Link between autoimmunity to anti-desmoglein 2(DSG2) and the long-term sequelae of SARS-CoV-2 infection

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The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in millions of deaths worldwide. While the majority of patients with COVID-19 have mild symptoms or are asymptomatic, some develop severe illness that can lead to hospitalization and death.

Recently, there have been reports of autoantibody production in COVID-19 patients, which may contribute to the severity of the disease. Desmoglein 2 (Dsg2), a protein found in the heart, has been identified as a target of autoantibodies in COVID-19 patients. In this analysis, we will examine the association between SARS-CoV-2 infection and anti-Dsg2 autoantibody detection.

Desmosomes are specialized intercellular junctions found in tissues that are subjected to mechanical stress, such as the skin, heart, and epithelial tissues. These junctions play a crucial role in cell adhesion, maintaining tissue integrity, and providing mechanical strength to tissues. In this report, we will discuss the structure and function of desmosomes and their role in the body.

Structure of Desmosomes

Desmosomes consist of two main components: desmoglein (Dsg) and desmocollin (Dsc), which are members of the cadherin superfamily of calcium-dependent cell adhesion molecules. Dsg and Dsc are transmembrane glycoproteins that span the plasma membrane and protrude into the extracellular space. The cytoplasmic domains of these proteins are linked to intermediate filaments, such as keratin filaments in epithelial cells or desmin filaments in cardiac muscle cells, through a complex network of cytoplasmic proteins, including plakoglobin, plakophilin, and desmoplakin.

Function of Desmosomes

Desmosomes play a critical role in cell adhesion and tissue integrity. They provide mechanical strength to tissues by anchoring cells together and linking them to intermediate filaments. This is particularly important in tissues subjected to mechanical stress, such as the skin, where desmosomes help to maintain the integrity of the epidermis and prevent the separation of the epidermal layers.

In addition to their structural role, desmosomes also play a crucial role in signaling and communication between cells. They have been shown to regulate cell proliferation and differentiation, and to modulate cellular responses to mechanical stress and tension. Desmosomes are also involved in tissue development and repair, as well as in the pathogenesis of several diseases, including skin diseases, cardiomyopathies, and autoimmune diseases.

Role of Desmosomes in the Skin

Desmosomes play a critical role in maintaining the integrity of the skin. In the epidermis, desmosomes link adjacent keratinocytes together and anchor them to the underlying basement membrane. This is important for maintaining the structural integrity of the epidermis and preventing the separation of the epidermal layers, which can result in blistering and skin disorders such as pemphigus vulgaris.

Role of Desmosomes in the Heart

Desmosomes are also critical for the function of the heart. In cardiac muscle cells, desmosomes link adjacent cells together and transmit mechanical stress between cells during contraction. They also help to maintain the structural integrity of the heart and prevent the separation of the cardiac muscle layers, which can result in cardiomyopathies such as arrhythmogenic right ventricular dysplasia.

Autoimmunity in COVID-19

Autoimmunity is a process in which the immune system attacks the body’s own tissues, leading to damage and dysfunction. There is increasing evidence that autoimmunity may play a role in the pathogenesis of COVID-19. In particular, several studies have reported the presence of autoantibodies in COVID-19 patients, including those targeting the angiotensin-converting enzyme 2 (ACE2) receptor, which is the primary receptor for SARS-CoV-2 entry into cells.

Anti-Dsg2 Autoantibodies in COVID-19

Desmoglein 2 (Dsg2) is a protein found in the heart and is essential for normal cardiac function. Recent studies have identified Dsg2 as a target of autoantibodies in COVID-19 patients. These autoantibodies can interfere with the function of Dsg2, leading to cardiac damage and dysfunction.

In a new study the researchers have found raised DSG2 protein and a higher frequency of DSG2 autoantibody production in patients with or following severe COVID-19. Increased anti-DSG2 autoantibodies are not induced to all infections as evidenced by the relative absence of anti- DSG2 responses in other groups including a cohort of influenza patients.

Furthermore, the detection of perturbed DSG2 staining in post-mortem human heart tissue from COVID-19 patients reveals structural changes of the cardiomyocyte intercalated discs which are rich in DSG2.

There is an extensive literature on the association between numerous viral infections and autoimmunity. This can be due to a number of mechanisms including molecular mimicry, epitope spreading and bystander activation. COVID-19 is no exception with clinical syndromes such as autoimmune cytopenia, Guillain-Barre syndrome, autoimmune encephalitis, lupus and acquired haemophilia being reported 16.

COVID-19 infection results in the post-translational modification of a vast number of proteins with high intrinsic propensity to become autoantigens, offering an explanation for the diverse autoimmune complications observed 17.

Although low-titre, transient autoantibodies occur with many acute viral infections 18 their clinical significance and pathogenic potential are uncertain. We have previously reported an increase in autoantibodies post-COVID-19 1 with a specific pattern of autoantibodies against cardiac, skin and muscle and shown that these were still present at 6 months post-infection.

Similarly, in this study we find an increased rate of DSG2 autoantibodies and that these persist to 6 months following an episode of severe COVID-19. These are unlikely to be present transiently due to a single episode of infection as the half-life for IgG is approximately 3 weeks.

The potential for chronicity of these antibodies is further supported by the serological response being similar between the chronic COVID-19 group, the acute group and the cardiac group. Nevertheless, further studies, particularly longitudinal studies, are necessary to provide more conclusive insights as alternative interpretations of these data cannot be ruled out at this stage.

The finding of autoantibodies at 6 months raises the possibility that there may be an ongoing clinical consequence; however, future study is required of longitudinal samples with clinical follow up data to establish causation.

DSG2 autoantibodies have the potential to be pathogenic and have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and familial dilated cardiomyopathy7. Furthermore, DSG2 autoantibodies have been shown to disrupt DSG2 protein function with the consequence of interfering with cell-to-cell adhesion 7,19.

Consequent intercellular space widening at the level of the intercalated disc (desmosomes/adherens junction) and reduction in action potential velocity results in the increased arrhythmia susceptibility observed 20.

Cardiac injury following COVID-19 infection is now well described in the literature, although the mechanisms behind this remain uncertain 11. Clinical studies have reported post-covid-19 complications such as thromboembolism, ischaemia, arrhythmias, conduction defections and myocarditis 21-23 and post-mortem studies have found increased neutrophil extracellular trap (NET) formation and mononuclear cell infiltration 13.

Given that cardiac involvement is an important and long-term consequence of COVID-19, and potential also within the spectrum of syndromes observed in “long-COVID”, we examined post-mortem heart tissue for DSG2 protein. We found that DSG2 is localised to the intercalated discs, confirming previous studies, and importantly that these discs were only found to be widened in COVID-19 tissue samples as is seen in ARVC 8,20.

Previous in vitro studies for ARVC have found that inhibition of DSG2 binding, or mutation of DSG2 protein, disrupts intercalated discs and subsequently the cell to cell contact necessary for cardiomyocyte adhesion. It is increasingly recognised that DSG2 is a multifunctional protein and may have a role in carcinogenesis 24, angiogenesis and re-localisation of actin 25, early haematopoietic development in the bone marrow, in particular myeloid progenitors 25, and intestinal epithelial apoptosis and haemostasis 26.

Finally, DSG2 has been identified as the primary high-affinity receptor used by a number of adenovirus (Ad) serotypes which cause severe respiratory disease in humans27,28.

The presence of these autoantibodies may be indirect markers of historic tissue damage or alternatively they may play a pathogenic role by disrupting intercalated discs and therefore normal cardiac function. The visualisation of IgG deposition on intercalated discs further raises the possibility of antibody interference.

Future studies will have to examine how DSG2 autoantibodies may interfere with DSG2 protein function and the clinical consequences of this and replicated in larger studies with clinically associated data, this may offer a potential biomarker for the multiple and diverse long-term sequelae following COVID-19 infection.

In conclusion, the findings of DSG2 autoantibodies and intercalated disc widening offer a potential autoimmune mechanism for some of the complications found post-COVID-19 infection. Further studies in well characterised clinical cohorts, with comorbid complications, are required to prove whether the presence of DSG2 antibodies serves as a marker of post- acute COVID-19 syndrome or long COVID.

Detailed mechanistic studies are required to reveal the link between autoimmunity to DSG2 and the long-term sequelae of SARS-CoV-2 infection.

reference link :https://www.medrxiv.org/content/10.1101/2022.07.26.22278002v1.full-text

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