Desmosomes are composed of a number of proteins, including cadherins, armadillo proteins and plakoplilins, which are responsible for mediating cell-cell adhesion. Cadherins are transmembrane proteins that bind to each other on adjacent cells, forming a strong adhesive bond between the cells. In normal tissues, desmosomes help to maintain the structural integrity of the tissue by holding the cells together. During carcinogenesis, the structure and function of desmosomes may be altered. For example, in oral cancer, the expression of certain cadherins may be increased, leading to increased cell-cell adhesion and a more cohesive tumour mass. This may contribute to the ability of cancer cells to evade the immune system and resist chemotherapy. In addition to their role in cell adhesion, desmosomes also play a role in cell signaling. The proteins that make up desmosomes can interact with signaling pathways that regulate cell proliferation, migration and survival. Dysregulation of these pathways may contribute to the development and progression of oral cancer. There is also evidence that desmosomes may be involved in the process of invasion and metastasis, which is the spread of cancer cells from the primary tumour to other parts of the body. Cancer cells that have disrupted or abnormal desmosomes may be more likely to migrate and invade other tissues. Overall, desmosomes appear to be important in the development and progression of oral cancer. Further research is needed to fully understand the role of these cell-cell junctions in the disease and to identify potential therapeutic targets.

Pemphigus is a rare disease characterized by bullous lesions of the skin and mucous membranes. The aetiology is autoimmune and related to the formation of IgG autoantibodies against desmogleins, which are structural proteins of desmosomes that ensure the stability of contacts between cells. Cardiac involvement in patients with pemphigus is poorly documented. We report the data in the literature on this topic and a case of pemphigus-associated autoimmune myocarditis with damage of intercalated disc responding to immunosuppressive therapy. The occurrence of cardiomyopathy with left ventricular dysfunction in patients affected by pemphigus should be appropriately screened with endomyocardial biopsy as it could be the myocardial extension of a potentially reversible autoimmune disorder.

Pemphigus vulgaris is an autoimmune blistering disease with an increased potential for mortality. The epithelium is key in understanding the pathobiology as it is specialized to perform functions like mechanical protection, immunological defense, and proprioception. In order to perform these array of functions, epithelial integrity is important. This integrity is maintained by a host of molecules which orchestrate the ability of the keratinocytes to function as a single unit. Desmoglein 3 antibodies formed in genetically susceptible individuals are known to cause the disruption of the intact oral mucosa leading to the formation of blisters in pemphigus vulgaris patients. However, there are underlying complex triggering pathways leading to the clinical disease. The aim of the review is to congregate and critically appraise the various triggering pathways which contribute toward the pathobiology of pemphigus vulgaris. Articles relevant to the pathobiology of pemphigus vulgaris were identified from various search databases till the year 2020. The pathogenesis of pemphigus vulgaris is complex, and it involves an in-depth understanding of the various predisposing factors, provoking factors, and progression mechanisms. Congregation of the various triggering pathways will open our minds to understand pemphigus vulgaris better and in turn develop a reliable treatment in the near future.

Understanding the function of oral mucosal epithelial barriers is essential for a plethora of research fields such as tumor biology, inflammation and infection diseases, microbiomics, pharmacology, drug delivery, dental and biomarker research. The barrier properties are comprised by a physical, a transport and a metabolic barrier, and all these barrier components play pivotal roles in the communication between saliva and blood. The sum of all epithelia of the oral cavity and salivary glands is defined as the blood-saliva barrier. The functionality of the barrier is regulated by its microenvironment and often altered during diseases. A huge array of cell culture models have been developed to mimic specific parts of the blood-saliva barrier, but no ultimate standard in vitro models have been established. This review provides a comprehensive overview about developed in vitro models of oral mucosal barriers, their applications, various cultivation protocols and corresponding barrier properties.

Pemphigus is a group of rare, potentially devastating autoimmune diseases of the skin and mucous membranes with high morbidity and potentially lethal outcome. The major clinical variant, pemphigus vulgaris (PV) is caused by a loss of intercellular adhesion of epidermal keratinocytes which is induced by IgG autoantibodies against components of desmosomes. Specifically, IgG against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), preferentially target their ectodomains which are presumably critical for the transinteraction and signalling function of these adhesion molecules. There is a close immunogenetic association of PV with the human leukocyte antigen (HLA) class II alleles, HLA-DRB1*04:02 and HLA-DQB1*05:03. These have been shown to be critical for the presentation of immunodominant peptides to autoreactive CD4+ T helper cells. The importance of autoaggressive T-B cell interaction in the induction of pathogenic IgG autoantibodies which directly cause epidermal loss of adhesion has been demonstrated both clinically (by the use of the anti-CD20 monoclonal antibody rituximab) and experimentally (in PV mouse models). The strong association of clinically active pemphigus with autoantibodies of the IgG4 and IgE subclasses strongly suggests that T helper 2 cells are critical regulators of the immune pathogenesis of pemphigus. Novel therapeutic approaches target autoreactive T and B cells to specifically interfere with the T cell-dependent activation of B cells leading to the generation of autoantibody-producing plasma cells. Our improved understanding of the autoantibody-driven effector phase of pemphigus has led to the introduction of novel therapies that target pathogenic autoantibodies such as immunoadsorption and drugs that block pathogenic autoantibody-induced cell signalling events.

The relationship between clinical phenotypes and desmosomal gene mutations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is poorly characterized. Therefore, we performed a meta-analysis to explore the genotype-phenotype relationship in patients with ARVC. Any studies reporting this genotype-phenotype relationship were included. In total, 11 studies involving 1,113 patients were included. The presence of desmosomal gene mutations was associated with a younger onset age of ARVC (32.7 ± 15.2 versus 43.2 ± 13.3 years; P = 0.001), a higher incidence of T wave inversion in V1-3 leads (78.5% versus 51.6%; P = 0.0002) or a family history of ARVC (39.5% versus 27.1%; P = 0.03). There was no difference in the proportion of males between desmosomal-positive and desmosomal-negative patients (68.3% versus 68.9%; P = 0.60). The presence of desmosomal gene mutations was not associated with global or regional structural and functional alterations (63.5% versus 60.5%; P = 0.37), epsilon wave (29.4% versus 26.2%; P = 0.51) or ventricular tachycardia of left bundle-branch morphology (62.6% versus 57.2%; P = 0.30). Overall, patients with desmosomal gene mutations are characterized by an earlier onset age, a higher incidence of T wave inversion in V1-3 leads and a strong family history of ARVC.

Inherited desmosomal diseases are characterised by skin and/or cardiac features. Dermatological features might be a clue in the determination of the underlying life-threatening cardiac disease. This article aims to propose a dermatological algorithm for the diagnosis of desmosomal diseases after a systematic review of published articles. Palmoplantar keratoderma (PPK), hair shaft anomalies and skin fragility are the major features in the 458 patients analysed. Isolated PPK or isolated hair shaft anomalies are associated with a desmosomal disease limited to skin. The combination of PPK and hair shaft anomalies was recorded in 161 patients, and this association is at high risk of cardiac disease (129/161, 80.1%). Skin features had led to cardiac monitoring in only 2.3% of those patients. We delineated three major phenotypes: the PPK-hair shaft anomalies-non-fragile skin subtype (77%), always associated with cardiac involvement; the PPK-hair shaft anomalies-skin fragility-normal cardiac function subtype (19.9%), frequently associated with PKP1 mutations; the PPK-hair shaft anomalies-skin fragility-cardiac involvement subtype (3.1%), always due to DSP mutations. Three mutation hotspots in DSP and JUP account for 90.8% of the patients with cardiac involvement. The combination of PPK and hair shaft anomalies justifies long-term cardiac monitoring.

Cadherins are a family of transmembranous glycoproteins responsible for calcium-dependent intercellular adhesion. Absence or loss of function of E-cadherin leads to the disappearance of epithelial characteristics of the cells and generates higher invasiveness for extracellular matrices. That is why cadherin expression is considered to be a decisive indicator for differentiation, aggressive behaviour, high proliferation, metastasis, poor prognosis and invasiveness of human carcinoma cells. In this review, the role of cadherin expression was focused on, both in development and carcinogenesis, paying particular attention to mechanisms involved in its down-regulation. The elements common to this process in both physiological and pathological situations was analysed, particularly in relation to one of the most common malignancy, oral squamous cell carcinoma.

Desmosomes have long been appreciated as intercellular junctions that are vital for maintaining the structural integrity of stratified epithelia. More recent clinical investigations of patients with diseases such as arrhythmogenic cardiomyopathy have further highlighted the importance of desmosomes in cardiac tissue, where they help to maintain coordination of cardiac myocytes. Here, we review clinical and mechanistic studies that provide insight into the functions of desmosomal proteins in skin and heart during homeostasis and in disease. While intercellular junctions are organized differently in cardiac and epithelial tissues, studies conducted in epithelial systems may inform our understanding of cardiac desmosomes. We explore traditional and non-traditional roles of desmosomal proteins, ranging from adhesive capacities to nuclear functions. Finally, we discuss how these studies can guide future investigations focused on determining the molecular mechanisms by which desmosomal mutations promote the development of cardiac diseases.

Failure of desmosomal adhesion with ensuing keratinocyte separation - a phenomenon called acantholysis - can result from genetic, autoimmune or infectious proteolytic causes. Rare hereditary disorders of desmosomal formation have been identified in animals. Familial acantholysis of Angus calves and hereditary suprabasal acantholytic mechanobullous dermatosis of buffaloes appear to be similar to acantholytic epidermolysis bullosa of human beings. A genetic acantholytic dermatosis resembling human Darier disease has been rarely recognized in dogs. In autoimmune blistering dermatoses, circulating autoantibodies bind to the extracellular segments of desmosomal proteins and induce acantholysis. Autoantibodies against desmoglein-3 are found in canine pemphigus vulgaris and paraneoplastic pemphigus. Autoantibodies against desmoglein-1 have been rarely detected in dogs with pemphigus foliaceus. When circulating autoantibodies target desmogleins-1 and -3, mucocutaneous pemphigus vulgaris develops in dogs. Finally, several infectious agents can release proteases that cleave desmosomal bonds. In superficial pustular dermatophytosis of dogs and horses, Trichophyton hyphae colonize the stratum corneum, and acantholysis presumably develops because of proteases secreted by the dermatophytes. In exudative epidermitis of piglets, Staphylococcus bacteria - usually Staphylococcus hyicus- release exfoliatin toxins that bind to and specifically cleave desmoglein-1. Any of the above mechanisms can result in impairment of desmosomal function with subsequent acantholysis. The end point of adhesion failure is identical among these diseases: there is cleft formation where desmosomes are affected. The similarity of mechanisms explains why clinical and microscopic skin lesions overlap between entities, thus leaving clinicians and dermatopathologists with the conundrum of determining whether the acantholysis is of genetic, autoimmune or infectious origin.