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Seminars in Immunopathology Jan 2016Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed... (Review)
Review
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.
Topics: Animals; Antibodies, Monoclonal; Autoantibodies; Autoantigens; Desmogleins; Disease Progression; Epitopes; Genetic Predisposition to Disease; Humans; Immune Sera; Immunoglobulin Idiotypes; Mutation; Organ Specificity; Pemphigus; Signal Transduction; T-Lymphocyte Subsets; Translational Research, Biomedical
PubMed: 26597100
DOI: 10.1007/s00281-015-0541-1 -
Biochemical Pharmacology Oct 2021Pnn, a multiple functional protein, plays roles in embryonic development, cellular differentiation, tumorigenesis, and metastasis. In the past two decades, the functions... (Review)
Review
Pnn, a multiple functional protein, plays roles in embryonic development, cellular differentiation, tumorigenesis, and metastasis. In the past two decades, the functions of Pnn in regulating RNA alternative splicing, gene regulation, and cell-cell connection have been revealed. Although Pnn is originally identified as a desmosome-associated protein for linking desmosome and intermediated filament, emerging evidence implies that Pnn not only is a desmosome protein but also plays critical roles in the nucleus. To date, through cell biology investigation and the generation of animal models with genetic manipulation, the physiological role of Pnn has been characterized in the research fields of developmental biology, tumor biology, and neuroscience. Through proteomic and molecular biology studies, transcription regulators, splicing regulators, and cytoskeletal proteins were found to interact with Pnn. In addition, histopathological and biochemical evidence has pointed to an association of Pnn expression level with tumorigenesis and metastasis. A previous clinical study also demonstrated a correlation between a reduced expression of Pnn and human dementia. Besides, experimental studies showed a protective role of Pnn against ischemic stress in astrocytes. All indicated a variety of roles of Pnn in different cell types. In this review article, we introduced the role of Pnn in embryogenesis and pathogenesis as well as discussed its potential clinical application.
Topics: Animals; Carcinogenesis; Cell Adhesion Molecules; Cell Proliferation; Embryonic Development; Humans; Nuclear Proteins
PubMed: 34237338
DOI: 10.1016/j.bcp.2021.114672 -
Frontiers in Immunology 2019Desmosomes reinforce cohesion of epithelial cells at the interface between adjacent cells. They include the cadherin-type adhesion molecules desmoglein 1 (Dsg1) and...
Desmosomes reinforce cohesion of epithelial cells at the interface between adjacent cells. They include the cadherin-type adhesion molecules desmoglein 1 (Dsg1) and Dsg3. Pemphigus vulgaris (PV) is an autoimmune disease in which circulating autoantibodies (PV-IgG) targeting Dsg1 and 3 cause characteristic epidermal blister formation. It has been shown that PV-IgG binding induced activation of kinases such as ERK and PKC, and inhibition of these signaling pathways prevented loss of cell cohesion in cell cultures. However, the role of Erk and PKC in blister formation and regulation of desmosome ultrastructure in human skin are unknown. Accordingly, we assessed the role of PKC and ERK signaling pathways in blister formation and regulation of desmosome ultrastructure in human epidermis. Here we performed electron microscopy analyses using human skin explants injected with PV-IgG together with inhibitors for PKC or ERK signaling. Inhibition of PKC was not effective to prevent suprabasal blister formation or ultrastructural alterations of desmosomes. In contrast, inhibition of ERK signaling significantly ameliorated blister formation and decrease in the number of desmosomes whereas shortening and splitting of desmosomes and keratin filament insertion were not different from samples treated with PV-IgG alone. However, apical desmosomes between basal and suprabasal cells remained unaltered when ERK signaling was inhibited. Therefore, our results show that inhibition of ERK but not PKC signaling appears to be effective to ameliorate blistering and alterations of desmosome ultrastructure triggered by PV-IgG in human skin.
Topics: Desmosomes; Epidermis; Humans; MAP Kinase Signaling System; Pemphigus; Protein Kinase C
PubMed: 31867019
DOI: 10.3389/fimmu.2019.02883 -
Frontiers in Cell and Developmental... 2022Considerable progress has been made in our knowledge of the morphological and functional varieties of anchoring junctions. Cell-cell adhesion contacts consist of... (Review)
Review
Considerable progress has been made in our knowledge of the morphological and functional varieties of anchoring junctions. Cell-cell adhesion contacts consist of discrete junctional structures responsible for the mechanical coupling of cytoskeletons and allow the transmission of mechanical signals across the cell collective. The three main adhesion complexes are adherens junctions, tight junctions, and desmosomes. Microscopy has played a fundamental role in understanding these adhesion complexes on different levels in both physiological and pathological conditions. In this review, we discuss the main light and electron microscopy techniques used to unravel the structure and composition of the three cell-cell contacts in epithelial and endothelial cells. It functions as a guide to pick the appropriate imaging technique(s) for the adhesion complexes of interest. We also point out the latest techniques that have emerged. At the end, we discuss the problems investigators encounter during their cell-cell adhesion research using microscopic techniques.
PubMed: 35517500
DOI: 10.3389/fcell.2022.819534 -
Europace : European Pacing,... Jul 2016This review aims to give an update on the pathogenesis, clinical manifestations, and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic... (Review)
Review
This review aims to give an update on the pathogenesis, clinical manifestations, and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Arrhythmogenic right ventricular cardiomyopathy is mainly an autosomal dominant inherited disease linked to mutations in genes encoding desmosomes or desmosome-related proteins. Classic symptoms include palpitations, cardiac syncope, and aborted cardiac arrest due to ventricular arrhythmias. Heart failure may develop in later stages. Diagnosis is based on the presence of major and minor criteria from the Task Force Criteria revised in 2010 (TFC 2010), which includes evaluation of findings from six different diagnostic categories. Based on this, patients are classified as having possible, borderline, or definite ARVC. Imaging is important in ARVC diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting structural and functional abnormalities, but importantly these findings may occur after electrical alterations and ventricular arrhythmias. Electrocardiograms (ECGs) and signal-averaged ECGs are analysed for depolarization and repolarization abnormalities, including T-wave inversions as the most common ECG alteration. Ventricular arrhythmias are common in ARVC and are considered a major diagnostic criterion if originating from the RV inferior wall or apex. Family history of ARVC and detection of an ARVC-related mutation are included in the TFC 2010 and emphasize the importance of family screening. Electrophysiological studies are not included in the diagnostic criteria, but may be important for differential diagnosis including RV outflow tract tachycardia. Further differential diagnoses include sarcoidosis, congenital abnormalities, myocarditis, pulmonary hypertension, dilated cardiomyopathy, and athletic cardiac adaptation, which may mimic ARVC.
Topics: Arrhythmias, Cardiac; Arrhythmogenic Right Ventricular Dysplasia; Cell Adhesion Molecules; Desmocollins; Diagnosis, Differential; Echocardiography; Electrocardiography; Family Health; Heart Failure; Heart Ventricles; Humans; Magnetic Resonance Imaging; Mutation; Nuclear Proteins
PubMed: 26498164
DOI: 10.1093/europace/euv340 -
Cell and Tissue Research Jun 2015Corneodesmosomes are modified desmosomes present in the stratum corneum (SC). They are crucial for SC cohesion and, thus, constitute one of the pivotal elements of the... (Review)
Review
Corneodesmosomes are modified desmosomes present in the stratum corneum (SC). They are crucial for SC cohesion and, thus, constitute one of the pivotal elements of the functional protective barrier of human skin. Expression of corneodesmosomes and, notably, the process of their degradation are probably altered during several dermatoses leading to the disruption of the permeability barrier or to abnormal, often compensative, SC accumulation. These different situations are reviewed in the present paper.
Topics: Animals; Desmosomes; Epidermis; Genetic Diseases, Inborn; Humans; Models, Biological; Skin Diseases
PubMed: 25378284
DOI: 10.1007/s00441-014-2019-1 -
Expert Review of Clinical Immunology 2016Autoimmune bullous diseases (AIBDs) are characterized by autoantibodies against structural proteins of the dermal-epidermal junction (in pemphigoid diseases) and the... (Review)
Review
Autoimmune bullous diseases (AIBDs) are characterized by autoantibodies against structural proteins of the dermal-epidermal junction (in pemphigoid diseases) and the epidermal/ epithelial desmosomes (in pemphigus diseases). By far, the most common AIBD is bullous pemphigoid, which is immunopathologically characterized by autoantibodies against BP180 (type XVII collagen) and BP230. IgG and, to a lesser extent, IgA autoantibodies are the major autoantibody isotypes in these disorders. IgE autoantibodies are increasingly reported in particular in bullous pemphigoid. The development of specific and sensitive anti-BP180 IgE ELISA systems, the report of two experimental murine models employing IgE autoantibodies against BP180, and the successful treatment of bullous pemphigoid with the anti-IgE antibody omalizumab have raised interest in the role of IgE autoantibodies and the modulation of their production in AIBDs. Here, the relevance of IgE autoantibodies in the diagnosis, pathophysiology, and treatment decisions of AIBDs, with a focus on bullous pemphigoid, is reviewed.
Topics: Animals; Autoantibodies; Autoantigens; Autoimmunity; Desmosomes; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin E; Mice; Non-Fibrillar Collagens; Pemphigoid, Bullous; Collagen Type XVII
PubMed: 26588556
DOI: 10.1586/1744666X.2016.1123092 -
Upsala Journal of Medical Sciences 2022
Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Desmosomes; Humans; Lung
PubMed: 35140873
DOI: 10.48101/ujms.v127.8250 -
Medicinal Research Reviews Nov 2014Desmosomes are adhering junctions present in all cells of simple and complex epithelia. They are most abundant in cells of tissues subjected to extensive mechanical... (Review)
Review
Desmosomes are adhering junctions present in all cells of simple and complex epithelia. They are most abundant in cells of tissues subjected to extensive mechanical stress such as keratinocytes and cardiomyocytes. The core of desmosomes is built up of desmosomal cadherins, cadherin-type adhesion molecules that are tethered to intermediate filaments via adaptor proteins of the armadillo and the plakin family. In addition, desmosomal cadherins are present outside of desmosomes. Recent investigations indicate that these molecules are involved in adhesion-dependent and adhesion-independent signaling and thus have functions different from the adhesive properties of their counterparts within desmosomes. Impaired adhesion of desmosomal cadherins both within and outside of desmosomes is the cause of the blistering skin disease pemphigus. Autoantibodies interfere with the binding of desmosomal cadherins and alter intracellular signaling pathways, the latter of which is necessary for loss of cell adhesion. Among the plethora of signaling molecules reported, altered activities of p38MAPK, protein kinase C, and epidermal growth factor receptor (EGFR) are most relevant. This review highlights the recent data on signaling by desmosomal cadherins and the mechanisms involved in pemphigus skin blistering.
Topics: Autoantibodies; Cadherins; Cell Adhesion; Desmosomes; Humans; Pemphigus; Signal Transduction
PubMed: 24549583
DOI: 10.1002/med.21310 -
Biomedicines Jul 2023The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation... (Review)
Review
The history of arrhythmogenic cardiomyopathy (AC) as a genetically determined desmosomal disease started since the original discovery by Lancisi in a four-generation family, published in 1728. Contemporary history at the University of Padua started with Dalla Volta, who haemodynamically investigated patients with "auricularization" of the right ventricle, and with Nava, who confirmed familiarity. The contemporary knowledge advances consisted of (a) AC as a heart muscle disease with peculiar electrical instability of the right ventricle; (b) the finding of pathological substrates, in keeping with a myocardial dystrophy; (c) the inclusion of AC in the cardiomyopathies classification; (d) AC as the main cause of sudden death in athletes; (e) the discovery of the culprit genes coding proteins of the intercalated disc (desmosome); (f) progression in clinical diagnosis with specific ECG abnormalities, angiocardiography, endomyocardial biopsy, 2D echocardiography, electron anatomic mapping and cardiac magnetic resonance; (g) the discovery of left ventricular AC; (h) prevention of SCD with the invention and application of the lifesaving implantable cardioverter defibrillator and external defibrillator scattered in public places and playgrounds as well as the ineligibility for competitive sport activity for AC patients; (i) genetic screening of the proband family to unmask asymptomatic carriers. Nondesmosomal ACs, with a phenotype overlapping desmosomal AC, are also treated, including genetics: Transmembrane protein 43, SCN5A, Desmin, Phospholamban, Lamin A/C, Filamin C, Cadherin 2, Tight junction protein 1.
PubMed: 37509658
DOI: 10.3390/biomedicines11072018