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Dermatology Research and Practice 2024Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially life-threatening mucocutaneous blistering diseases that clinically can...
BACKGROUND
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially life-threatening mucocutaneous blistering diseases that clinically can resemble autoimmune bullous diseases. Moreover, it has been shown that autoantibodies against epidermal proteins are present in SJS/TEN.
OBJECTIVES
To establish the presence of antibodies against desmosomal and hemidesmosomal proteins in confirmed SJS/TEN patients.
METHODS
Serum of SJS/TEN patients diagnosed based on clinical criteria, e.g., epidermal detachment with erosions and severe mucosal lesions, (suspicion of) a culprit drug, and matching histologic results was evaluated by various techniques, e.g., indirect immunofluorescence on monkey esophagus, salt split skin and rat bladder, immunoblotting (IB) and immunoprecipitation (IP), ELISAs against desmogleins and BP180, keratinocyte footprint assay, and keratinocyte binding assay.
RESULTS
A total of 28 patients were included in this study, 15 men and 13 women with a mean age of 56 years. In most patients, none of the serological tests were positive. In two patients, an elevated DSG3 titer was found suspicious for pemphigus vulgaris. Three patients had elevated NC16a titers, suggesting bullous pemphigoid. However, in all these patients, no other tests were positive and in these patients, the biopsy for direct immunofluorescence showed no evidence for an autoimmune bullous disease. Three patients showed reactivity against rat bladder rat bladder; these were, however, completely negative for A2ML1, envoplakin, and periplakin in the IB as well as the IP.
CONCLUSIONS
Serological analysis for desmosomal and hemidesmosomal antibodies is reliable to rule an autoimmune bullous disease in patients with suspected SJS/TEN. However, one should not rely on one single test method since false positive results can occur. Moreover, this study also makes it less plausible that antibodies against desmosomal and/or hemidesmosomal components are involved in the pathogenesis of SJS/TEN.
PubMed: 38803350
DOI: 10.1155/2024/5504462 -
Biomedicines Apr 2024Desmoglein-2 mutations are detected in 5-10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of...
Desmoglein-2 mutations are detected in 5-10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant () or haploinsufficient () mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old and mice and in young mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged and mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in mice but not in wild types. hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult mice. Prolonged ventricular activation times in the hearts of trained mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients.
PubMed: 38790949
DOI: 10.3390/biomedicines12050985 -
The Journal of Clinical Investigation May 2024Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment for myocarditis is often supportive. Mutations in DSP, a gene...
BACKGROUND
Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment for myocarditis is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis with biomarkers and pathological features indistinguishable from other forms of myocarditis. DSP-associated myocarditis can progress to dilated cardiomyopathy with heightened arrhythmia risk.
METHODS
To model the cardiomyocyte aspects of DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients and gene-edited healthy control hiPSC lines. Homozygous and heterozygous DSP disrupted EHTs were generated to contain 90% hiPSC-CMs and 10% healthy control human cardiac fibroblasts. We measured innate immune activation and function at baseline and in response to Toll-like receptor (TLR) stimulation in EHTs.
RESULTS
At baseline, DSP-/- EHTs displayed a transcriptomic signature of immune activation which was mirrored by EHT cytokine release. Importantly, DSP-/- EHTs were hypersensitive to TLR stimulation demonstrating greater contractile function impairment compared to isogenic controls. Compared to homozygous DSP-/- EHTs, heterozygous DSP patient-derived EHTs had less functionally impairment but also displayed heightened sensitivity to TLR stimulation. When subjected to strain, heterozygous DSP EHTs developed greater functional deficit indicating reduced contractile reserve compared to healthy control. Colchicine or NFΚB inhibitors improved baseline force production and strain-induced force deficits in DSP EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs.
CONCLUSIONS
Genetic reduction of DSP renders cardiomyocytes susceptible to innate immune activation and strain-dependent contractile deficits. EHTs replicate electrical and contractile phenotypes seen in human myocarditis implicating cytokine release as a key part of the myogenic susceptibility to inflammation. This heightened innate immune activation and sensitivity is a target for clinical intervention.
PubMed: 38768074
DOI: 10.1172/JCI180254 -
BioRxiv : the Preprint Server For... May 2024Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in...
Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion.
PubMed: 38766211
DOI: 10.1101/2024.05.03.592394 -
BioRxiv : the Preprint Server For... Apr 2024Cholesterol- and sphingolipid-enriched domains called lipid rafts are hypothesized to selectively coordinate protein complex assembly within the plasma membrane to...
Cholesterol- and sphingolipid-enriched domains called lipid rafts are hypothesized to selectively coordinate protein complex assembly within the plasma membrane to regulate cellular functions. Desmosomes are mechanically resilient adhesive junctions that associate with lipid raft membrane domains, yet the mechanisms directing raft association of the desmosomal proteins, particularly the transmembrane desmosomal cadherins, are poorly understood. We identified the desmoglein-1 (DSG1) transmembrane domain (TMD) as a key determinant of desmoglein lipid raft association and designed a panel of DSG1 variants to assess the contribution of TMD physicochemical properties (length, bulkiness, and palmitoylation) to DSG1 lipid raft association. Sucrose gradient fractionations revealed that TMD length and bulkiness, but not palmitoylation, govern DSG1 lipid raft association. Further, DSG1 raft association determines plakoglobin recruitment to raft domains. Super-resolution imaging and functional assays uncovered a strong relationship between the efficiency of DSG1 lipid raft association and the formation of morphologically and functionally robust desmosomes. Lipid raft association regulated both desmosome assembly dynamics and DSG1 cell surface stability, indicating that DSG1 lipid raft association is required for both desmosome formation and maintenance. These studies identify the biophysical properties of desmoglein transmembrane domains as key determinants of lipid raft association and desmosome adhesive function.
PubMed: 38712246
DOI: 10.1101/2024.04.24.590936 -
Medicine May 2024Despite an increase in global research on the subject of Pemphigus, which seriously affects patient health and quality of life, there is no bibliometric research on this...
Despite an increase in global research on the subject of Pemphigus, which seriously affects patient health and quality of life, there is no bibliometric research on this subject in literature to date. The aim of this study was to conduct a holistic analysis of scientific articles published on Pemphigus, using bibliometric methods. Articles published on the subject of Pemphigus between 1980 and 2021 were downloaded from the web of science (WoS) database and analyzed using various statistical methods. To determine trend subjects, collaboration between countries, and the most effective studies with citation analyses, visual network maps were obtained with bibliometric analyses. A total of 3034 articles were analyzed. The 3 countries making the greatest contribution to literature were the USA (n:831, 27.3%), Japan (n:402, 13.2%), and Germany (n:221, 7.2%). The 3 most active institutions were Keio University (n:163, 5.3%), Kurume University (n:130, 4.2%) and Tel Aviv University (n:107, 3.5%). The 3 journals publishing the most articles were the British Journal of Dermatology (n: 88), Journal of the American Academy of Dermatology (n:171) and the Journal of Investigative Dermatology (n:143). The 3 leading journals according to the mean number of citations (NC) per article (citation count: CC) were the New England Journal of Medicine (CC:246), the Lancet (CC:143) and the Journal of Cell Biology (CC:133). The author with the most articles published was Hashimoto Takashi (n.168, 5.5%). As a result of cluster analysis, it was seen that 9 different main clusters had been studied on Pemphigus subjects to date (1: desmoglein, 2: paraneoplastic Pemphigus (PNP) - Pemphigus types-desmosome, 3: desmoglein 1 ve 3-autoimmunity, 4: treatment-rituximab, 5: acantholysis-apoptosis, 6: quality of life-remission-relapse, 7: autoantibodies, 8: epidemiology-mortality, 9: corticosteroids). The most commonly studied subjects were determined to be pemphigus vulgaris (PV), pemphigus foliaceus (PF), autoimmunity, rituximab, PNP, desmoglein (desmoglein3-desmoglein1), autoantibodies, acantholysis, autoantibody, treatment, autoimmune disease, desmosome, ELISA, and immunofluorescence. The primary trending topic was rituximab drug, which is used in the treatment of Pemphigus. The other most studied trend topics were azathioprine drug used in treatment, intravenous immunoglobulin treatment, quality of life, mortality rates, Pemphigus herpetiformis, and wound healing.
Topics: Bibliometrics; Pemphigus; Humans; Periodicals as Topic; Biomedical Research; Efficiency
PubMed: 38701303
DOI: 10.1097/MD.0000000000038047 -
The Journal of Investigative Dermatology Apr 2024During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact Ca-independently. Previous data indicate that...
During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact Ca-independently. Previous data indicate that hyper-adhesion protects keratinocytes from pemphigus vulgaris autoantibody (PV-IgG)-induced loss of intercellular adhesion although the underlying mechanism remains to be elucidated. Thus, we here investigated the effect of hyper-adhesion on PV-IgG-induced direct inhibition of desmoglein (Dsg) 3 interactions by atomic force microscopy. Hyper-adhesion abolished loss of intercellular adhesion and corresponding morphological changes of all pathogenic antibodies used. Pemphigus autoantibodies putatively targeting several parts of the Dsg3 extracellular domain (ECD) and 2G4, targeting a membrane-proximal domain of Dsg3, induced direct inhibition of Dsg3 interactions only in non-hyper-adhesive keratinocytes. In contrast, AK23, targeting the N-terminal ECD1 of Dsg3, caused direct inhibition under both adhesive states. However, antibody binding to desmosomal cadherins was not different between the distinct pathogenic antibodies used and was not changed during acquisition of hyper-adhesion. Additionally, heterophilic Dsc3-Dsg3 and Dsg2-Dsg3 interactions did not cause reduced susceptibility to direct inhibition under hyper-adhesive condition in wt keratinocytes. Taken together, the data suggest that hyper-adhesion reduces susceptibility to autoantibody-induced direct inhibition in dependency on autoantibody-targeted ECD but also demonstrate that further mechanisms are required for the protective effect of desmosomal hyper-adhesion in PV.
PubMed: 38677661
DOI: 10.1016/j.jid.2024.03.042 -
BMC Cancer Apr 2024Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in...
BACKGROUND
Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in cancer in a context-dependent manner. Their specific roles on breast cancer (BC) and the potential mechanisms remain unclear.
METHODS
The expressions of Dsg2 and Dsc2 in human BC tissues and cell lines were assessed by using bioinformatics analysis, immunohistochemistry and western blotting assays. Wound-healing and Transwell assays were performed to evaluate the cells' migration and invasion abilities. Plate colony-forming and MTT assays were used to examine the cells' capacity of proliferation. Mechanically, Dsg2 and Dsc2 knockdown-induced malignant behaviors were elucidated using western blotting assay as well as three inhibitors including MK2206 for AKT, PD98059 for ERK, and XAV-939 for β-catenin.
RESULTS
We found reduced expressions of Dsg2 and Dsc2 in human BC tissues and cell lines compared to normal counterparts. Furthermore, shRNA-mediated downregulation of Dsg2 and Dsc2 could significantly enhance cell proliferation, migration and invasion in triple-negative MDA-MB-231 and luminal MCF-7 BC cells. Mechanistically, EGFR activity was decreased but downstream AKT and ERK pathways were both activated maybe through other activated protein tyrosine kinases in shDsg2 and shDsc2 MDA-MB-231 cells since protein tyrosine kinases are key drivers of triple-negative BC survival. Additionally, AKT inhibitor treatment displayed much stronger capacity to abolish shDsg2 and shDsc2 induced progression compared to ERK inhibition, which was due to feedback activation of AKT pathway induced by ERK inhibition. In contrast, all of EGFR, AKT and ERK activities were attenuated, whereas β-catenin was accumulated in shDsg2 and shDsc2 MCF-7 cells. These results indicate that EGFR-targeted therapy is not a good choice for BC patients with low Dsg2 or Dsc2 expression. Comparatively, AKT inhibitors may be more helpful to triple-negative BC patients with low Dsg2 or Dsc2 expression, while therapies targeting β-catenin can be considered for luminal BC patients with low Dsg2 or Dsc2 expression.
CONCLUSION
Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.
Topics: Humans; Desmocollins; Desmoglein 2; Female; Cell Proliferation; Cell Movement; Triple Negative Breast Neoplasms; Cell Line, Tumor; Breast Neoplasms; Neoplasm Invasiveness; Gene Expression Regulation, Neoplastic; beta Catenin; Signal Transduction
PubMed: 38671389
DOI: 10.1186/s12885-024-12229-2 -
Frontiers in Cell and Developmental... 2024
PubMed: 38665429
DOI: 10.3389/fcell.2024.1408075 -
The Journal of Investigative Dermatology Apr 2024Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity....
Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity. Especially for the acute phase, additional treatment options allowing to reduce corticosteroids would fulfill an unmet medical need. Here, we provide evidence that epidermal growth factor receptor (EGFR) inhibition by erlotinib ameliorates pemphigus vulgaris immunoglobulin G (PV-IgG) -induced acantholysis in intact human epidermis. PV-IgG caused phosphorylation of EGFR (Y845) and SRC in human epidermis. In line with that, a phosphotyrosine kinome analysis revealed a robust response associated with EGFR and SRC family kinase signaling in response to PV-IgG but not pemphigus foliaceus autoantibodies. Erlotinib inhibited PV-IgG-induced epidermal blistering and EGFR phosphorylation, loss of desmosomes as well as ultrastructural alterations of desmosome size, plaque symmetry, keratin filament insertion and restored the desmosome midline considered as hallmark of mature desmosomes. Erlotinib enhanced both single molecule DSG3 binding frequency and strength and delayed DSG3 fluorescence recovery supporting that EGFR inhibition increases DSG3 availability and cytoskeletal anchorage. Our data indicate that EGFR is a promising target for pemphigus therapy due to its link to several signaling pathways known to be involved in pemphigus pathogenesis.
PubMed: 38642796
DOI: 10.1016/j.jid.2024.03.040