Human anti-desmoglein 2 levels are associated with COVID-19 severity

In a recent study posted to the medRxiv* preprint server, researchers assessed the association between anti-desmoglein (DSG) 1, 2 and 3 auto-antibodies (auto-Abs) in acute and convalescent serum samples obtained from patients with coronavirus disease 2019 (COVID-19) of varying severity.

Study: SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection. Image Credit: Sutthituch/Shutterstock
Study: SARS-CoV-2 infection is associated with anti-desmoglein 2 autoantibody detection. Image Credit: Sutthituch/Shutterstock

Post-acute cardiovascular sequelae are known complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The authors of the present study previously showed that auto-Abs against antigens in the muscle, heart, and skin are present in individuals following severe SARS-CoV-2 infections, particularly anti-DSG auto-Abs in the skin samples of patients with critical COVID-19.

About the study

In the present study, researchers evaluated auto-Ab titers against DSG1, DSG2 and DSG3 proteins in acute and convalescent serum samples of COVID-19 patients to determine the relationship between DSG proteins and COVID-19 severity.

To investigate if the auto-Abs were specific for particular diseases, three cohorts were recruited for comparison, which were as follows: (i) a cohort of influenza patients, (ii) a cohort of patients with cardiovascular comorbidities and (iii) a cohort of healthy controls. For the analysis, the intensive therapy unit (ITU)-admitted severe COVID-19 patients (n=39) and COVID-19 convalescents three to six months post-ITU discharge (n=25) were recruited.

Additionally, healthcare workers (n=40) were included who had participated in the COvid-19 COnvalescent immunity (COCO) study and had SARS-CoV-2 infections not requiring hospitalization in the initial COVID-19 wave to investigate if COVID-19 patterns or rates differed based on COVID-19 severity and hospitalization requirements.

For comparison, 16 non-COVID-19 ICU-admitted individuals, 44 healthy individuals and 50 COVID-19-naïve COCO study participants were recruited as controls. Pre-pandemic sera were obtained from the mechanisms of severe acute influenza Consortium (MOSAIC) study participants hospitalized due to influenza infections from 2009 to 2011 (n=42).

For exploring the association between cardiovascular comorbidities and anti-DSG2 auto-Abs, pre-pandemic serum samples were obtained from BBC-AF (Birmingham and black country atrial fibrillation registry) patients (n=34) who had several cardiovascular comorbidities such as atrial fibrillation, heart failure, hypertension, myocardial infarction and coronary artery disease.

Further, post-mortem tissues from pre-pandemic cases without acute cardiac pathologies and incurable COVID-19 cases were obtained as a part of the LoST-SoCC study to explore the relevance of DSG2 auto-Abs and cardiovascular damage in patients with critical COVID-19. Immunohistochemistry (IHC) analysis was performed to examine DSG2 staining patterns in the post-mortem cardiac tissues.

Serum DSG levels were measured by enzyme-linked immunosorbent assays (ELISA) using DSG1, DSG2, DSG3, human desmoplakin (DSP) proteins and human junctional plakoglobin (JUP) proteins. Indirect immunofluorescence (IIF) analysis was performed to detect auto-Abs against the heart, skeletal muscles and epithelium in COVID-19 patients and to explore if skin auto-Abs (detected in 30 COVID-19 patients by inter-cellular cement staining) were associated with DSG1, 2 and 3 proteins.

Results

Elevated DSG2 levels were observed in sera obtained from acute COVID-19 ITU patients (298pg/ml) in comparison to the non-COVID-19 ITU patients (157pg/ml) and healthy controls (222pg/ml). Likewise, the corresponding DSP levels were 4.1 ng/ml, 1.7 ng/ml and 0.95 ng/ml, respectively. The findings indicated a potential association between DSG2 levels and COVID-19 severity.

Anti-DSG2 auto-Ab titers were significantly higher in acute and convalescent severe COVID-19 sera (median ODs of 0.9 and 1.1, respectively) but not in influenza convalescents or healthy controls. Sera of mild COVID-19 convalescents did not exhibit elevated DSG2 auto-Ab titers, neither did sera of non-COVID-19 ITU-admitted individuals and nor did sera from influenza convalescents (median OD=0.4).

In the IIF analysis, elevated titers of epidermal, skeletal muscle and cardiac auto-Abs in the acute COVID ITU group, with 46%, 23% and 8% positive patients, respectively. The corresponding increases in convalescent ITU patients were 52%, 30% and 40%, respectively. Contrastingly, cardiac auto-Abs were the only auto-Abs detected in 6% of non-COVID ITU patients with low titers in influenza patients.

None of the SARS-CoV-2 infection samples with skin auto-Abs showed positivity for anti-DSG1 or anti-DSG3 auto-Abs and contrastingly, 80% of them had anti-DSG2 auto-Ab levels higher than the topmost interquartile range (IQR) for healthy controls (median OD=0.4). Further, auto-Ab titers in sera from patients with severe COVID-19 were comparable to those with non-COVID-19-associated cardiovascular illness (median OD=1.1). The cardiovascular comorbidity type or COVID-19 severity could not estimate the presence of anti-DSG2 auto-Abs.

In non-COVID-19 post-mortem cardiac tissues, the DSG2 staining pattern comprised solitary, distinct bands. On the contrary, COVID-19 post-mortem cardiac tissues showed distinctive regions of DSG2-stained double bands (in addition to solitary bands), indicative of intercalated disc disruptions between cardiomyocytes consistent with DSG2 separation.

Overall, the study findings showed that human DSG2 levels were associated with COVID-19 severity and highlighted the structural changes in cardiomyocyte intercalated discs enriched with DSG2.

*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.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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