pathogenic B cell activation (42).…”

“…They are three main potential clinical implications of the present findings. Firstly because, anti-SARS-CoV-2 IgG responses against the regions containing these two epitopes were previously shown to correlate with COVID-19 severity (15) and because the presence of anti-apoA-1 IgG has been predictive of poorer outcomes (21, 22, 25, 26, 34, 38, 40), these findings may have possible implications for COVID-19 patients’ prognosis and risk stratification. Indeed, corroborating these previous observations, our results indicate that SARS-CoV-2-induced IgGs against aa 456-464 of TLR2 (and cross-reacting with anti-apoA-1 IgG (20)) could significantly predict 28-day mortality in ICU patients despite a limited sample size, with a NPV reaching 100% using a post-hoc defined cut-off.…”