To date, there have been over 400 million confirmed cases of coronavirus disease 2019 (COVID-19). The causative virus of COVID-19 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a single-stranded virus of the family Coronaviridae. Throughout the current pandemic, there has been the emergence of new variants, of which each contains distinct advantages such as improved ability to evade neutralizing antibodies.
At the same time, a large scientific effort to investigate COVID-19 pathophysiology has discovered indications that patients with severe COVID-19 may have systemic immunological dysregulation of both innate and adaptive immune responses. This is mostly manifested as cytokine storm syndrome, which is characterized by hyperactivation of both myeloid and lymphoid cells, as well as neutrophilia and lymphopenia.
Autoantibodies in healthy individuals are responsible for regulating many physiological processes and are typically present at consistent levels. However, when the level of autoantibodies reaches abnormal levels, it can often be a sign of preclinical autoimmune disease. Abnormal autoantibody levels can also trigger inflammation dysregulation pathways, aggravating inflammatory conditions.
Autoantibodies and SARS-CoV-2
As seen in other viruses, SARS-CoV-2 has been shown to alter the profiles of autoantibodies and could promote a loss of self-tolerance that could lead to a myriad of autoimmune conditions of which all have the potential to be life-threatening. However, the characterization of the full spectrum of autoantibodies seen in patients with COVID-19 that may cause a loss of self-tolerance is not yet completed.
Autoantibodies targeting immune-related proteins, such as type I interferons (IFNs), the exoproteome (cytokines, chemokines, and their receptors, as well as complement factors), G protein-coupled receptors (GPCRs), and renin-angiotensin system (RAS)-related molecules, were recently discovered in COVID-19.
There have been links established between COVID-19 and autoantibodies that are associated with common autoimmune conditions, such as thyroid antigens, anti-nuclear antibodies (ANAs), chromatin proteins, and ribosomal P proteins. Still, comprehensive research that broadly characterizes autoantibodies induced by SARS-CoV-2 is lacking.
In a recent study published on the medRxiv* preprint server, a broad evaluation of autoimmune disease-associated autoantibodies that have been observed in COVID-19 patients was performed. In this study, a cohort of 248 adults from the US was included in the analysis, of which 171 had PCR-confirmed symptomatic COVID-19. The authors carried out an ELISA test on sera collected from the participants to measure anti-SARS-CoV-2 antibodies and autoantibodies linked to autoimmune diseases.
Progressive increase of autoantibodies in COVID-19 patients according to disease severity
Progressive dysregulation was observed through multi-study factor analysis (MSFA) concerning latent factors from patients with mild, moderate, and severe COVID-19. Compared to the mild and control groups, patients with moderate and severe COVID-19 displayed fewer latent factors, which may result from a change in the levels of autoantibodies. In all the COVID-19 positive participants, increased levels of IgG and IgA autoantibodies were observed when comparing levels to healthy controls, with the most prominent increase seen in patients with severe disease.
Concurrent with the results from the MSFA, the authors observed an incremental rise of autoantibodies targeting autoantigens such as those associated with a variety of autoimmune conditions, including Alzheimer’s disease and multiple sclerosis. A decrease in levels of IgG autoantibodies was also seen, which shows a breakdown of self-tolerance in COVID-19 patients that is paralleled with disease severity. The results also indicated that the change in autoantibody levels was correlated to an increase in serum anti-SARS-CoV-2 antibody concentration.
Autoantibody generation correlates with severe SARS-CoV-2 infection and loss of smell (anosmia)
The authors’ utilized bivariate correlation analysis to investigate the relationship between disease severity and IgA and IgG autoantibodies signatures. When healthy individuals were compared to those with mild COVID-19, the results showed that autoantibody correlation signatures only exhibited a few differences. However, Patients with moderate COVID-19 began to show novel positive and negative autoantibody correlations, whereas those with severe COVID-19 had the most dissimilar topological correlation pattern, increasingly with mainly positive autoantibody correlations.
When the assessments were carried out to test the correlation between autoantibody generation and anosmia, severe patients were excluded because of the severity of the condition and the nature of the analysis. When compared to COVID-19 without anosmia, the authors found that the linkages among autoantibodies are reduced in both mild and moderate COVID-19 with anosmia. This implies that multiple factors influence autoantibody signatures, including illness severity and anosmia, which affect autoantibody associations in distinct ways.
SARS-CoV-2 infection dysregulates autoantibody levels in relation to age
The authors examined whether age influenced IgG and IgA autoantibody predictors regarding the severity of the disease. The disease and control groups were further categorized by their age (young <60 and elderly ≥60). The results showed increased autoantibody numbers in elderly patients with moderate and severe COVID-19 compared to the younger cohort. The highest levels of IgG and IgA autoantibodies were observed in the elderly patients with severe COVID-19. However, age did not appear to affect the levels of anti-SARS-CooV-2 antibodies. Only a few age-dependent significant variations were observed in the autoantibody predictors of COVID-19 severity in patients with anosmia versus no anosmia.
Implications
This research presents a complete picture of the range of autoantibodies connected to autoimmune disorders caused by SARS-CoV-2 infection. The junction between COVID-19 and autoimmunity is mapped in this study, indicating the dysregulation of various autoantibodies associated with autoimmune conditions throughout SARS-CoV-2 infections and changed correlation signatures based on disease severity and anosmia.
The findings point to autoantibodies becoming more involved in the severity of COVID-19 with time. The researchers discovered several new clinically relevant autoantibodies that can be used as biomarkers to predict COVID-19 severity and provide new therapeutic options.
*Important notice
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
