-
Frontiers in Medicine 2023Pemphigus is a life-threatening autoimmune blistering disease affecting skin and mucous membranes. Despite its etiopathogenesis remains largely unknown, several trigger... (Review)
Review
Pemphigus is a life-threatening autoimmune blistering disease affecting skin and mucous membranes. Despite its etiopathogenesis remains largely unknown, several trigger and predisposing factors have been reported. Pemphigus is caused by autoantibodies that target desmoglein 1 and desmoglein 3, impacting desmosome function. However, circulating autoantibodies are often the consequence of a precipitating factor that occurs in predisposed individuals. This review aims to describe and discuss almost all trigger and predisposing factors reported as possible or probable cause of the disease. Among the reported trigger factors that may induce or exacerbate pemphigus, we have found of particular interest: drug intake (especially thiol- and phenol-containing compounds), vaccines, infections, as well as some reports about pregnancy, radiations, emotional stress, pesticides and physical trauma. Moreover, we discuss the possible role of food intake in pemphigus onset and particular attention is given to dietary factors containing thiol, phenol and tannin compounds. A trigger factor is "the straw that breaks the camel's back," and often acts together with predisposing factors. Here we discuss how pemphigus onset may be influenced by genetic susceptibility and comorbidities like thyroid diseases, malignancies and other autoimmune disorders. To identify other hitherto unknown trigger and predisposing factors, well designed prospective studies are needed. In this context, future research should explore their connection with the aim to advance our understanding of pemphigus pathogenesis.
PubMed: 38213911
DOI: 10.3389/fmed.2023.1326359 -
Translational Research : the Journal of... Sep 2023Arrhythmogenic cardiomyopathy is a rare inherited entity, characterized by a progressive fibro-fatty replacement of the myocardium. It leads to malignant arrhythmias and... (Review)
Review
Arrhythmogenic cardiomyopathy is a rare inherited entity, characterized by a progressive fibro-fatty replacement of the myocardium. It leads to malignant arrhythmias and a high risk of sudden cardiac death. Incomplete penetrance and variable expressivity are hallmarks of this arrhythmogenic cardiac disease, where the first manifestation may be syncope and sudden cardiac death, often triggered by physical exercise. Early identification of individuals at risk is crucial to adopt protective and ideally personalized measures to prevent lethal episodes. The genetic analysis identifies deleterious rare variants in nearly 70% of cases, mostly in genes encoding proteins of the desmosome. However, other factors may modulate the phenotype onset and outcome of disease, such as microRNAs. These small noncoding RNAs play a key role in gene expression regulation and the network of cellular processes. In recent years, data focused on the role of microRNAs as potential biomarkers in arrhythmogenic cardiomyopathy have progressively increased. A better understanding of the functions and interactions of microRNAs will likely have clinical implications. Herein, we propose an exhaustive review of the literature regarding these noncoding RNAs, their versatile mechanisms of gene regulation and present novel targets in arrhythmogenic cardiomyopathy.
Topics: Humans; MicroRNAs; Genetic Predisposition to Disease; Arrhythmogenic Right Ventricular Dysplasia; Biomarkers; Death, Sudden, Cardiac
PubMed: 37105319
DOI: 10.1016/j.trsl.2023.04.003 -
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 -
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 -
Biomedicine & Pharmacotherapy =... Nov 2023Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition... (Review)
Review
Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition to common clinical and pathological features, ACM caused by mutant DSG2 has specific characteristics, manifesting as left ventricle involvement and a high risk of heart failure. Pathological studies have shown extensive cardiomyocyte necrosis, infiltration of immune cells, and fibrofatty replacement in both ventricles, as well as abnormal desmosome structures in the hearts of humans and mice with mutant DSG2-related ACM. Although desmosome dysfunction is a common pathway in the pathogenesis of mutant DSG2-related ACM, the mechanisms underlying this dysfunction vary among mutations. Desmosome dysfunction induces cardiomyocyte injury, plakoglobin dislocation, and gap junction dysfunction, all of which contribute to the initiation and progression of ACM. Additionally, dysregulated inflammation, overactivation of transforming growth factor-beta-1 signaling and endoplasmic reticulum stress, and cardiac metabolic dysfunction contribute to the pathogenesis of ACM caused by mutant DSG2. These features demonstrate that patients with mutant DSG2-related ACM should be managed individually and precisely based on the genotype and phenotype. Further studies are needed to investigate the underlying mechanisms and to identify novel therapies to reverse or attenuate the progression of ACM caused by mutant DSG2.
PubMed: 37696084
DOI: 10.1016/j.biopha.2023.115448 -
Kidney International May 2024Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The...
Desmosomes are multi-protein cell-cell adhesion structures supporting cell stability and mechanical stress resilience of tissues, best described in skin and heart. The kidney is exposed to various mechanical stimuli and stress, yet little is known about kidney desmosomes. In healthy kidneys, we found desmosomal proteins located at the apical-junctional complex in tubular epithelial cells. In four different animal models and patient biopsies with various kidney diseases, desmosomal components were significantly upregulated and partly miss-localized outside of the apical-junctional complexes along the whole lateral tubular epithelial cell membrane. The most upregulated component was desmoglein-2 (Dsg2). Mice with constitutive tubular epithelial cell-specific deletion of Dsg2 developed normally, and other desmosomal components were not altered in these mice. When challenged with different types of tubular epithelial cell injury (unilateral ureteral obstruction, ischemia-reperfusion, and 2,8-dihydroxyadenine crystal nephropathy), we found increased tubular epithelial cell apoptosis, proliferation, tubular atrophy, and inflammation compared to wild-type mice in all models and time points. In vitro, silencing DSG2 via siRNA weakened cell-cell adhesion in HK-2 cells and increased cell death. Thus, our data show a prominent upregulation of desmosomal components in tubular cells across species and diseases and suggest a protective role of Dsg2 against various injurious stimuli.
Topics: Animals; Humans; Mice; Cell Adhesion; Desmoglein 2; Desmosomes; Heart; Kidney Diseases
PubMed: 38395410
DOI: 10.1016/j.kint.2024.01.037 -
Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis.JCI Insight Aug 2023Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell...
Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. To better understand the underlying mechanisms leading to disease in these conditions, we performed RNA-seq on lesional skin samples from patients. The transcriptomic profiles of Darier, Hailey-Hailey, and Grover diseases were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases. Analysis of enriched pathways showed a shared increase in keratinocyte differentiation, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grover diseases. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in the acantholytic skin diseases. Furthermore, upstream regulator analysis suggested that a decrease in SRF/MRTF activity was responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared with normal skin. These findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grover diseases, and identify decreases in actin organization pathways as a unique signature present in these conditions.
Topics: Humans; Actins; Skin; Acantholysis; Skin Diseases
PubMed: 37471166
DOI: 10.1172/jci.insight.168955