The possible contribution of anti-desmoglein 2 autoantibodies to post-COVID-19 cardiac sequelae

The UK research team has investigated the presence of anti-desmoglein (Dsg) Dsg1, Dsg2 and Dsg3 autoantibodies in sera from patients with acute COVID-19 and in those who have recovered from C-19 infection. The results indicate the possible association of anti-desmoglein 2 autoantibodies and post-COVID-19 cardiac sequelae. Cardiac sequelae are recognized as post-acute complications of SARS-CoV-2 infection.

The same research group had previously reported an increase in autoantibodies in post-COVID-19 patients with a specific pattern of autoantibodies against cardiac, skin and muscle tissues. These antibodies were present at six months post-infection.

Desmosomes and desmogleins

Desmosomes are intercellular junctions found in various tissues subjected to significant mechanical stress. Desmosomes provide strong cell-cell adhesion and play an essential role in maintaining the structural integrity of tissues. They are composed of desmosomal proteins from three families: the cadherin family, the aremedillo family, and the plakin family. 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, but, Dsg2 is widely expressed in all epithelia containing desmosomes, including pulmonary, gastrointestinal, renal and myocardial tissues. Desmosomes connect cardiomyocytes at their intercalated discs. Dsg2 is not necessary for cardiac development, but, it is required for mechanical integrity.

The production of autoantibodies against Dsg 1, 2 and 3 and desmosomal dysfunction has been implicated in a number of diseases. Autoantibodies to Dsg2 have been associated with arrhythmic right ventricular cardiomyopathy in humans. With intercalated disc disruption, there is an increase in 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.

About the study

The UK research team has investigated the presence of anti-Dsg autoantibodies in sera from patients with acute C-19 and in those who have recovered from C-19 infection. To determine if these autoantibodies are disease specific, they have recruited three comparison cohorts, one with severe influenza infection, a healthy control cohort and a cohort of patients with common underlying cardiac complications.

The authors also examined cardiac tissue, obtained postmortem from patients who died from C-19, to explore the potential clinical relevance of the anti-Dsg2 autoantibodies and cardiac damage.

The results showed the presence of skeletal, cardiac and epidermal autoantibodies in the acute C-19 group, with 23%, 8%, and 46% patients positive respectively. These high levels were also observed in convalescent C-19 patients where positivity increased to 30% skeletal, 40% cardiac, and 52% epidermal autoantibodies. In comparison, cardiac autoantibodies were the only autoantibodies found in only 6% of non-COVID-19 patients. Low levels were also observed in influenza patients.

The results also showed significantly elevated levels of anti-Dsg2 IgG autoantibodies in sera from both acute and convalescent C-19 cohorts following severe disease. The levels of autoantibodies in the sera of patients who have recovered from severe C-19 infection were comparable to levels in patients with cardiac disease that is not associated with C-19.

However, sera from convalescent patients following mild disease, the hospitalized patients recovering from influenza infection and healthy controls did not have elevated levels of Dsg2 autoantibodies.

To determine whether there was any link between severe C-19 and Dsg2, the authors stained the postmortem cardiac tissues from patients who died from C-19 infection. The findings showed structural changes and disruption of the intercalated disc between cardiomyocytes.

The authors noted that their findings revealed the possibility that autoimmunity to Dsg2 contributes to unexpected pathologies associated with C-19 infection. The anti-Dsg2 autoantibodies are potentially pathogenic and have been associated with arrhythmogenic right ventricular cardiomyopathy and familial dilated cardiomyopathy. The researchers concluded that their results of the possible association of anti-desmoglein 2 autoantibodies and post-COVID-19 cardiac sequelae could identify Dsg2 autoantibodies as a new biomarker for post-C-19 cardiac damage.

This article was published in the scientific journal Clinical and Experimental Immunology. Ward KE et al. SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection, Clinical and Experimental Immunology, 2023. (Open Access).