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Frontiers in Immunology 2023Autoimmune blistering diseases (AIBD) are paradigms of autoantibody-mediated organ-specific autoimmune disorders that involve skin and/or mucous membranes. Compared to... (Review)
Review
Autoimmune blistering diseases (AIBD) are paradigms of autoantibody-mediated organ-specific autoimmune disorders that involve skin and/or mucous membranes. Compared to other autoimmune diseases, the pathogenicity of autoantibodies in AIBD is relatively well described. Pemphigus is a potentially lethal autoantibody driven autoimmune disorder with a strong HLA class II association. It is mainly characterized by IgG against the desmosomal adhesion molecules desmoglein 3 (Dsg3) and Dsg1. Several murine pemphigus models were developed subsequently, each allowing the analysis of a characteristic feature, such as pathogenic IgG or Dsg3-specific T or B cells. Thus, the models can be employed to preclinically evaluate potentially novel therapies. We here thoroughly summarize past and recent efforts in developing and utilizing pemphigus mouse models for pathomechanistic investigation and therapeutic interventions.
Topics: Mice; Animals; Pemphigus; Autoantibodies; Skin; Autoimmune Diseases; Blister; Disease Models, Animal; Immunoglobulin G
PubMed: 37180099
DOI: 10.3389/fimmu.2023.1169947 -
Seminars in Immunopathology Jan 2024The lungs serve as the primary organ for respiration, facilitating the vital exchange of gases with the bloodstream. Given their perpetual exposure to external... (Review)
Review
The lungs serve as the primary organ for respiration, facilitating the vital exchange of gases with the bloodstream. Given their perpetual exposure to external particulates and pathogens, they possess intricate protective barriers. Cellular adhesion in the lungs is robustly maintained through tight junctions, adherens junctions, and desmosomes. Furthermore, the pulmonary system features a mucociliary clearance mechanism that synthesizes mucus and transports it to the outside. This mucus is enriched with chemical barriers like antimicrobial proteins and immunoglobulin A (IgA). Additionally, a complex immunological network comprising epithelial cells, neural cells, and immune cells plays a pivotal role in pulmonary defense. A comprehensive understanding of these protective systems offers valuable insights into potential pathologies and their therapeutic interventions.
Topics: Humans; Lung; Animals; Mucociliary Clearance; Respiratory Mucosa; Tight Junctions; Cell Adhesion; Mucus
PubMed: 38451292
DOI: 10.1007/s00281-024-01003-y -
The Journal of Investigative Dermatology Mar 2022Pemphigus and pemphigoid are paradigms for understanding the mechanisms of antibody-mediated autoimmune disease in humans. In pemphigus, IgG4-predominant autoantibodies... (Review)
Review
Pemphigus and pemphigoid are paradigms for understanding the mechanisms of antibody-mediated autoimmune disease in humans. In pemphigus, IgG4-predominant autoantibodies cause intraepidermal blistering by direct interference with desmoglein interactions and subsequent disruption of desmosomes and signaling pathways. In pemphigoid, IgG1, IgG4, and IgE autoantibodies against basement membrane zone antigens directly interfere with hemidesmosomal adhesion, activating complement and Fc receptor‒mediated effector pathways. Unraveling disease mechanisms in pemphigus and pemphigoid has identified numerous opportunities for clinical trials, which hold promise to identify safer and more effective therapies for these potentially life-threatening diseases.
Topics: Autoantibodies; Autoimmune Diseases; Humans; Immunoglobulin G; Pemphigoid, Bullous; Pemphigus
PubMed: 34756581
DOI: 10.1016/j.jid.2021.04.040 -
BioRxiv : the Preprint Server For... Sep 2023Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic...
Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in over 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations on desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma tumor cells. In further support of a microenvironmental origin, we find that loss-of-function knockdowns of the desmosome in keratinocytes yield markedly increased proliferation of adjacent melanocytes in keratinocyte/melanocyte co-cultures. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanocytes for neoplastic transformation.
PubMed: 37786690
DOI: 10.1101/2023.09.19.558457 -
Open Biology Feb 2020Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication... (Review)
Review
Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication are prerequisites of such cohesive sheets of cells, and cell connectivity is mediated through several junctional assemblies, namely desmosomes, adherens, tight and gap junctions. These cell-cell junctions form signalling hubs that not only mediate cell-cell adhesion but impact on multiple aspects of cell behaviour, helping to coordinate epithelial cell shape, polarity and function. This review will focus on the tight and adherens junctions, constituents of the apical junctional complex, and aims to provide a comprehensive overview of the complex signalling that underlies junction assembly, integrity and plasticity.
Topics: Adherens Junctions; Animals; Cell Adhesion; Cell Communication; Cell Polarity; Desmosomes; Epithelial Cells; Gap Junctions; Gene Regulatory Networks; Humans; Intercellular Junctions
PubMed: 32070233
DOI: 10.1098/rsob.190278 -
The Journal of Cardiovascular Aging Feb 2023Arrhythmogenic cardiomyopathy (ACM) is hereditary cardiomyopathy caused by pathogenic variants (mutations) in genes encoding the intercalated disc (ID), particularly...
INTRODUCTION
Arrhythmogenic cardiomyopathy (ACM) is hereditary cardiomyopathy caused by pathogenic variants (mutations) in genes encoding the intercalated disc (ID), particularly desmosome proteins. ACM caused by mutations in the gene encoding desmoplakin (DSP) is characterized by the prominence of cell death, myocardial fibrosis, and inflammation, and is referred to as desmoplakin cardiomyopathy.
AIM
The aim of this article was to gain insight into the pathogenesis of DSP cardiomyopathy.
METHODS AND RESULTS
The gene was exclusively deleted in cardiac myocytes using tamoxifen-inducible MerCreMer ( ) and floxed ( ) mice ( : ). Recombination was induced upon subcutaneous injection of tamoxifen (30 mg/kg/d) for 5 days starting post-natal day 14. Survival was analyzed by Kaplan-Meier plots, cardiac function by echocardiography, arrhythmias by rhythm monitoring, and gene expression by RNA-Seq, immunoblotting, and immunofluorescence techniques. Cell death was analyzed by the TUNEL assay and the expression levels of specific markers were by RT-PCR and immunoblotting. Myocardial fibrosis was assessed by picrosirius red staining of the myocardial sections, RT-PCR, and immunoblotting. The : mice showed extensive molecular remodeling of the IDs and the differential expression of ~10,000 genes, which predicted activation of KDM5A, IRFs, and NFκB and suppression of PPARGC1A and RB1, among others in the DSP-deficient myocytes. Gene set enrichment analysis predicted activation of the TNFα/NFκB pathway, inflammation, cell death programs, and fibrosis. Analysis of cell death markers indicated PANoptosis, comprised of apoptosis (increased CASP3, CASP8, BAD and reduced BCL2), necroptosis (increased RIPK1, RIPK3, and MLKL), and pyroptosis (increased GSDMD and ASC or PYCARD) in the DSP-deficient myocytes. Transcript levels of the pro-inflammatory and pro-fibrotic genes were increased and myocardial fibrosis comprised ~25% of the myocardium in the DSP-deficient hearts. The : mice showed severe cardiac systolic dysfunction and ventricular arrhythmias, and died prematurely with a median survival rate of ~2 months.
CONCLUSION
The findings identify PANoptosis as a prominent phenotypic feature of DSP cardiomyopathy and set the stage for delineating the specific molecular mechanisms involved in its pathogenesis. The model also provides the opportunity to test the effects of pharmacological and genetic interventions on myocardial fibrosis and cell death.
PubMed: 36818425
DOI: 10.20517/jca.2022.34 -
Birth Defects Research Oct 2022Human stems cells have sparked many novel strategies for treating heart disease and for elucidating their underlying mechanisms. For example, arrhythmogenic right... (Review)
Review
Human stems cells have sparked many novel strategies for treating heart disease and for elucidating their underlying mechanisms. For example, arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder that is associated with fatal arrhythmias often occurring in healthy young adults. Fibro-fatty infiltrate, a clinical hallmark, progresses with the disease and can develop across both ventricles. Pathogenic variants in genes have been identified, with most being responsible for encoding cardiac desmosome proteins that reside at myocyte boundaries that are critical for cell-to-cell coupling. Despite some understanding of the molecular signaling mechanisms associated with ARVC mutations, their relationship with arrhythmogenesis is complex and not well understood for a monogenetic disorder. This review article focuses on arrhythmia mechanisms in ARVC based on clinical and animal studies and their relationship with disease causing variants. We also discuss the ways in which stem cells can be leveraged to improve our understanding of the role cardiac myocytes, nonmyocytes, metabolic signals, and inflammatory mediators play in an early onset disease such as ARVC.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Heart Ventricles; Humans; Mutation; Stem Cells
PubMed: 35396927
DOI: 10.1002/bdr2.2010 -
Biochimica Et Biophysica Acta.... Sep 2020Desmosomes are cadherin-based adhesion structures that mechanically couple the intermediate filament cytoskeleton of adjacent cells to confer mechanical stress... (Review)
Review
Desmosomes are cadherin-based adhesion structures that mechanically couple the intermediate filament cytoskeleton of adjacent cells to confer mechanical stress resistance to tissues. We have recently described desmosomes as mesoscale lipid raft membrane domains that depend on raft dynamics for assembly, function, and disassembly. Lipid raft microdomains are regions of the plasma membrane enriched in sphingolipids and cholesterol. These domains participate in membrane domain heterogeneity, signaling and membrane trafficking. Cellular structures known to be dependent on raft dynamics include the post-synaptic density in neurons, the immunological synapse, and intercellular junctions, including desmosomes. In this review, we discuss the current state of the desmosome field and put forward new hypotheses for the role of lipid rafts in desmosome adhesion, signaling and epidermal homeostasis. Furthermore, we propose that differential lipid raft affinity of intercellular junction proteins is a central driving force in the organization of the epithelial apical junctional complex.
Topics: Cadherins; Cell Adhesion; Cholesterol; Cytoskeleton; Desmosomes; Epidermis; Humans; Membrane Lipids; Membrane Microdomains; Signal Transduction; Sphingolipids
PubMed: 32376221
DOI: 10.1016/j.bbamem.2020.183329 -
Frontiers in Endocrinology 2023Cell-cell junctions form strong intercellular connections and mediate communication between blastomeres during preimplantation embryonic development and thus are crucial... (Review)
Review
Cell-cell junctions form strong intercellular connections and mediate communication between blastomeres during preimplantation embryonic development and thus are crucial for cell integrity, polarity, cell fate specification and morphogenesis. Together with cell adhesion molecules and cytoskeletal elements, intercellular junctions orchestrate mechanotransduction, morphokinetics and signaling networks during the development of early embryos. This review focuses on the structure, organization, function and expressional pattern of the cell-cell junction complexes during early embryonic development. Understanding the importance of dynamic junction formation and maturation processes will shed light on the molecular mechanism behind developmental abnormalities of early embryos during the preimplantation period.
Topics: Animals; Female; Pregnancy; Mechanotransduction, Cellular; Intercellular Junctions; Embryonic Development; Morphogenesis; Signal Transduction; Mammals
PubMed: 37152932
DOI: 10.3389/fendo.2023.1150017 -
JPMA. the Journal of the Pakistan... Aug 2020Cell-adhesion complex within a tissue is important for its stability, structural integrity, functioning, cellular migration and morphogenesis. Disruption of desmosomal... (Review)
Review
Cell-adhesion complex within a tissue is important for its stability, structural integrity, functioning, cellular migration and morphogenesis. Disruption of desmosomal cell-adhesions complex results in epithelial conditions such as epidermolysis bullosa and bullous pemphigoid. Desmosome assembly and disassembly is regulated post-translationally by calcium, kinase/phosphatase activity, proteolytic processing, and also through adhesive junctions. Altered functions of desmosomal proteins desmocollin and desmoglein can cause blistering disorders, such as pemphigus foliaceus and pemphigus vulgaris, and non-Hodgkin Lymphoma while defective desmoplakin can cause supra-basal clefting in epithelium and conditions such as Carvajal syndrome, palmo-plantar keratoderma etc. This review summarises major functions of demosomal complex family and how mis-regulation of demosomal structural proteins occur in pathogenesis of non-, pre- and malignant oral lesions with disrupted epithelium.
Topics: Desmosomes; Humans; Mouth Mucosa; Pemphigus
PubMed: 32794499
DOI: 10.5455/JPMA.15798