HDAC Inhibitors as Epigenetic Regulators

Of note, we did not include asymptomatic individuals infected with SARS-CoV-2 in this article because their sera were not available at the time of data acquisition for this study. are available at the following link: https://github.com/lschimke/The-relationship-between-autoantibodies-targeting-GPCRs-and-the-renin-angiotensin-system-associates- Abstract COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the Fosfructose trisodium chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity. Fosfructose trisodium Subject terms: Autoimmunity, Predictive markers, Molecular medicine, Antibodies COVID-19, similarly to systemic autoimmune diseases, is characterised by the presence of autoantibodies. Authors show here that the abundance and network signature of autoantibodies targeting G protein-coupled receptors and RAS-related proteins are altered in COVID-19 patients, and the level of disruption marks clinical severity. Introduction Autoantibodies have been identified in patients with coronavirus disease 2019 (COVID-19), suggesting that the infection by severe acute respiratory syndrome virus 2 (SARS-CoV-2) can display features similar to a systemic autoimmune disease1C5. For instance, high levels of antiphospholipid autoantibodies have been linked to severe respiratory disease by inducing neutrophil extracellular traps (NET) and venous thrombosis4,6C9. Further, high titers of neutralizing immunoglobulin G (IgG) autoantibodies against type I interferons (IFN) have been reported in patients with life-threatening COVID-1910. Most recently, a wide range of autoantibodies in patients with COVID-19 have been characterized using rapid extracellular antigen profiling (REAP)11. This is a technology that allows the comprehensive and high-throughput identification of autoantibodies by recognizing 2770 extracellular and secreted protein components of the exoproteome Fosfructose trisodium (extracellular protein epitopes)12. Wang et al. 11 showed that COVID-19 patients have multiple autoantibodies against the exoproteome. While patients with mild disease or asymptomatic infection exhibit increased autoantibody reactivity relative to uninfected individuals, those with severe disease have the highest reactivity scores. These results are in line with our previous report13 on autoantibodies targeting the largest superfamily of integral membrane proteins in humans14, i.e., G protein-coupled receptors (GPCR), suggesting that these autoantibodies are natural components of human biology that become dysregulated in autoimmune diseases15. Our prior work indicated that GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis13. Likewise, recent studies have detected functional antibodies against GPCRs in the sera of patients with COVID-19 Fosfructose trisodium and have indicated that they may be associated with disease severity16C18. However, these investigations focused only on a few anti-GPCR autoantibodies. Importantly, they did not investigate their relationship with the potential presence of autoantibodies targeting other?GPCRs and renin-angiotensin system (RAS)-related molecules, which play a central role in the development of severe COVID-19. Thus, we employ a systems immunology approach (Fig.?1a) to characterize the relationship between autoantibodies targeting a broad group of GPCRs and RAS-related molecules with COVID-19 severity by determining their correlation signatures across SARS-CoV-2-infected patients versus healthy individuals. Open in a separate window Fig. 1 Study workflow.a After data acquisition, we carried out different statistical analyses (written on the top) to characterize the signature of autoantibodies against GPCRs and COVID-19-associated molecules (e.g., renin-angiotensin system) in COVID-19 patients when compared with healthy controls. Created with BioRender.com. b Interaction network of autoantibody targets: molecules belonging or influencing the RAS (on the right) as well as additional molecules (other GPCRs, NRP1, and STAB1; on the left). Rabbit polyclonal to AHCYL1 The Fosfructose trisodium network highlights interactions among the autoantibody targets (blue edges), ACE-2 interactors connecting to the other targets (green edges), and gene ontology (GO) biological processes (node color). The number of interacting partners for each target is proportional to the node size. The circles associated with each autoantibody target are formed by their interactors, whose names are omitted. c Circos plot illustrating the functional relationships between the antibody targets and biological processes as indicated by GO enriched processes, which are denoted by letters: A renin-angiotensin system, B adrenergic signaling in cardiomyocytes, C calcium signaling, D renin secretion, E.