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Frontiers in Medicine 2018Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by auto-antibodies (auto-Abs) directed against epithelial desmosomal components and leading to... (Review)
Review
Pemphigus vulgaris (PV) is a severe autoimmune blistering disease caused by auto-antibodies (auto-Abs) directed against epithelial desmosomal components and leading to disruption of cell-cell adhesion. The exact mechanisms underlying the disease pathogenesis remain unknown and treatment is still based on immunosuppressive drugs, such as corticosteroids, which are associated with potentially significant side effects. Ethnic susceptibility, familial occurrence, and autoimmune comorbidity, suggest a genetic component to the pathogenesis of the disease, which, if discovered, could advance our understanding of PV pathogenesis and thereby point to novel therapeutic targets for this life-threatening disorder. In this article, we review the evidence for a genetic basis of PV, summarize the different approaches used to investigate susceptibility traits for the disease and describe past and recent discoveries regarding genes associated with PV, most of which belong to the human leukocyte antigen (HLA) locus with limited data regarding association of non-HLA genes with the disease.
PubMed: 30155467
DOI: 10.3389/fmed.2018.00226 -
British Journal of Biomedical Science 2023Autoimmune blistering diseases (AIBD) comprise a heterogeneous group of uncommon disorders of the skin and mucous membranes, characterised by antibodies targeting... (Review)
Review
Autoimmune blistering diseases (AIBD) comprise a heterogeneous group of uncommon disorders of the skin and mucous membranes, characterised by antibodies targeting structural proteins within epithelial tissue and the underlying basement membrane. There can be significant overlap in clinical presentation of these diseases and accurate diagnosis relies on the detection and characterisation of relevant autoantibodies. Immunofluorescence provides the gold-standard diagnostic tool for these diseases, identifying both tissue-bound autoantibodies in biopsy material using direct immunofluorescence and circulating antibodies in serum through indirect immunofluorescence. Following advances in the identification and subsequent characterisation of numerous antigenic targets in these diseases, the development of antigen-specific tests, in particular, enzyme-linked immunosorbent assays on serum specimens, has provided a third key tool to not only identify, but also quantify AIBD autoantibodies. This quantification has proven particularly useful in monitoring disease activity and informing clinical management decisions. Accurate diagnosis of these diseases is important since optimal treatment strategies differ between them and, prognostically, some diagnoses are associated with an increased risk of malignancy. This review outlines the molecular pathology underlying the major AIBD and describes how the three principal techniques can be used in combination, to provide best practice for diagnosis and treatment monitoring.
Topics: Humans; Autoimmune Diseases; Blister; Autoantibodies; Enzyme-Linked Immunosorbent Assay
PubMed: 38074463
DOI: 10.3389/bjbs.2023.11809 -
Frontiers in Cell and Developmental... 2022Mechanical stability is a fundamental and essential property of epithelial cell sheets. It is in large part determined by cell-cell adhesion sites that are tightly...
Mechanical stability is a fundamental and essential property of epithelial cell sheets. It is in large part determined by cell-cell adhesion sites that are tightly integrated by the cortical cytoskeleton. An intimate crosstalk between the adherens junction-associated contractile actomyosin system and the desmosome-anchored keratin intermediate filament system is decisive for dynamic regulation of epithelial mechanics. A major question in the field is whether and in which way mechanical stress affects junctional plasticity. This is especially true for the desmosome-keratin scaffold whose role in force-sensing is virtually unknown. To examine this question, we inactivated the actomyosin system in human keratinocytes (HaCaT) and canine kidney cells (MDCK) and monitored changes in desmosomal protein turnover. Partial inhibition of myosin II by para-nitro-blebbistatin led to a decrease of the cells' elastic modulus and to reduced desmosomal protein turnover in regions where nascent desmosomes are formed and, to a lower degree, in regions where larger, more mature desmosomes are present. Interestingly, desmosomal proteins are affected differently: a significant decrease in turnover was observed for the desmosomal plaque protein desmoplakin I (DspI), which links keratin filaments to the desmosomal core, and the transmembrane cadherin desmoglein 2 (Dsg2). On the other hand, the turnover of another type of desmosomal cadherin, desmocollin 2 (Dsc2), was not significantly altered under the tested conditions. Similarly, the turnover of the adherens junction-associated E-cadherin was not affected by the low doses of para-nitro-blebbistatin. Inhibition of actin polymerization by low dose latrunculin B treatment and of ROCK-driven actomyosin contractility by Y-27632 treatment also induced a significant decrease in desmosomal DspI turnover. Taken together, we conclude that changes in the cortical force balance affect desmosome formation and growth. Furthermore, they differentially modulate desmosomal protein turnover resulting in changes of desmosome composition. We take the observations as evidence for a hitherto unknown desmosomal mechanosensing and mechanoresponse pathway responding to an altered force balance.
PubMed: 36268507
DOI: 10.3389/fcell.2022.946190 -
Frontiers in Cell and Developmental... 2022Desmin () is a classical type III intermediate filament protein encoded by the gene. Desmin is abundantly expressed in cardiac, skeletal, and smooth muscle cells. In... (Review)
Review
Desmin () is a classical type III intermediate filament protein encoded by the gene. Desmin is abundantly expressed in cardiac, skeletal, and smooth muscle cells. In these cells, desmin interconnects several protein-protein complexes that cover cell-cell contact, intracellular organelles such as mitochondria and the nucleus, and the cytoskeletal network. The extra- and intracellular localization of the desmin network reveals its crucial role in maintaining the structural and mechanical integrity of cells. In the heart, desmin is present in specific structures of the cardiac conduction system including the sinoatrial node, atrioventricular node, and His-Purkinje system. Genetic variations and loss of desmin drive a variety of conditions, so-called desminopathies, which include desmin-related cardiomyopathy, conduction system-related atrial and ventricular arrhythmias, and sudden cardiac death. The severe cardiac disease outcomes emphasize the clinical need to understand the molecular and cellular role of desmin driving desminopathies. As the role of desmin in cardiomyopathies has been discussed thoroughly, the current review is focused on the role of desmin impairment as a trigger for cardiac arrhythmias. Here, the molecular and cellular mechanisms of desmin to underlie a healthy cardiac conduction system and how impaired desmin triggers cardiac arrhythmias, including atrial fibrillation, are discussed. Furthermore, an overview of available (genetic) desmin model systems for experimental cardiac arrhythmia studies is provided. Finally, potential implications for future clinical treatments of cardiac arrhythmias directed at desmin are highlighted.
PubMed: 36158202
DOI: 10.3389/fcell.2022.986718 -
Frontiers in Immunology 2022Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg)1 and... (Review)
Review
Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg)1 and Dsg3. PV patient lesions are characterized by flaccid blisters and ultrastructurally by defined hallmarks including a reduction in desmosome number and size, formation of split desmosomes, as well as uncoupling of keratin filaments from desmosomes. The pathophysiology underlying the disease is known to involve several intracellular signaling pathways downstream of PV-IgG binding. Here, we summarize our studies in which we used transmission electron microscopy to characterize the roles of signaling pathways in the pathogenic effects of PV-IgG on desmosome ultrastructure in a human skin model. Blister scores revealed inhibition of p38MAPK, ERK and PLC/Ca to be protective in human epidermis. In contrast, inhibition of Src and PKC, which were shown to be protective in cell cultures and murine models, was not effective for human skin explants. The ultrastructural analysis revealed that for preventing skin blistering at least desmosome number (as modulated by ERK) or keratin filament insertion (as modulated by PLC/Ca) need to be ameliorated. Other pathways such as p38MAPK regulate desmosome number, size, and keratin insertion indicating that they control desmosome assembly and disassembly on different levels. Taken together, studies in human skin delineate target mechanisms for the treatment of pemphigus patients. In addition, ultrastructural analysis supports defining the specific role of a given signaling molecule in desmosome turnover at ultrastructural level.
Topics: Acantholysis; Animals; Blister; Desmosomes; Humans; Immunoglobulin G; Keratins; Mice; Pemphigus; p38 Mitogen-Activated Protein Kinases
PubMed: 35720332
DOI: 10.3389/fimmu.2022.884067 -
Journal of Clinical Medicine Mar 2020Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease characterized by a scarred ventricular myocardium with a distinctive propensity to ventricular arrhythmias... (Review)
Review
Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease characterized by a scarred ventricular myocardium with a distinctive propensity to ventricular arrhythmias (VAs) and sudden cardiac death, especially in young athletes. Arrhythmogenic right ventricular cardiomyopathy (ARVC) represents the best characterized variant of AC, with a peculiar genetic background, established diagnostic criteria and management guidelines; however, the identification of nongenetic causes of the disease, combined with the common demonstration of biventricular and left-dominant forms, has led to coin the term of "arrhythmogenic cardiomyopathy", to better define the broad spectrum of the disease phenotypic expressions. The genetic basis of AC are pathogenic mutations in genes encoding the cardiac desmosomes, but also non-desmosomal and nongenetic variants were reported in patients with AC, some of which showing overlapping phenotypes with other non-ischemic diseases. The natural history of AC is characterized by VAs and progressive deterioration of cardiac performance. Different phases of the disease are recognized, each characterized by pathological and clinical features. Arrhythmic manifestations are age-related: Ventricular fibrillation and SCD are more frequent in young people, while sustained ventricular tachycardia is more common in the elderly, depending on the different nature of the myocardial lesions. This review aims to address the genetic basis, the clinical course and the phenotypic variants of AC.
PubMed: 32210158
DOI: 10.3390/jcm9030878 -
JACC. Cardiovascular Imaging May 2015Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial cardiomyopathy resulting in progressive right ventricular (RV) dysfunction and malignant... (Review)
Review
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial cardiomyopathy resulting in progressive right ventricular (RV) dysfunction and malignant ventricular arrhythmias. Although ARVD/C is generally considered an inherited cardiomyopathy, the arrhythmogenic nature of the disease is striking. Affected individuals typically present in the second to fourth decade of life with arrhythmias originating from the right ventricle. Over the past decade, pathogenic ARVD/C-causing mutations have been identified in 5 genes encoding the cardiac desmosome. Disruption of the desmosomal connection system between cardiomyocytes may be represented structurally by ventricular enlargement, global or regional contraction abnormalities, RV aneurysms, or fibrofatty replacement. These abnormalities are typically observed in predilection areas, including the subtricuspid region, basal RV free wall, and left ventricular posterolateral wall. As such, structural and functional abnormalities on cardiac imaging constitute an important diagnostic criterion for the disease. This paper discusses the current status and role of echocardiography, cardiac magnetic resonance imaging, and computed tomography for suspected ARVD/C.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Echocardiography; Humans; Magnetic Resonance Imaging; Multimodal Imaging; Myocardium; Predictive Value of Tests; Prognosis; Tomography, X-Ray Computed; Ventricular Function, Right
PubMed: 25937197
DOI: 10.1016/j.jcmg.2015.02.007 -
EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation.JCI Insight Mar 2023Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new...
Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of the epidermal growth factor receptor (EGFR) in cardiomyocyte cohesion. We inhibited EGFR under physiological and pathophysiological conditions using the murine plakoglobin-KO AC model, in which EGFR was upregulated. EGFR inhibition enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and atomic force microscopy (AFM) revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly were observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to cell borders. PamGene Kinase assay performed in HL-1 cardiomyocytes treated with erlotinib, an EGFR inhibitor, revealed upregulation of Rho-associated protein kinase (ROCK). Erlotinib-mediated desmosome assembly and cardiomyocyte cohesion were abolished upon ROCK inhibition. Thus, inhibiting EGFR and, thereby, stabilizing desmosome integrity via ROCK might provide treatment options for AC.
Topics: Animals; Mice; Cell Adhesion; Desmoglein 2; Desmosomes; ErbB Receptors; Erlotinib Hydrochloride; Myocytes, Cardiac; rho-Associated Kinases
PubMed: 36795511
DOI: 10.1172/jci.insight.163763 -
Frontiers in Cell and Developmental... 2021Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural... (Review)
Review
Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.
PubMed: 34631720
DOI: 10.3389/fcell.2021.745670 -
Genes Sep 2023Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to... (Review)
Review
Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to have a strong genetic basis, including arrhythmogenic cardiomyopathy (ACM), which predisposes patients to arrhythmic episodes. Variants in one of the five genes ( and ) encoding proteins of the desmosome are known to cause a subset of ACM, which we classify as desmosome-related ACM (dACM). Phenotypically, this disease may lead to sudden cardiac death in young athletes and, during late stages, is often accompanied by myocardial fibrofatty infiltrates. While the pathogenicity of the desmosome genes has been well established through animal studies and limited supplies of primary human cells, these systems have drawbacks that limit their utility and relevance to understanding human disease. Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for modeling ACM in vitro that can overcome these challenges, as they represent a reproducible and scalable source of cardiomyocytes (CMs) that recapitulate patient phenotypes. In this review, we provide an overview of dACM, summarize findings in other model systems linking desmosome proteins with this disease, and provide an up-to-date summary of the work that has been conducted in hiPSC-cardiomyocyte (hiPSC-CM) models of dACM. In the context of the hiPSC-CM model system, we highlight novel findings that have contributed to our understanding of disease and enumerate the limitations, prospects, and directions for research to consider towards future progress.
Topics: Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Cardiomyopathies; Phenotype
PubMed: 37895213
DOI: 10.3390/genes14101864