Figure - available from: Frontiers in Immunology
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Pemphigus autoantibodies interfere with desmosome turnover. Left panel: a simplified view of the assembly pathway of desmosomes. Desmosomal cadherins and the plaque components desmoplakin (DP), plakophilins (Pkps), as well as the keratins are transported to the plasma membrane by distinct routes and may involve an intermediate complex containing adherens junction proteins. Right panel: Pemphigus autoantibodies interfere with the assembly of nascent desmosomes and promote the disassembly of existing desmosomes. The modulation of desmosome turnover is tied to changes of intracellular-signaling cascades which, for instance, lead to the phosphorylation or cleavage of desmosomal components. Linear arrays represent zones of desmosome disassembly. Split desmosomes may occur if the already-weakened desmosomes are exposed to shear stress.
Source publication
Pemphigus is a severe autoimmune-blistering disease of the skin and mucous membranes caused by autoantibodies reducing desmosomal adhesion between epithelial cells. Autoantibodies against the desmosomal cadherins desmogleins (Dsgs) 1 and 3 as well as desmocollin 3 were shown to be pathogenic, whereas the role of other antibodies is unclear. Dsg3 in...
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Citations
... Other target molecules of epidermal adhesion are now identified in the pathogenesis of pemphigus, as well as mitochondrial proteins, cholinergic receptors, and other molecules, which act synergistically with anti-Dsg1 and Dsg3 antibodies in epidermal acantholysis. 9--- 18 As both PV and PF are prevalent in southeastern Brazil, there is an opportunity for outpatient follow-up of a large series of patients. 4,5 In the PF series, over a 25-year period, it was observed that 6,64 % of the patients, in addition to being positive for anti-Dsg1, also had reactive titers to Dsg3 in the ELISA test, without, however, showing a phenotype of mucosal lesions. ...
... Without this resistance, the epidermis becomes easily broken or even detached. In a mild case, such loss of resistance may result in local skin sensitization and inflammation; however, patients with a severe case, such as Butterfly Girl, may suffer from epidermolysis [41][42][43][44][45]. In a previous study, ZNPs were shown to widen the gap between epidermal keratinocytes, increasing the probability of skin sensitization and inflammation [10]. ...
Zinc oxide nanoparticles (ZNPs) are widely used in sunscreens and nanomedicines, and it was recently confirmed that ZNPs can penetrate stratum corneum into deep epidermis. Therefore, it is necessary to determine the impact of ZNPs on epidermis. In this study, ZNPs were applied to mouse skin at a relatively low concentration for one week. As a result, desmosomes in epidermal tissues were depolymerized, epidermal mechanical strain resistance was reduced, and the levels of desmosomal cadherins were decreased in cell membrane lysates and increased in cytoplasmic lysates. This finding suggested that ZNPs promote desmosomal cadherin endocytosis, which causes desmosome depolymerization. In further studies, ZNPs were proved to decrease mammalian target of rapamycin complex 1 (mTORC1) activity, activate transcription factor EB (TFEB), upregulate biogenesis of lysosome-related organelle complex 1 subunit 3 (BLOC1S3) and consequently promote desmosomal cadherin endocytosis. In addition, the key role of mTORC1 in ZNP-induced decrease in mechanical strain resistance was determined both in vitro and in vivo. It can be concluded that ZNPs reduce epidermal mechanical strain resistance by promoting desmosomal cadherin endocytosis via the mTORC1-TFEB-BLOC1S3 axis. This study helps elucidate the biological effects of ZNPs and suggests that ZNPs increase the risk of epidermal fragmentation.
Graphical abstract
... Most patients with PV have mucosal involvement first, which then develops into skin involvement [42,43]. Research discovered that in the mucosal-dominant phase of pemphigus vulgaris, autoantibodies (PV-IgG) primarily against Dsg3 are pathogenic, which is the most abundant desmoglein isoform in the mucosal epithelium [44]. During the mucocutaneous phase, the presence of both anti-Dsg3 and anti-Dsg1 antibodies can be found, and Dsg1 is strongly expressed in the superficial epidermis, usually correlating with skin blistering [44]. ...
... Research discovered that in the mucosal-dominant phase of pemphigus vulgaris, autoantibodies (PV-IgG) primarily against Dsg3 are pathogenic, which is the most abundant desmoglein isoform in the mucosal epithelium [44]. During the mucocutaneous phase, the presence of both anti-Dsg3 and anti-Dsg1 antibodies can be found, and Dsg1 is strongly expressed in the superficial epidermis, usually correlating with skin blistering [44]. The combination of systemic corticosteroids and corticosteroid-sparing adjuvant drugs is considered the main therapy for PV [45,46]. ...
... Patients with PF usually show skin erosions, ulcers and scabs [50]. In PF, autoantibodies (PF-IgG) primarily against Dsg1 cause superficial epidermal blistering [44]. These fragile, superficial blisters and bullae of the cutaneous surface easily rupture to yield erosive lesions [51]. ...
Pemphigus is a chronic recurrent disease in dermatology. Although it is not very common, its treatment has been an increasing concern in recent years because it is difficult and long-lasting. At present, there are many papers on pemphigus treatment, and to better understand the research trends and research frontiers of pemphigus treatment, it is necessary to conduct a comprehensive systematic review and analysis. We combined bibliometric and visualization methods to analyze 1365 papers published in the Web of Science database from 1992 to 2022, including basic information about countries, institutions and authors, to gain a general understanding of the treatment of pemphigus. Among them, the United States is the country with the most output, Iran's Tehran University of Medical Sciences is the institution with the most published works, and Ahmed, A. Razzaque of Tufts University is the most influential scholar. In addition, we also learned about the research hotspots and frontiers of pemphigus treatment through a series of analyses on the frequency, clustering, keywords bursts and cited literature, and we briefly reviewed the highly cited literature. We found that the current research focuses in the study of pemphigus treatment are the types, pathogenesis, and treatment of pemphigus, including glucocorticoids, immunosuppressants and many other major treatment methods. Hailey-Hailey disease, genetic susceptibility, and traditional Chinese medicine are potential research hotspots. Rituximab is a research frontier. In conclusion, we hope to provide new research ideas for promoting the development of pemphigus treatment.
... A well-coordinated balance of cell-cell adhesion via desmosomes, adherens junctions, and tight junctions, as well as differentiation of keratinocytes into the cornified layer, is important to maintain barrier functions of the epidermis (Candi et al., 2005). Alterations in several desmosomal components lead to barrier and differentiation defects of the epidermis, highlighting the importance of desmosomal cadherins for maintaining tissue integrity and mediating a proper differentiation process (Jonkman et al., 2005;Chidgey et al., 2001;Sumigray and Lechler, 2015;Koch et al., 1997;Spindler and Waschke, 2018). However, the precise underlying mechanisms are only partially understood. ...
Glycosylation is essential to facilitate cell–cell adhesion and differentiation. We determined the role of the dolichol phosphate mannosyltransferase (DPM) complex, a central regulator for glycosylation, for desmosomal adhesive function and epidermal differentiation. Deletion of the key molecule of the DPM complex, DPM1, in human keratinocytes resulted in weakened cell–cell adhesion, impaired localization of the desmosomal components desmoplakin and desmoglein-2, and led to cytoskeletal organization defects in human keratinocytes. In a 3D organotypic human epidermis model, loss of DPM1 caused impaired differentiation with abnormally increased cornification, reduced thickness of non-corneal layers, and formation of intercellular gaps in the epidermis. Using proteomic approaches, SERPINB5 was identified as a DPM1-dependent interaction partner of desmoplakin. Mechanistically, SERPINB5 reduced desmoplakin phosphorylation at serine 176, which was required for strong intercellular adhesion. These results uncover a novel role of the DPM complex in connecting desmosomal adhesion with epidermal differentiation.
... Previously, it was described that DSG2 protein interaction is crucial for cardiomyocyte cohesion and that DSG2 [19,26,27]. Furthermore, autoantibodies against DSG1 and DSG3 found in pemphigus cause loss of keratinocyte adhesion, indicating that loss of intercellular adhesion caused by autoantibodies from patients with desmosomal diseases is a hallmark of pathogenicity [17,37,44,45]. To further assess the functional relevance of catalytic antibodies, we utilized cell-free AFM force spectroscopy to measure homophilic DSG2 and N-CAD interactions. ...
Sudden cardiac death (SCD) is defined as an unexpected, nontraumatic death with a possible cardiac or unknown cause. The lowest incidence is observed in infancy and childhood (1 per 100,000), and the incidence is approximately 50 per 100,000 in the middle-aged population, reaching a plateau around the age of 80 (200 per 100,000). While most SCD cases occur in older people with coronary artery disease, there is a predominance of monogenetic and polygenetic diseases in the young.
Postmortem genetic analysis (molecular autopsy) using next-generation sequencing reveals a definite pathogenic genetic alteration, which can explain SCD of young patients in near 20% of the cases. Hence, postmortem genetic analysis has become an important tool to unravel the inheritable cause of death. Furthermore, early identification of a pathogenic genetic sequence variant in the deceased is crucial to reduce risk in relatives due to preventive personalized measures.
Postmortem genetic analysis forms together with the clinical assessment the basis for early identification of at-risk relatives. A new guideline for the management of ventricular arrhythmias and prevention of sudden death was recently published by the European Society of Cardiology. The new recommendations give genetic testing, also in deceased patients a much higher priority reflecting increasing relevance of genetic testing for diagnostic evaluation, risk stratification and prevention.
... IgG antibodies against epidermal desmosomes, including desmoglein (Dsg) 1 and Dsg3, two major cell-cell adhesive structure proteins, cause loss of intercellular adhesion, acantholysis, and blister formation [2,3]. Furthermore, both anti-Dsg1 and -Dsg3 antibodies are involved in the activation of signaling pathways including Ca 2+ , p38 mitogen activated protein kinases (p38MAPK), protein kinase C (PKC), Src, EGFR/Erk, and several others, resulting in modulation of keratinocyte cell adhesion properties [4]. ...
Background
Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has been reported to have an adjuvant treatment effect against PV. However, the mechanism underlying the inhibitory effect of FK506 on PV-IgG-induced acantholysis is unclear.
Objective
The objective of this study was to explore the effect of FK506 on desmoglein (Dsg) expression and cell adhesion in an immortalized human keratinocyte cell line (HaCaT cells) stimulated with PV sera.
Methods
A cell culture model of PV was established by stimulating HaCaT cells with 5% PV sera with or without FK506 and clobetasol propionate (CP) treatment. The effects of PV sera on intercellular junctions and protein levels of p38 mitogen-activated protein kinase (p38MAPK), heat shock protein 27 (HSP27), and Dsg were assayed using western blot analysis, immunofluorescence staining, and a keratinocyte dissociation assay.
Results
PV sera-induced downregulation of Dsg3 was observed in HaCaT cells and was blocked by FK506 and/or CP. Immunofluorescence staining revealed that linear deposits of Dsg3 on the surface of HaCaT cells in the PV sera group disappeared and were replaced by granular and agglomerated fluorescent particles on the cell surface; however, this effect was reversed by FK506 and/or CP treatment. Furthermore, cell dissociation assays showed that FK506 alone or in combination with CP increased cell adhesion in HaCaT cells and ameliorated loss of cell adhesion induced by PV sera. Additionally, FK506 noticeably decreased the PV serum-induced phosphorylation of HSP 27, but had no effect on p38MAPK phosphorylation.
Conclusion
FK506 reverses PV-IgG induced-Dsg depletion and desmosomal dissociation in HaCaT cells, and this effect may be obtained by inhibiting HSP27 phosphorylation.
... Previously, it was described that DSG2 protein interaction is crucial for cardiomyocyte cohesion and that DSG2 [19,26,27]. Furthermore, autoantibodies against DSG1 and DSG3 found in pemphigus cause loss of keratinocyte adhesion, indicating that loss of intercellular adhesion caused by autoantibodies from patients with desmosomal diseases is a hallmark of pathogenicity [17,37,44,45]. To further assess the functional relevance of catalytic antibodies, we utilized cell-free AFM force spectroscopy to measure homophilic DSG2 and N-CAD interactions. ...
Aims
Arrhythmogenic cardiomyopathy (AC) is a severe heart disease predisposing to ventricular arrhythmias and sudden cardiac death caused by mutations affecting intercalated disc (ICD) proteins and aggravated by physical exercise. Recently, autoantibodies targeting ICD proteins, including the desmosomal cadherin desmoglein 2 (DSG2), were reported in AC patients and were considered relevant for disease development and progression, particularly in patients without underlying pathogenic mutations. However, it is unclear at present whether these autoantibodies are pathogenic and by which mechanisms show specificity for DSG2 and thus can be used as a diagnostic tool.
Methods and Results
IgG fractions were purified from 15 AC patients and 4 healthy controls. Immunostainings dissociation assays, atomic force microscopy (AFM), Western blot analysis and Triton X-100 assays were performed utilizing human heart left ventricle tissue, HL-1 cells and murine cardiac slices. Immunostainings revealed that autoantibodies against ICD proteins are prevalent in AC and most autoantibody fractions have catalytic properties and cleave the ICD adhesion molecules DSG2 and N-cadherin, thereby reducing cadherin interactions as revealed by AFM. Furthermore, most of the AC-IgG fractions causing loss of cardiomyocyte cohesion activated p38MAPK, which is known to contribute to a loss of desmosomal adhesion in different cell types, including cardiomyocytes. In addition, p38MAPK inhibition rescued the loss of cardiomyocyte cohesion induced by AC-IgGs.
Conclusion
Our study demonstrates that catalytic autoantibodies play a pathogenic role by cleaving ICD cadherins and thereby reducing cardiomyocyte cohesion by a mechanism involving p38MAPK activation. Finally, we conclude that DSG2 cleavage by autoantibodies could be used as a diagnostic tool for AC.
... To the Editor, Rituximab (RTX), a chimeric monoclonal antibody targeting CD20 on B lymphocytes, is an effective diseasemodifying agent in the treatment of pemphigus vulgaris (PV), a rare autoimmune blistering disease (AIBD) (Witte et al. 2018;Yuan et al. 2022). PV is caused by serum IgG autoantibodies targeting adhesion molecules of the cadherin family, particularly desmoglein (Dsg)3 and Dsg1, two major components of desmosomes (Spindler and Waschke 2018). PV usually arise with oral erosions first and then spreading to the skin with a chronic-relapsing course (Feliciani et al. 2018). ...
... antigens cause flaccid blistering in the epidermis and in mucous membranes of the oral cavity and elsewhere [5][6][7] . Mechanisms leading to loss of keratinocyte cohesion comprise direct inhibition of Dsg3 interaction and dysregulation of a plethora of intracellular signaling pathways upon autoantibody binding [8][9][10][11] . Dsg1 and Dsg3 act as signal transducers and regulate autoantibody-specific signaling pathways 12,13 . ...
Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used in psoriasis, prevents skin blistering in pemphigus vulgaris. Apremilast abrogates pemphigus autoantibody-induced loss of keratinocyte cohesion in ex-vivo human epidermis, cultured keratinocytes in vitro and in vivo in mice. In parallel, apremilast inhibits keratin retraction as well as desmosome splitting, induces phosphorylation of plakoglobin at serine 665 and desmoplakin assembly into desmosomal plaques. We established a plakoglobin phospho-deficient mouse model that reveals fragile epidermis with altered organization of keratin filaments and desmosomal cadherins. In keratinocytes derived from these mice, intercellular adhesion is impaired and not rescued by apremilast. These data identify an unreported mechanism of desmosome regulation and propose that apremilast stabilizes keratinocyte adhesion and is protective in pemphigus. Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes.
... A well-coordinated balance of cell-cell adhesion via desmosomes, adherence junctions and tight junctions, as well as differentiation into the cornified layer is important to maintain barrier functions [10]. Alterations in several desmosomal components have led to barrier and differentiation defects, highlighting the importance of these desmosomal cadherins for maintaining tissue integrity and to mediate a proper differentiation process [11][12][13][14][15]. However, the precise underlying mechanisms are only partially understood. ...
Glycosylation is an essential mediator of cell-cell adhesion and epidermal differentiation. We used CRISPR/Cas9-based gene editing to determine the role of dolichol phosphate mannosyltransferase 1 (DPM1), a key enzyme for N- and O-glycosylation. DPM1 loss resulted in weakening of cell-cell adhesion, impaired localization of the desmosome components desmoplakin and desmoglein 2, and cytoskeletal organization defects in human keratinocytes. In a 3D organotypic human epidermis model, loss of DPM1 resulted in impaired differentiation with abnormally increased cornification, reduced thickness of non-corneal layers, and the formation of intercellular gaps in the epidermis. Using proteomic approaches, SERPINB5 was identified as novel interaction partner of desmoplakin, ameliorating the effects of DPM1 loss on cell-cell adhesion and epidermal differentiation. Further analysis showed that the changes induced by DPM1 and SERPINB5 loss were at least in part dependent on elevated TGF-β signalling. Together, we identify DPM1 through SERPINB5 as a novel regulator of cell-cell adhesion and differentiation.
