SARS-CoV-2 infection induces the production of autoantibodies in severe COVID-19 patients in an age-dependent manner

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) outcomes due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, diabetes, chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health & disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 outcomes (with 71 mild, 61 moderate, and 27 severe patients) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multivariate regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid {beta} peptide, {beta} catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe elderly COVID-19 patients. Follow-up analysis using binomial regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies indicated a significantly increased likelihood of developing a severe COVID-19 phenotype, presenting a synergistic effect on worsening COVID-19 outcomes. These findings provide new key insights to explain why elderly patients less favorable outcomes have than young individuals, suggesting new associations of distinct autoantibody levels with disease severity.

Autoantibodies linked to autoimmune diseases associate with COVID-19 outcomes

The SARS-CoV-2 infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a wide spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients, in a cohort of 248 individuals, of which171 were COVID-19 patients (74 with mild, 65 moderate, and 32 with severe disease) and 77were healthy controls. Dysregulated autoantibody serum levels, characterized mainly by elevated concentrations, occurred mostly in patients with moderate or severe COVID-19 infection, and was accompanied by a progressive disruption of physiologic IgG and IgA autoantibody signatures. A similar perturbation was found in patients with anosmia. Notably, autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations, being both indicated by random forest classification as strong predictors of COVID-19 outcome, together with age. Moreover, higher levels of autoantibodies (mainly IgGs) were seen in the elderly with severe disease compared with young COVID-19 patients with severe disease. These findings suggest that the SARS-CoV-2 infection induces a broader loss of self-tolerance than previously thought, providing new ideas for therapeutic interventions.

The relationship between autoantibodies targeting GPCRs and the renin-angiotensin system associates with COVID-19 severity

The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.

Smoking and the intestinal microbiome.

Studies are emerging alluding to the role of intestinal microbiome in the pathogenesis of diseases. Intestinal microbiome is susceptible to the influence of environmental factors such as smoking, and recent studies have indicated microbiome alterations in smokers. The aim of the study was to review the literature regarding the impact of smoking on the intestinal microbiome. A literature review of publications in PUBMED was performed using combinations of the terms "Intestinal/Gut/Gastrointestinal/Colonic" with "Microbiome/Microbiota/Microbial/Flora" and "Smoking/Smoker/Tobacco". We selected studies that were published between the years 2000 and 2016 as our inclusion criteria. Observational and interventional studies suggest that the composition of intestinal microbiome is altered due to smoking. In these studies, Proteobacteria and Bacteroidetes phyla were increased, as well as the genera of Clostridium, Bacteroides and Prevotella. On the other hand, Actinobacteria and Firmicutes phyla as well as the genera Bifidobacteria and Lactococcus were decreased. Smoking also decreased the diversity of the intestinal microbiome. Mechanisms that have been suggested to explain the effect of smoking on intestinal microbiome include: oxidative stress enhancement, alterations of intestinal tight junctions and intestinal mucin composition, and changes in acid-base balance. Interestingly, some smoking-induced alterations of intestinal microbiome resemble those demonstrated in conditions such as inflammatory bowel disease and obesity. Further studies should be performed to investigate this connection. Smoking has an effect on intestinal microbiome and is suggested to alter its composition. This interaction may contribute to the development of intestinal and systemic diseases, particularly inflammatory bowel diseases.

Polycystic ovary syndrome and autoimmunity.

Polycystic ovary syndrome (PCOS) is characterized by laboratory and/or clinical features consisting of hyperandrogenism with chronic anovulation and is currently one of the most common endocrinopathies in women of fertile age. PCOS is associated with a variety of endocrine and metabolic disturbances. It was demonstrated that the prevalence of autoimmune thyroiditis is high among these patients. Recent studies reveal a higher incidence of autoantibodies such as anti-histone, anti-dsDNA presented in systemic autoimmune disease, however their clinical significance is still unknown. According to results of current research the syndrome could be possibly associated with some autoimmune diseases. Further studies are required to determine the role of organ-specific and non-specific autoantibodies in patients with PCOS.

Prediction and prevention of autoimmune skin disorders.

Autoimmune diseases can be preceded by a symptom-free phase which is defined by the presence of autoantibodies, and may last for many years. These autoantibodies may have a high positive predictive value for disease onset, severity and organ-specific complications, especially in genetically prone individuals. Characteristic autoantibodies and susceptible genes have been identified in many autoimmune systemic and mucocutaneous diseases such as systemic lupus erythematosus, pemphigus, vitiligo, dermatitis hepretiformis and even psoriasis. Prevention of overt disease may be achieved once high-risk individuals are identified and triggering factors are avoided. Numerous environmental factors, such as vitamin D deficiency, ultraviolet light, smoking, drugs, etc., that may trigger autoimmunity have been found. Alternatively, even if the autoimmune disease cannot be prevented, it may be postponed or attenuated. Thus, although large body of evidence has accumulated on characteristic autoantibodies, susceptible genes and environmental factors, many more large scale studies are needed to assess their predictive value, the preventive measurements and the means to apply them to clinical management of healthy population and high-risk individuals.

Intravenous immunoglobulin - indications and mechanisms in cardiovascular diseases.

Intravenous immunoglobulin (IVIG) is efficient in various immune mediated conditions. Various cardiovascular diseases are mediated by inflammatory processes and autoimmune mechanisms. Therefore, it seems conceivable to employ IVIG as an immunomodulating therapy in such indications. In this paper we review the possible anti-inflammatory effects of IVIG transfusion, and discuss the possible clinical implications in cardiology. Besides the established use of IVIG in Kawasaki disease, IVIG may be beneficial in some cases of heart failure, dilated cardiomyopathy, myocarditis, pericardial diseases, neonatal lupus, in the prevention of cardiac rejection following transplantation, and in modulating atherosclerosis. IVIG has been proven to be ineffective in rheumatic fever. Although uncommon, complications may arise including myocardial infarction, renal failure and hyperviscosity. IVIG should be administered based on accepted modes of transfusion.