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Elevated levels of anti-desmoglein 2 autoantibodies in sera from individuals with acute COVID-19 and COVID-19 convalescents

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a systemic multiple-organ disease characterized by a broad spectrum of clinical manifestations. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. In this study, the research team from the United Kingdom investigated the presence of anti-desmoglein (Dsg) autoantibodies in sera from patients with acute COVID-19 and convalescents who have recovered after severe COVID-19. 

Desmosomes are intercellular junctions found in various tissues subjected to significant mechanical stress. They provide strong cell-cell adhesion and play an essential role in maintaining the structural integrity of tissues. Desmosomes are composed of desmosomal proteins from three families. The desmosomal cadherin family, desmogleins (Dsg), and desmocollins mediate calcium-dependent cell-cell adhesion.

The expression of Dsg 1 and 3 is restricted to stratified epithelia. However, Dsg2 is widely expressed in epithelia of pulmonary, gastrointestinal, renal, and myocardial tissues. In myocardial tissue, desmosomes connect cardiomyocytes at their intercalated discs. Dsg2 is not necessary for cardiac development, it is required for mechanical integrity.

The production of autoantibodies against Dsg 1, 2, and 3 and desmosomal dysfunction has been implicated in many diseases. Autoantibodies to Dsg2 have been associated with arrhythmic right ventricular cardiomyopathy and familial dilated cardiomyopathy. 

About the study

The authors investigated the presence of anti-Dsg1, Dsg2, and Dsg3 autoantibodies in sera from patients with acute COVID-19 and those who have recovered from severe COVID-19. To analyze the relevance of the anti-Dsg2 autoantibodies for cardiac damage, researchers performed histopathological examination of postmortem cardiac tissue from patients who died from COVID-19.

To determine if anti-Dsg2 autoantibodies are disease-specific, scientists recruited three comparison groups, one with severe influenza infection, a healthy control cohort, and a cohort of patients with common underlying cardiac complications.

Results

The results showed that 23%, 8%, and 46% of individuals with acute SARS-CoV-2 infection had skeletal, cardiac, and epidermal autoantibodies, respectively. These high levels were also observed in  COVID-19 convalescents, in whom positivity increased to 30% skeletal, 40% cardiac, and 52% epidermal autoantibodies. However, only 6% of non-COVID-19 patients had cardiac autoantibodies. Low levels were also observed in influenza patients.

Significantly elevated levels of anti-desmoglein2 IgG autoantibodies were detected in sera from both groups, the patients suffering from acute COVID-19 and the group of convalescents who have recovered after severe COVID-19. The levels of anti-desmoglein2 autoantibodies in the sera of patients who have recovered from severe COVID-19 were comparable to those found in patients with cardiac disease that is not associated with SARS-CoV-2 infection. The elevated levels of anti-Dsg2 autoantibodies were not found in the sera from convalescent patients who have recovered from mild disease, patients recovering from influenza infection, and healthy controls.

A possible link between severe COVID-19 and Dsg2 was investigated by histopathological examination of postmortem cardiac tissues from patients who died from COVID-19. The findings showed structural changes and disruption of the intercalated discs between cardiomyocytes. The authors noted that disruption of the intercalated discs leads to increased fat deposition and scar tissue. Ultimately, this perturbation of gap junctions leads to an impaired capacity of cardiac action potentials to spread through cardiac tissue, resulting in cardiac conduction delay and ventricular arrhythmias.

Conclusion

This study has shown that autoimmunity to Dsg2 might contribute to unexpected pathologies associated with COVID-19. The anti-Dsg2 autoantibodies are potentially pathogenic and have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy. According to the authors, the possible association of anti-desmoglein 2 autoantibodies and post-COVID-19 cardiac sequelae can identify Dsg2 autoantibodies as a new biomarker for cardiac damage after infection with SARS-CoV-2.

This article was published in the Clinical and Experimental Immunology.

Journal Reference

Ward KE et al. SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection, Clinical and Experimental Immunology, 2023. (Open Access).  https://academic.oup.com/cei/advance-article/doi/10.1093/cei/uxad046/7140487

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