-
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 -
Dermatology Practical & Conceptual Feb 2022Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by... (Review)
Review
Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by serum IgG autoantibodies against desmoglein 1 and 3, two major components of desmosomes. The introduction of glucocorticoids improved dramatically the prognosis of patients affected by PV. However, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been recently approved as in-label therapy for PV, leading to an improvement of the prognosis and higher remission rate. Furthermore, other anti B-cell therapies and several anti-CD20 biosimilars have been introduced in the clinical practice. We focused on present and future therapeutic approaches in PV.
PubMed: 35223181
DOI: 10.5826/dpc.1201a37 -
Frontiers in Molecular Biosciences 2021Pemphigus represents a group of rare and severe autoimmune intra-epidermal blistering diseases affecting the skin and mucous membranes. These painful and debilitating... (Review)
Review
Pemphigus represents a group of rare and severe autoimmune intra-epidermal blistering diseases affecting the skin and mucous membranes. These painful and debilitating diseases are driven by the production of autoantibodies that are mainly directed against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). The search to define underlying triggers for anti-Dsg-antibody production has revealed genetic, environmental, and possible vaccine-driven factors, but our knowledge of the processes underlying disease initiation and pathology remains incomplete. Recent studies point to an important role of T cells in supporting auto-antibody production; yet the involvement of the myeloid compartment remains unexplored. Clinical management of pemphigus is beginning to move away from broad-spectrum immunosuppression and towards B-cell-targeted therapies, which reduce many patients' symptoms but can have significant side effects. Here, we review the latest developments in our understanding of the predisposing factors/conditions of pemphigus, the underlying pathogenic mechanisms, and new and emerging therapies to treat these devastating diseases.
PubMed: 35187073
DOI: 10.3389/fmolb.2021.808536 -
Acta Biochimica Polonica Feb 2020Numerous epidemiological studies have suggested a link between vitamin D deficiency and the development of various autoimmune diseases, including diabetes mellitus type... (Review)
Review
Numerous epidemiological studies have suggested a link between vitamin D deficiency and the development of various autoimmune diseases, including diabetes mellitus type 1, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis or systemic lupus erythematosus. More recently, such a link has been also proposed for autoimmune bullous diseases (AIBD). This is a relatively rare and potentially life-threatening, organ-specific group of inflammatory skin diseases characterized by the presence of tissue-bound and circulating autoantibodies against various molecules present in desmosomes (in pemphigus diseases) or hemidesmosomes (in pemphigoid diseases). In addition to the well-known role of vitamin D in calcium and phosphate homeostasis, the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol), exerts potent effects on cellular differentiation and regulation of immune responses via binding to the vitamin D receptor present in most cells of the immune system. Since cells of both, the innate and adaptive immune systems, are known to be relevant in AIBD, the role of vitamin D analogues in the treatment of patients with these disorders deserves much attention. This mini-review summarizes recent epidemiological and experimental studies on vitamin D involvement in the autoimmune bullous diseases.
Topics: Autoimmune Diseases; Humans; Skin Diseases, Vesiculobullous; Vitamin D
PubMed: 32049468
DOI: 10.18388/abp.2020_2905 -
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 -
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