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Canine trunk-dominant pemphigus foliaceus (PF) is mentioned rarely in the literature.The goal of this study was to provide clinical description of trunk-dominant PF and to demonstrate the prevalence of serum antikeratinocyte, anti-desmocollin-1 (DSC1) and anti-desmoglein-1 (DSG1) antibodies, and determine their diagnostic value in this particular PF phenotype.Clinically relevant information was collected from 31, 25 and 34 dogs with trunk-dominant and facial PF and superficial pyoderma (SP), respectively. Sera from these dogs were tested for antikeratinocyte, anti-DSC1 and anti-DSG1 antibodies using indirect immunofluorescence on canine tissues and DSC1- and DSG1-transfected cells. Sera from healthy dogs and dogs with clinically irrelevant diseases served as controls.Footpad involvement and grouped/polycyclic lesion organisation were identified as features of both PF phenotypes, and not of SP. Antikeratinocyte immunoglobulin (Ig)G was not specific for canine PF. By contrast, antigen-specific IgG was detected only in PF sera; anti-DSC1 IgG in 100% and 58% of dogs with facial and trunk-dominant PF, respectively, and anti-DSG1 IgG in 7% of dogs with trunk-dominant PF only.Trunk-dominant PF shares DSC1 as a major autoantigen with facial PF. The ability to detect anti-DSC1 IgG is lower in trunk-dominant PF, yet despite the lower sensitivity, the positive predictive value and accuracy of this particular anti-DSC1 IgG test are high. A negative test result, however, cannot exclude the diagnosis, and characteristic clinical features such as footpad involvement and/or grouped/polycyclic lesions must be considered when distinguishing trunk-dominant PF from its most relevant differential diagnosis: SP.Contexte - Le pemphigus foliacé (PF) dominant le tronc chez le chien est rarement mentionné dans la littérature. Hypothèse/Objectifs - Le but de cette étude était de fournir une description clinique du PF dominant le tronc et de démontrer la prévalence des anticorps sériques anti-kératinocytes, anti-desmocolline-1 (DSC1) et anti-desmogléine-1 (DSG1), et de déterminer leur valeur diagnostique dans ce phénotype particulier de PF. Matériels et méthodes - Des informations cliniquement pertinentes ont été recueillies auprès de 31, 25 et 34 chiens atteints respectivement de PF à dominante tronculaire et faciale et de pyodermite superficielle (SP). Les sera de ces chiens ont été testés pour les anticorps anti-kératinocytes, anti-DSC1 et anti-DSG1 en utilisant l'immunofluorescence indirecte sur des tissus canins et des cellules transfectées avec DSC1 et DSG1. Des sera de chiens sains et de chiens atteints de maladies cliniquement non pertinentes ont servi de témoins. Résultats - L'implication du coussinet plantaire et l'organisation des lésions groupées / polycycliques ont été identifiées comme des caractéristiques des deux phénotypes PF, et non de SP. L'immunoglobuline antikératinocytaire (Ig)G n'était pas spécifique du PF canin. En revanche, l'IgG spécifique de l'antigène n'a été détectée que dans les sera de PF ; IgG anti-DSC1 chez 100 % et 58 % des chiens atteints de PF faciale et tronc-dominante, respectivement, et anti-DSG1 IgG chez 7 % des chiens avec PF tronc-dominant uniquement. Conclusions - Le PF à dominante tronculaire partage DSC1 comme auto-antigène majeur avec le PF facial. La capacité à détecter les IgG anti-DSC1 est plus faible chez les PF à dominante tronculaire, mais malgré la sensibilité plus faible, la valeur prédictive positive et la précision de ce test IgG anti-DSC1 particulier sont élevées. Cependant, un résultat de test négatif ne peut pas exclure le diagnostic, et les caractéristiques cliniques caractéristiques telles que l'atteinte du coussinet plantaire et/ou les lésions groupées/polycycliques doivent être prises en compte lors de la distinction entre la PF à dominante tronculaire et son diagnostic différentiel le plus pertinent : la SP.Introducción- el pénfigo foliáceo (PF) de distribución truncal predominante se describe raramente n la literatura. Hipótesis/Objetivos- el objetivo de este estudio fue proporcionar una descripción clínica del PF truncal y demostrar la prevalencia de anticuerpos séricos antiqueratinocitos, antidesmocolina-1 (DSC1) y antidesmogleína-1 (DSG1), y determinar su valor diagnóstico en este fenotipo PF particular. Materiales y métodos- se recopiló información clínicamente relevante de 31, 25 y 34 perros con PF dominante truncal, PF dominante facial y pioderma superficial (PS), respectivamente. Los sueros de estos perros se analizaron en busca de anticuerpos antiqueratinocitos, anti-DSC1 y anti-DSG1 mediante inmunofluorescencia indirecta en tejidos caninos y células transfectadas con DSC1 y DSG1. Sueros de perros sanos y perros con enfermedades clínicamente irrelevantes sirvieron como controles. Resultados- la afectación de la almohadilla plantar y la organización de lesiones agrupadas/policíclicas se identificaron como características de ambos fenotipos de PF y no de SP. La inmunoglobulina (Ig)G antiqueratinocitos no fue específica para la PF canina. Por el contrario, la IgG específica de antígeno se detectó solo en sueros PF; IgG anti-DSC1 en el 100 % y el 58 % de los perros con PF predominante en la cara y el tronco, respectivamente, y IgG anti-DSG1 en el 7 % de los perros con PF predominante en el tronco solamente. Conclusiones- el PF dominante truncal comparte DSC1 como un autoantígeno importante con el PF facial. La capacidad para detectar IgG anti-DSC1 es menor en la PF dominante truncal; sin embargo, a pesar de la menor sensibilidad, el valor predictivo positivo y la precisión de esta prueba de IgG anti-DSC1 en particular son altos. Sin embargo, un resultado negativo de la prueba no puede excluir el diagnóstico, y deben tenerse en cuenta las características clínicas, como la afectación de las almohadillas plantares y/o las lesiones agrupadas/policíclicas, al distinguir la PF dominante truncal de su diagnóstico diferencial más relevante: SP.Hintergrund - Pemphigus foliaceus (PF), der dominant am Rumpf des Hundes vorkommt wird in der Literatur selten erwähnt. Hypothese/Ziele - Das Ziel dieser Studie war es, eine klinische Beschreibung des Pemphigus foliaceus (PF), der dominant am Rumpf des Hundes vorkommt, zu liefern und die Prävalenz von Serum Antikeratinozyten, Anti-Desmocollin-1 (DSC1) und Anti-Desmoglein-1 (DSG1) Antikörper zu demonstrieren und ihren diagnostischen Wert bei diesem, speziellen PF Phänotyp festzustellen. Materialien und Methoden - Es wurden klinisch relevante Informationen von 31, 25 und 34 Hunden mit Pemphigus foliaceus (PF), der dominant am Rumpf vorkommt, sowie von Gesichts PF und oberflächlicher Pyodermie (SP) gesammelt. Sera dieser Hunde wurden mittels indirekter Immunfluoreszenz in caninem Gewebe und in DSC-1 und DSG1-transfizierten Zellen auf Antikeratinozyten, Anti-DSC1 und Anti-DSG1 Antikörper getestet. Sera von gesunden Hunden und Hunden mit klinisch irrelevanten Krankheiten dienten als Kontrollen. Ergebnisse - Eine Beteiligung der Fußballen und eine gruppierte/polyzyklische Organisation der Veränderungen wurden als Merkmale beider PF Phänotypen identifiziert, jedoch nicht für SP. Antikeratinozyten Immunglobulin (Ig) G war nicht spezifisch für caninen PF. Im Gegenteil Antigen-spezifisches IgG wurde nur in PF Sera; anti-DSC1 IgG in 100% bzw. 58% der Hunde mit Gesichts- bzw. Rumpf-dominantem PF und anti-DSG1 IgG in 7% der Hunde mit ausschließlich Rumpf-dominantem PF gefunden. Schlussfolgerungen - Der PF, welcher dominant am Rumpf des Hundes vorkommt, teilt sich DSC1 als Major Autoantigen mit dem Gesichts PF. Die Fähigkeit anti-DSC1 IgG zu finden ist beim Rumpf-dominanten PF niedriger, dennoch ist trotz der niedrigeren Sensibilität, der positive prädiktive Wert und die Genauigkeit dieses speziellen anti-DSC1 IgG Tests hoch. Ein negatives Testergebnis kann jedoch die Diagnose nicht ausschließen und die charakteristischen klinischen Merkmale wie Beteiligung der Fußballen und/oder gruppierte/polyzyklische Veränderungen müssen beachtet werden, wenn eine Rumpf-dominate PF Form von seiner wesentlichsten Differentialdiagnose, der SP, unterschieden werden soll.背景 - 犬の体幹優位型落葉状天疱瘡(PF)は、文献上ほとんど言及されていない。 仮説/目的 - 本研究の目的は、体幹優位型落葉状天疱瘡の臨床情報を提供し、血清中の抗ケラチノサイト抗体、抗デスモコリン-1(DSC1)抗体および抗デスモグレイン-1(DSG1)抗体の陽性率を明らかにし、この特殊なPF表現型における診断的価値を決定することであった。 材料と方法 - 体幹優位型、顔面優位型のPFおよび表在性膿皮症(SP)の犬31頭、25頭および34頭からそれぞれ臨床的に関連する情報を収集した。これらの犬の血清を、犬組織とDSC1-およびDSG1-トランスフェクト細胞に対する間接免疫蛍光法を用いて、抗ケラチノサイト抗体、抗DSC1抗体および抗DSG1抗体について検査した。健常犬および臨床的に無関係な病気の犬の血清を対照とした。 結果 - 足蹠の浸潤と群発性/多発性病変の編成が両PF表現型の特徴として確認され、SPの特徴とはならなかった。抗ケラチノサイト免疫グロブリン(Ig)Gは、犬のPFに特異的ではなかった。一方、抗原特異的IgGはPFの血清にのみ検出された。顔面および体幹優位のPF犬では、それぞれ100%および58%に抗DSC1 IgGが、体幹優位のPFの犬のみでは7%に抗DSG1 IgGが検出された。 結論 - 体幹優位型PFは、顔面優位型PFと同様にDSC1が主要な自己抗原である。体幹優位型PFでは抗DSC1 IgGの検出能力は低いが、感度が低いにもかかわらず、この特殊な抗DSC1 IgG検査の陽性適中率と精度は高い。しかし、検査結果が陰性でも診断を除外することはできず、体幹優位型PFをその最も関連性の高い鑑別診断であるSPから鑑別する際には、足蹠病変および/または群発/多発性病変などの特徴的な臨床症状を考慮しなければならない。.背景-文献中很少提及犬躯干显性落叶型天疱疮(PF)。 假设/目的-本研究的目的是提供躯干显性PF的临床描述，并证明血清抗角质细胞、抗桥粒芯糖蛋白-1(DSC1)和抗桥粒芯糖蛋白-1(DSG1)抗体的流行率，并确定其在该特定PF表型中的诊断价值。 材料和方法-分别从31、25和34只躯干显性和面部PF以及浅表性脓皮病(SP)犬中收集临床相关信息。使用犬组织以及DSC1和DSG1转染细胞的间接免疫荧光法，检测这些犬血清中的抗角质形成细胞、抗DSC1和抗DSG1抗体。健康犬和临床无关疾病犬的血清作为对照。 结果-爪垫受累和分组/多环病变组织被确定为PF表型的特征，而不是SP的特征。抗角质细胞免疫球蛋白(Ig)G对犬PF无特异性。相比之下，仅在PF血清中检测到抗原特异性IgG；面部和躯干显性PF犬中抗DSC1 IgG分别占100%和58%，仅躯干显性PF犬中抗DSG1 IgG占7%。 结论-躯干显性PF与面部PF共享DSC1作为主要的自身抗原。在躯干显性PF中检测抗DSC1 IgG的能力较低，然而尽管敏感性较低，但这种特殊的抗DSC1 IgG检测的阳性预测值和准确性较高。然而，阴性检测结果不能排除诊断，在区分躯干显性PF与其最相关的鉴别诊断:SP时，必须考虑爪垫受累和(或)成群/多环病变等特征性临床特征。.Contexto - O pênfigo foliáceo (PF) canino predominante no tronco é raramente relatado na literatura. Hipótese/Objetivos - O objetivo deste estudo foi apresentar a descrição clínica do PF predominante no tronco e demonstrar a prevalência de anticorpos anti-queratinócitos, anti-desmocolina-1 (DSC1) e anti-desmogleína-1 (DSG1), e determinar o seu potencial diagnóstico neste tipo particular de PF. Materiais e métodos - Informações clinicamente relevantes foram coletadas de 31, 25 e 34 cães com PF predominante no tronco, PF facial e piodermite superficial (PS), respectivamente. Os soros destes cães foram testados para anticorpos anti-queratinócitos, anti-DSC1 e anti-DSG1 utilizando imunofluorescência indireta em tecidos caninos e em células DSC1 e DSG1 transfectadas. Os soros de cães saudáveis e cães com doenças clinicamente irrelevantes serviram de controle. Resultados - O acometimento dos coxins e a organização agrupada/policíclica das lesões foram identificadas como características de ambos os fenótipos de PF, não de PS. A imunoglobulina (Ig)G anti-queratinócitos não foi específica para PF. Em contraste, IgG antígeno-específica foi detectada apenas no soro de PF; IgG anti-DSC1 em 100% e 58% dos cães com PF facial e predominante no tronco, respectivamente, e IgG anti-DSG1 em 7% dos cães somente acometidos pelo PF predominante no tronco. Conclusões - O PF predominante no tronco compartilha DSC1 como um autoantígeno principal com PF facial. A capacidade de detectar IgG anti-DSC1 é menor no PF predominante no tronco, mas apesar da sensibilidade mais baixa, o valor preditivo positivo e a precisão do teste IgG anti-DSC1 específico são altos. Um resultado de teste negativo, no entanto, não pode excluir o diagnóstico, e características clínicas típicas, como envolvimento do coxim plantar e/ou lesões agrupadas/policíclicas, devem ser consideradas ao distinguir PF predominante no tronco de seu diagnóstico diferencial mais relevante: PS.

Background Anti-desmoglein 1 and 3 autoantibodies justify acantholysis in pemphigus; however, the pathogenesis of anti-desmoglein 2 is hypothetical. Objective To compare the participation of desmogleins 1, 2 and 3 through the production of serum autoantibodies, and protein and gene expression in the skin/mucosa of patients with pemphigus foliaceus and pemphigus vulgaris. Methods The autoantibodies were titrated by ELISA in 202 samples of pemphigus foliaceus, 131 pemphigus vulgaris, 50 and 57 relatives of patients with pemphigus foliaceus and pemphigus vulgaris, respectively, and 114 controls. Protein and gene expressions were determined by immunohistochemistry and qPCR in the skin/mucosa of 3 patients with pemphigus foliaceus and 3 patients with pemphigus vulgaris. Results Higher titers of anti-desmoglein 2 (optical density) resulted in pemphigus foliaceus and pemphigus vulgaris, when compared to controls (0.166; 0.180; 0.102; respectively; p < 0.0001). There was a correlation between anti-desmoglein 2 and anti-desmoglein 1 titers in pemphigus foliaceus (r = 0.1680; p = 0.0206). There was no cross-reaction of anti-desmoglein 2 with desmoglein 1 and 3. Protein overexpression of desmoglein 2 was observed in intact and lesional skin of patients with pemphigus compared to the skin of controls. Internalization granules of desmoglein 1 and 3, but not of desmoglein 2, were observed in lesions of pemphigus foliaceus and pemphigus vulgaris, respectively. Gene overexpression of desmoglein 2 was observed in the mucosa. Study limitations Small sample size for the statistical analysis of protein and gene expression. Conclusion Autoantibodies against desmoglein 2 are not pathogenic in pemphigus; protein and gene overexpression of desmoglein 2 in the skin and mucosa may be involved in acantholysis repair.

Background The detection of serum anti-desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that anti-Dsg autoantibodies remain detectable in some patients without active pemphigus lesions. Objectives To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti-Dsg IgG autoantibodies in remission. Methods We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay. Results When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti-Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (p = 0.885) and rate of relapse (p = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (p = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti-Dsg antibodies in active phase and remission showed similar pathogenicity. Conclusions This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.

Cutaneous eruptions caused by the combination of Chinese and Western medicine have attracted widespread attention; however, the underlying mechanism remains unclear. This study aimed to evaluate the potential mechanism of cutaneous eruptions in vivo and in vitro using the combination of Shuanghuanglian injection powder (SHL) and aspirin (ASA) as an example. ASA and SHL co-administration induced inflammatory responses in HaCat cells, as evidenced by marked increases in the expression of IL-4 and TNF-α, and the level of apoptosis. Additionally, histopathological investigation of mice skin tissues showed local inflammatory cell infiltration. Western boltting was used to detect the effects of ASA on desmoglein-1 (DSG1) expression; we found that DSG1 expression was down-regulated in vivo and in vitro. Finally, the key components of SHL were administered to HaCat cells with down-regulated DSG1; it was seen that neochlorogenic acid and rutin have a significant effect on HaCat cell apoptosis. These results demonstrate that DSG1 deficiency is a potential cause of cutaneous eruptions caused by the combination of SHL and ASA, and neochlorogenic acid and rutin are the main allergenic components. This study provides a new research strategy for the safety evaluation of integrated traditional Chinese and Western medicine.

The pemphigus group of autoimmune blistering diseases encompasses pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Lesion location in pemphigus has been elegantly postulated by the Desmoglein Compensation Hypothesis (DCH), which references the distribution of desmoglein (Dsg) proteins in the epidermis along with a patient’s autoantibody profile to describe three different lesion phenotypes: PF is characterized by subcorneal lesions in the presence of anti-Dsg1 antibodies only, while lesions in PV are suprabasilar and accompanied by anti-Dsg3 antibodies only in mucosal PV, or both anti-Dsg3 and anti-Dsg1 in the case of mucocutaneous PV. While the validity of this hypothesis has been supported by several studies and is prominently featured in textbooks of dermatology, a number of logical inconsistencies have been noted and exceptions have been published in several small-scale studies. We sought to comprehensively assess the extent to which patient clinical and autoantibody profiles contradict the DCH, and characterize these contradictions in a large sample size of 266 pemphigus patients. Remarkably, we find that roughly half of active PV and PF patients surveyed present with a combination of lesion morphology and anti-Dsg3/1 levels that contradict the DCH, including: patients with a cutaneous only PV presentation, mucocutaneous disease in the absence of either Dsg3, Dsg1, or both, and mucosal disease in the absence of Dsg3 or presence of Dsg1. We also find stark differences in fidelity to the DCH based on ethnicity and HLA-association, with the lowest proportion of adherence in previously understudied populations. These findings underscore the need to expand our understanding of pemphigus morphology beyond the DCH, in particular for populations that have not been a focus in previous investigation.

IgG4 is the least potent human IgG subclass for the FcγR-mediated antibody effector function. Paradoxically, IgG4 is also the dominant IgG subclass of pathogenic autoantibodies in IgG4-mediated diseases. Here, we show that the IgG subclass and Fc-FcγR interaction have a distinct impact on the pathogenic function of autoantibodies in different IgG4-mediated diseases in mouse models. While IgG4 and its weak Fc-FcγR interaction have an ameliorative role in the pathogenicity of anti-ADAMTS13 autoantibodies isolated from thrombotic thrombocytopenic purpura (TTP) patients, they have an unexpected exacerbating effect on anti-Dsg1 autoantibody pathogenicity in pemphigus foliaceus (PF) models. Strikingly, a non-pathogenic anti-Dsg1 antibody variant optimized for FcγR-mediated effector function can attenuate the skin lesions induced by pathogenic anti-Dsg1 antibodies by promoting the clearance of dead keratinocytes. These studies suggest that IgG effector function contributes to the clearance of autoantibody-Ag complexes, which is harmful in TTP, but beneficial in PF and may provide new therapeutic opportunity.

Background Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome comprise a rare genodermatosis associated with biallelic (homozygous or compound heterozygous) mutations in the DSG1 (desmoglein-1) gene, or heterozygous mutations in the DSP (desmoplakin) gene. To date, while many patients with SAM syndrome have been described, the number of cases with SAM syndrome with deep-intronic variants, together its genetic aetiology, remain limited. Objectives We report the case of a five-year-old Chinese boy with atypical SAM syndrome. Materials & methods Relevant blood specimens from the family were collected. DNA isolation, RNA isolation and cDNA synthesis, and next-generation sequencing using a multi-gene panel were applied to verify the pathogenic gene. To test the functional consequences and pathogenic mechanism of the deep-intronic mutation in vitro, a mini gene strategy was constructed. Results A heterozygous DSG1 deletion (c.2437_2450delACCTATCCCTCGGG: p.Tyr814Trpfs*6) and a deep-intronic (c.1688-30A > T) variant were identified. The identified intronic variant was shown to create an alternative splice site, leading to nonsense-mediated mRNA decay of the aberrant transcript. Conclusion This is the first study to demonstrate a causal role for a deep-intronic DSG1 mutation in a patient with SAM syndrome. Our findings underline the need to analyse the intronic regions of DSG1 in patients with SAM syndrome. Improved diagnosis and a better understanding of prognosis will lead to clearer a picture of the concept of atypical SAM syndrome.

A 73-year-old male noticed a localized nose erosion that we thought was possibly an exacerbation of skin erosion due to the direct influence of friction from wearing a mask. Blood examination revealed a remarkable increase in serum anti-desmoglein-1 and anti-desmoglein-3 antibodies. A skin biopsy showed acantholysis in the epidermal granular layer. Based on the clinical manifestation and laboratory examination, we diagnosed his eruption as anti-desmoglein-1 and anti-desmoglein-3 antibody - positive pemphigus vulgaris. His skin eruption responded well to oral prednisolone and azathioprine and gradually improved. Pemphigus was a candidate as a differential diagnosis in this case, in which the direct mechanical friction from wearing a mask was thought to be an exacerbating factor of skin eruption.

In the endemic variants of pemphigus foliaceus (PF), in Brazil and Tunisia, patients generate pathogenic IgG4 anti-desmoglein 1 autoantibodies. Additionally, these patients possess antibodies against salivary proteins from sand flies that react with Dsg1, which may lead to skin disease in susceptible individuals living in endemic areas. This minireview focuses on recent studies highlighting the possible role of salivary proteins from Lutzomyia longipalpis (L. longipalpis) in EPF from Brazil and Phlebotomus papatasi (P. papatasi) in EPF from Tunisia. We will briefly discuss the potential mechanisms of molecular mimicry and epitope spreading in the initiation and development of endemic PF (EPF) in Brazil and Tunisia.

Pemphigus is a life-threatening autoimmune disease. Several phenotypic variants are part of this family of bullous disorders. The disease is mainly mediated by pathogenic autoantibodies, but is also directed against two desmosomal adhesion proteins, desmoglein 1 (DSG1) and 3 (DSG3), which are expressed in the skin and mucosae. By binding to their antigens, autoantibodies induce the separation of keratinocytes, in a process known as acantholysis. The two main Pemphigus variants are Pemphigus vulgaris and foliaceus. Several models of Pemphigus have been described: in vitro, ex vivo and in vivo, passive or active mouse models. Although no model is ideal, different models display specific characteristics that are useful for testing different hypotheses regarding the initiation of Pemphigus, or to evaluate the efficacy of experimental therapies. Different disease models also allow us to evaluate the pathogenicity of specific Pemphigus autoantibodies, or to investigate the role of previously not described autoantigens. The aim of this review is to provide an overview of Pemphigus disease models, with the main focus being on active models and their potential to reproduce different disease subgroups, based on the involvement of different autoantigens.

The autoimmune dermatosis pemphigus foliaceus (PF) is predominantly caused by IgG autoantibodies against the desmosomal cadherin desmoglein (Dsg) 1. The exact mechanisms that lead to the characteristic epidermal blistering are not yet fully understood. In the present study, we used a variety of biophysical methods to examine the fate of membrane-bound Dsg1 after incubation with PF patients’ IgG. Dispase-based dissociation assays confirmed that PF-IgG used for this study reduced intercellular adhesion in a manner dependent on phospholipase C (PLC)/Ca2+ and extracellular signal-regulated kinase (ERK) 1/2 signaling. Atomic force microscopy (AFM) revealed that Dsg1 binding on single molecule level paralleled effects on keratinocyte adhesion under the different conditions. Stimulated emission depletion (STED) super-resolution microscopy was used to investigate the localization of Dsg1 after PF-IgG incubation for 24 h. Under control conditions, Dsg1 was found to be in part co-localized with desmoplakin and thus inside of desmosomes as well as extra-desmosomal along the cell border. Incubation with PF-IgG reduced the extra-desmosomal Dsg1 fraction. In line with this, fluorescence recovery after photobleaching (FRAP) experiments demonstrated a strongly reduced mobility of Dsg1 in the cell membrane after PF-IgG treatment indicating remaining Dsg1 molecules were primarily located inside desmosomes. Mechanistically, experiments confirmed the involvement of PLC/Ca2+ since inhibition of PLC or 1,4,5-trisphosphate (IP3) receptor to reduce cytosolic Ca2+ reverted the effects of PF-IgG on Dsg1 intra-membrane mobility and localization. Taken together, our findings suggest that during the first 24 h PF-IgG induce redistribution predominantly of membrane-bound extradesmosomal Dsg1 in a PLC/Ca2+ dependent manner whereas Dsg1-containing desmosomes remain.

Pemphigus is a group of autoimmune diseases characterized by flaccid lesions on the skin and mucous membranes. In pemphigus vulgaris, the most common subtype of pemphigus, lesions might be appeared anywhere on the oral mucosa, mostly in the buccal mucosa. However, the gingiva is a less frequently affected site. Here, we performed a retrospective study at Tehran University of Medical Sciences, covering a two-year period to identify pemphigus patients with active lesions confined to the gingiva. Considering 1787 initially evaluated pemphigus cases, 512 (28.6%) were found to have a history of gingival involvement. Among them, 31 patients had only gingival involvement during their last visit, including 29 (93.5%) women and only two (6.5%) men. The mean of disease duration in this group was 5.29 ± 3.46 years, and they had gingival involvement for a mean of 23.9 ± 19.3 months. Of 28 patients, nine were negative for anti-Dsg3 and 24 were negative for anti-Dsg1. In 24 patients, who received rituximab, the mean pemphigus disease area index specifically for gingiva was 4.76 ± 0.74 at baseline, which had changed to 4.13 ± 0.75 and 3.26 ± 0.63 three and 6 months after rituximab administration, respectively. After 3 months, gingival lesions were either entirely resolved (n = 3), partially resolved (n = 11), remained unchanged (n = 2), or progressed (n = 7). Gingiva-confined presentation of lesions in pemphigus could be non-anti-Dsg1/3 dependent in some patients. Such patients do not respond well to conventional treatments and rituximab therapy. More studies on the pathogenesis of gingiva-confined presentation of pemphigus are required.

Background The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence. Methods Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence–positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lubeck. Results In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic. Limitations Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic. Conclusions The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD.

BACKGROUND Pemphigus is a group of rare and severe autoimmune blistering disease mediated by pathogenic autoantibodies against desmogleins. Plasmapheresis can directly remove autoantibodies from circulation, which has been applied to the treatment of pemphigus as an adjuvant therapy. But the results of the researches are controversial. This study aims to evaluate the efficacy and safety of double filtration plasmapheresis (DFPP) combined with immunosuppressive treatment for patients with severe pemphigus in our single center. METHODS We retrospectively analyzed 17 patients with severe pemphigus who were unresponsive to high-dose corticosteroid and received DFPP treatment between January 2010 and January 2020. The information on demographic characteristics, clinical and laboratory data, treatment regimens, and clinical outcomes were collected. RESULTS All the patients were diagnosed as severe pemphigus and had a period of at least 1 week of high-dose prednisone (1-1.5 mg/kg/day), but they were unresponsive to corticosteroid and immunosuppressants treatment. They received DFPP treatment as an adjuvant therapy. After DFPP treatment, the titers of desmogleins antibodies significantly decreased (P

Background: Pemphigus is an autoimmune disease of the skin and mucous membranes. Glucocorticoids have been the most effective drug for the treatment of pemphigus; however, some patients are insensitive to glucocorticoid therapy. Cyclophosphamide has been extensively used in the treatment of pemphigus. Objectives: To observe and evaluate the efficacy and safety of high-dose glucocorticoid with weekly intravenous cyclophosphamide in the treatment of refractory pemphigus vulgaris insensitive to glucocorticoids. Methods: Clinical data of 19 patients with refractory pemphigus vulgaris (insensitive to glucocorticoid) who were treated with high-dose glucocorticoids(1.5 mg/kg/day prednisone) and weekly intravenous infusion of cyclophosphamide, and 24 patients who were sensitive to glucocorticoid therapy received a medium dose of glucocorticoid alone (1 mg/kg/day prednisone) were retrospectively analyzed. Results: By the time the disease was brought under control, the average total dose of cyclophosphamide was 2.02 g. Comparison between the glucocorticoid-insensitive and glucocorticoid-sensitive groups showed that the average time to disease control was 2.68 vs. 2 weeks, and the average daily dosage of steroid was 1.33 ± 0.53 vs. 0.90 ± 0.28 mg/kg. At the 12- and 18-month follow-ups, the recurrence rate of the glucocorticoid-insensitive group was significantly lower than that of the sensitive group (5.3 vs. 37.5%, 15.8 vs. 45.8%). No serious adverse reactions were observed. Conclusion: High-dose glucocorticoid plus weekly intravenous infusion of cyclophosphamide safely, effectively, and rapidly controlled the conditions of the patients with refractory pemphigus who were insensitive to glucocorticoids, shortened the duration of hospitalization, avoided the risk of complications that could be caused by further increasing the dose of glucocorticoids (>1.5 mg/kg/day), and lowered the recurrence rate within 18 months.

OBJECTIVES A holistic understanding of the many ways that systemic dehydration affects vocal fold biology is still evolving. There are also myriad physiologically relevant methodologies to induce systemic dehydration. To untangle the effects of systemic dehydration on vocal fold biology, we need to utilize realistic, clinically translatable paradigms of systemic dehydration in lab animals. Restricted access to water accommodates clinical translation. We investigated whether systemic dehydration via reduced water intake would negatively affect vocal fold biology. STUDY DESIGN Prospective, in vivo study design. METHODS Male Sprague Dawley rats (N = 13) were provided 4 mL/100 g of water/day for 5 days, whereas male control rats (N = 8) were given ad lib access to water. Following euthanasia, tissues were processed for histological staining, gene expression, and protein assays. RESULTS Renin gene expression level in kidneys increased significantly (P ≤ .05), validating dehydration. Dehydration induced by restricted water access downregulated the gene expression of interleukin-1α and desmoglein-1 (P ≤ .05). Hyaluronidase-2 gene expression increased after dehydration (P ≤ .05). The protein level of desmoglein-1 decreased after dehydration (P ≤ .05). Histological analyses suggested decreased hyaluronan (P ≤ .05) in the water-restricted rat vocal fold. CONCLUSION Reduced daily water intake for just 5 days impairs vocal fold biology by disrupting inflammatory cytokine release, reducing plasma membrane integrity, and disrupting the hyaluronan network. This is the first study investigating the dehydrating effects of restricted water intake on vocal fold tissue in an in vivo model. LEVEL OF EVIDENCE NA (prospective animal study). Laryngoscope, 131:839-845, 2021.

There is concern that using depot-medroxyprogesterone acetate (DMPA) for pregnancy prevention heightens HIV susceptibility. While no clinical data establishes causal link between HIV acquisition and use of this injectable progestin, prior work from our laboratory showed that DMPA comparably lowers genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and weakens genital epithelial barrier function in female mice and women. We likewise saw DMPA increase mouse susceptibility to multiple genital pathogens including HIV. Herein, we sought to confirm and extend these findings by comparing genital epithelial barrier function in untreated rhesus macaques (RM) vs. RM treated with DMPA or DMPA and estrogen (E). Compared to controls, genital tissue from RM with pharmacologically relevant serum levels of medroxyprogesterone acetate displayed significantly lower DSG1 levels and greater permeability to low molecular mass molecules. Conversely, DMPA-mediated effects on genital epithelial integrity and function were obviated in RM administered DMPA and E. These data corroborate the diminished genital epithelial barrier function observed in women initiating DMPA and identify RM as a useful preclinical model for defining effects of exogenous sex steroids on genital pathogen susceptibility. As treatment with E averted DMPA-mediated loss of genital epithelial barrier function, our results also imply that contraceptives releasing progestin and E may be less likely to promote transmission of HIV and other sexually transmitted pathogens than progestin-only compounds.

Background Both enzyme-linked immunosorbent assays (ELISAs) and indirect immunofluorescence (IIF) are available for the diagnosis of autoimmune bullous diseases (AIBD). Many studies have reported on the performance of ELISAs and concluded that ELISAs could replace IIF. This study compares the diagnostic accuracy of ELISA and IIF for the detection of autoantibodies to desmoglein 1 (DSG1), desmoglein 3 (DSG3), bullous pemphigoid antigen 2 (BP180) and bullous pemphigoid antigen 1 (BP230) to support the diagnosis of pemphigus vulgaris (PV), pemphigus foliaceus (PF) and bullous pemphigoid (BP). Methods A literature search was performed in the PubMed database. The meta-analysis was performed using summary values and a bivariate random effect model. Results The five included studies on PV did not demonstrate significant differences between IIF and DSG3-ELISA (sensitivity 82.3% vs. 81.6%, p = 0.9284; specificity 95.6% vs. 93.9%, p = 0.5318; diagnostic odds ratio [DOR] 101.60 vs. 67.760, p = 0.6206). The three included studies on PF did not demonstrate significant differences between IIF and DSG1-ELISA (sensitivity 80.6% vs. 83.1%, p = 0.8501; specificity 97.5% vs. 93.9%, p = 0.3614; DOR 160.72 vs. 75.615, p = 0.5381). The eight included studies on BP showed that BP230-ELISA differed significantly from both IIF on monkey esophagus (MO) and BP180-ELISA with regard to DOR (11.384 vs. 68.349, p = 0.0008; 11.384 vs. 41.699, p = 0.0125, respectively) Conclusions Our meta-analysis shows that ELISA performs as well as IIF for diagnosing PV, PF and BP.

Background: Pemphigus vulgaris is an autoimmune blistering disease affecting the skin and mucous membranes. Current treatments for pemphigus vulgaris include anti-inflammatory and immunosuppressive...

Desmoglein (Dsg) 1 and 3 are the 2 major autoantigens in pemphigus foliaceus (PF) and pemphigus vulgaris (PV).We aimed to determine anti-Dsg1 and 3 Abs'usefulness in the diagnosis of pemphigus and to assess the correlation of these antibodies (Abs) with clinical phenotype and disease activity in south Tunisian patients.We retrospectively analyzed 131 samples from 82 patients (52 with PF and 30 with PV) during follow-up. Anti-Dsg1 and 3 Abs were measured by ELISA. Consecutive anti-Dsg1 and 3 Abs were correlated with disease activity. Receiver operating characteristics (ROC) curve were calculated to determine anti-Dsg1 and 3 Abs'cut-offs with optimal sensitivity and specificity for disease activity.Anti-Dsg1 and 3 levels were associated to in PF and PV patients respectively (p0,001). Anti-Dsg1 and 3 Ab were associated with skin (95%) and mucosal (60%) lesions, respectively. A significant decrease of anti-Dsg1 Abs was observed in patients with PF in clinical remission (36 ± 62 U/mL; (p=0,04). No correlation was found between anti-Dsg3 Abs and the course of mucosal lesions in PV (p=0,3). During follow-up, anti-Dsg1 Abs correlated with relapses (177 ±60 U/mL ; p=0,04). The 161,5 U/mL cut-off for anti-Dsg1 Abs provided 100% specificity and 86,4% sensitivity in PF disease activity. The 30,7U/mL cut-off for anti-Dsg3 provided 89,5% sensitivity and 100% specificity in PV.High anti-Dsg3 Abs values are not always associated with PV disease activity. Anti-Dsg1 Abs showed a closer relationship with skin activity in PS and should be therefore taken into account in management of pemphigus patients.

Desmosomes are important epidermal adhesion units and signalling hubs, which play an important role in pemphigus pathogenesis. Different expression patterns of the pemphigus autoantigens desmoglein (Dsg)1 and Dsg3 across different epidermal layers have been demonstrated. However, little is known about changes in desmosome composition in different epidermal layers or in patient skin. The aim of this study was thus to characterize desmosome composition in healthy and pemphigus skin using super-resolution microscopy. An increasing Dsg1/Dsg3 ratio from lower basal (BL) to uppermost granular layer (GL) was observed. Within BL desmosomes, Dsg1 and Dsg3 were more homogeneously distributed whereas superficial desmosomes mostly comprised one of the two molecules or domains containing either one but not both. Extradesmosomal, desmoplakin (Dp)-independent, co-localization of Dsg3 with plakoglobin (Pg) was found mostly in BL and extradesmosomal Dsg1 co-localization with Pg in all layers. In contrast, in the spinous layer (SL) most Dsg1 and Dsg3 staining was confined to desmosomes, as revealed by the co-localization with Dp. In pemphigus patient skin, Dsg1 and Dsg3 immunostaining was altered especially along blister edges. The number of desmosomes in patient skin was reduced significantly in basal and spinous layer keratinocytes with only few split desmosomes found. In addition, Dsg1-Pg co-localization at the apical BL and Dsg3-Pg co-localization in SL were significantly reduced in patients, suggesting that that extradesmosomal Dsg molecules were affected. These results support the hypothesis that pemphigus is a desmosome assembly disease and may help to explain histopathologic differences between pemphigus phenotypes.

To examine the prevalence of this novel pattern among Iranian patients with pemphigus and peruse the relationship between the presence of a punctate pattern with clinical severity of disease and histopathological findings.One hundred recently diagnosed patients with pemphigus were enrolled. DIF evaluation and routine light microscopy were performed on their biopsy specimens. Disease severity was determined using the Pemphigus Disease Area Index. Serum samples were collected to measure autoantibody titers using enzyme-linked immunosorbent assay.All the samples evaluated by DIF showed a continuous linear pattern of intercellular IgG deposition, whereas none of them had a punctate pattern. Despite a significant correlation between the Pemphigus Disease Area Index score and autoantibody values, no association between histopathological findings and disease severity has been found.We could not detect any punctate pattern among Iranian patients with pemphigus. The importance of this pattern in the diagnosis of pemphigus might be different among patients with different ethnic and genetic factors.

pemphigus vulgaris (PV) is an autoimmune condition characterized by the loss of adhesion between the epithelial cells and blister formation. The production of autoantibodies against desmosomal proteins, namely, desmoglein (DSG) 1 and DSG3, is considered a main event of PV. A full understanding of the role of adhesion molecules in the pathogenesis of PV is not fully elucidated yet. This study aimed to evaluate and correlate the immunohistochemical expression of E-cadherin (E-cad), DSG1, and DSG3 proteins in oral and skin PV.this study was a retrospective analysis study. Positive PV cases were stained with anti-E-cad, anti-DSG1, and anti-DSG3 antibodies. The expression of each marker was determined by two pathologists according to an established scoring system: (E-cad: negative, weak, moderate, and strong), (DSG1: negative, weak, and strong), and (DSG3: negative and positive). The Chi-square and Pearson´s correlation tests were used to statistically analyze the data.forty-three biopsies (26 skin and 17 oral tissue samples) from 22 males and 21 female PV patients were included. The median age was 40.50 years. In total, the immunohistochemical expression was negative for DSG3, E-cad, and DSG1 in 81.4%, 18.5%, and 16.4%, respectively. DSG1 expression was significantly higher in males than females. A statistically significant correlation was found between E-cad and DSG3 expressions.a significant difference in the expression of markers of both oral and skin PV was absent. Downregulation of DSG3 expression was the hallmark feature that also showed a positive correlation with E-cad expression.

Pemphigus is a blistering autoimmune disease that is characterized by autoantibodies against desmogleins (Dsg), including anti-Dsg1 and anti-Dsg3. Despite the diagnosis of diseases, the anti-Dsg test by enzyme-linked immunosorbent assay (ELISA) is negative in a small group of pemphigus patients. The aim of this study was to evaluate the clinical course, clinical symptoms, and response to treatment in pemphigus patients with negative levels of anti-Dsg1 and anti-Dsg3. In this study, the data of pemphigus patients referred to Razi Hospital were retrospectively collected from the medical records from 2016 to 2020. Eight patients, whose initial anti-Dsg1/anti-Dsg3 was negative by the ELISA test, were enrolled and their clinical course, clinical signs, and response to treatment were evaluated. The mean age of the subjects (8 females) was 38.75 ± 12.09. The most common phenotype of the subjects was pemphigus vulgaris (PV) with mucosal involvement. Additionally, the common site of blister inception was mouth of the patients. The mean prednisolone dose received by the patients at the initiation was 32.5 ± 13.62 mg/day. According to Pemphigus disease area index (PDAI), six patients had mild severity, while two cases had moderate severity. Among the patients, six subjects received rituximab (RTX). Also, five patients experienced remission after 6.2 ± 5.21 months. PV is the most common phenotype of the disease and mucosal involvement is more common in patients with negative anti-Dsg-1/3 results. The severity of the lesions in most of the patients is mild at baseline and most patients seems to respond to RTX therapy and reach remission.

Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.

SUMMARYSorting and trafficking transmembrane cargo is essential for tissue development and homeostasis. However, the importance of intracellular trafficking in the development and regeneration of stratified epidermis has not been investigated. Here we identify the interaction between VPS35, an essential component of the retromer endosomal trafficking complex, and the desmosomal cadherin, Desmoglein 1 (Dsg1). Dsg1 is specifically expressed in stratified tissues and when properly localized on the plasma membrane, promotes epidermal stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support keratinocyte stratification and differentiation. The retromer enhancing chaperone, R55 promotes the plasma membrane localization of Dsg1 and a Dsg1 mutant associated with Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome, enhancing the ability of SAM-Dsg1 to promote stratification. Our work provides the first evidence for retromer function in epidermal regeneration and identifies it as a potential therapeutic skin disease target.

Background: Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. Objectives: To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Methods: Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg −1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Results: Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg −1 and 13 of 15 (87%) patients receiving 25 mg kg −1, with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg kg −1 per day (range 0·06–0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2–41 weeks. Conclusions: Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.

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BACKGROUND Clinical studies have clarified the usefulness of moisturizers for dry skin diseases. However, few reports exist on the appropriate application of moisturizers with respect to the skin physiological functions. AIMS To clarify the optimal moisturizer application method on the basis of skin physiological functions. METHODS This study investigated the appropriate time, dose, and frequency of moisturizer application from the perspective of skin physiology. In healthy subjects, the stratum corneum water content (SCW) was compared between different moisturizer application times (immediately [≤5 min] and 90 min after bathing), doses (0.5, 1.0, and 2.0 mg/cm2 ), and frequencies (once and twice daily). Thereafter, patients with dry skin were treated with the moisturizer once or twice daily for 8 weeks at the time, and application dose was determined to be optimal for the healthy subjects; the moisturizing effect was evaluated based on the SCW, trypsin activity, and desmoglein 1 localization score in the stratum corneum. RESULTS In healthy subjects, compared to at control sites, the SCW was significantly higher at sites treated with the moisturizer immediately after bathing, with 1.0 and 2.0 mg/cm2 of the moisturizer, and with once- and twice-daily applications. In patients with dry skin, the SCW was significantly higher compared to control sites and the desmoglein 1 localization score was significantly lower after 8 weeks only when the moisturizer was applied twice daily. CONCLUSIONS Moisturizer application of ≥1.0 mg/cm2 twice daily (immediately after bathing at night and in the morning) had a moisturizing effect, as verified from the skin physiological functions.

BackgroundPemphigus vulgaris (PV) is a rare and severe autoimmune blistering disorder affecting the skin and mucous membranes, characterized by the production of autoantibodies against two desmosomal adhesion proteins, desmoglein 1 and 3. In patients with advanced squamous cell carcinoma of the skin unfit for surgery and radiotherapy, immune check-point inhibitors, including the anti-Programmed Death-1 (PD-1) agent cemiplimab have been successfully employed proving relevant clinical outcomes. Cemiplimab is a monoclonal antibody capable of inhibiting PD-1 signalling that has recently been approved for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma. Although the peculiar setting of advanced CSCC involving elderly patients, rare and unusual skin immune-related adverse events such as PV could be observed in cemiplimab treated patients.Case ReportA 95-year-old man without a history of autoimmune disease was treated with cemiplimab for multiple and advanced squamous cell carcinomas of the head obtaining a complete response to therapy. After seven cycles of cemiplimab administered every 21 days, the patient developed a mucocutaneous blistering eruption. Clinical diagnosis of PV was suspected on the basis of the diffuse involvement of trunk and extremities with large blisters and necrotic eschar. It was carried out an ELISA test, that showed high level of circulating antibodies against desmoglein 1, thus confirming the diagnosis of PV. For this reason, cemiplimab infusion was discontinued and complete resolution of skin lesions was obtained using oral prednisone 0,8 mg/kg/daily for four weeks. Once remission was achieved, a maintenance dose of 10 mg/day was administered, observing a good control of bullous disease and low value of desmoglein 1. Response to CSCC persisted also during cemiplimab discontinuation, until obtaining a complete remission still persisting at 9 months after the last cycle of therapy.ConclusionThe case we observed is the first description of PV revealed from cemiplimab therapy, thus suggesting that cemiplimab could allow the arise of underlying autoimmune PV, through a mechanism both T and B-cell-mediated.

The early chimeric antigen receptor (CAR)-T cell therapies were developed to target cancers, particularly to those B cell hematologic malignancies that occur during childhood. This chapter focuses on one of the skin diseases caused by autoantibodies, those mediated by autoimmune B cells. The most common entities of this group of diseases are two autoimmune blistering diseases—pemphigus vulgaris and bullous pemphigoid—which are targeted by autoantibodies against epidermal cell surface components and epidermal-dermal junction components, respectively. Pemphigus vulgaris is manifested clinically as a superficial blistering disease. Anti-desmoglein 1–specific chimeric autoantibody receptor-T cells will also be a perfect living medication to treat patients affected by pemphigus foliaceus, which is mediated by autoantibodies to desmoglein 1 only. The treatment schedule is important to establish in light of the prohibitive cost of this living medication, as a single dose of CD19-specific CAR-T cell treatment for hematologic B cell lymphoma costs approximately $40,000.

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo-plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis-localization, leading to enhanced epidermal desquamation. We investigated two Arab-Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo-plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis-localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age- and gender-matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling.

Objective Analyzing ectocervical biopsy tissue from women before and after they initiated use of depot-medroxyprogesterone acetate (DMPA), we previously reported this progestin reduces levels of the cell – cell adhesion molecule (CCAM) desmoglein-1 and increases genital mucosal permeability. We likewise saw treating mice with 1.0 mg of DMPA reduced vaginal CCAM expression and increased genital pathogen susceptibility. Herein, we used dose – response studies to delimit DMPA doses and serum MPA levels in mice associated with impaired genital mucosal barrier function and enhanced susceptibility to low-dose herpes simplex virus type 2 (HSV-2) infection. Study d esign We compared genital CCAM expression, genital mucosal permeability, and susceptibility to genital inoculation with 103 plaque-forming units of HSV-2 among mice in estrus vs. after treatment with 0.01 mg, 0.1 mg, 0.3 mg, or 1.0 mg of DMPA. Results Compared to mice in estrus, DMPA treatment in dose-dependent fashion significantly reduced desmoglein 1α (Dsg1a) and desmocollin-1 (Dsc1) gene expression, reduced DSG1 protein levels, and increased genital mucosal permeability to low molecular weight molecules. While no mice infected with HSV-2 in estrus died, we respectively saw 50% and 100% mortality in mice administered 0.1 mg or 0.3 mg of DMPA. At time of infection, mean serum MPA levels in mice administered the 0.1 mg or 0.3 mg doses were 3.8 nM and 13.0 nM respectively (values comparable to trough and peak MPA serum levels in women using DMPA). Conclusions Mice with pharmacologically relevant serum MPA concentrations display significant changes in genital CCAM expression, genital mucosal barrier function, and HSV-2 susceptibility.

Pemphigus consists of a group of rare and severe autoimmune blistering diseases mediated by pathogenic autoantibodies mainly directed against two desmosomal adhesion proteins, desmoglein (Dsg)1 and Dsg3 (also known as DG1 and DG3), which are present in the skin and surface-close mucosae. The binding of autoantibodies to Dsg proteins induces a separation of neighbouring keratinocytes, in a process known as acantholysis. The two main pemphigus variants are pemphigus vulgaris, which often originates with painful oral erosions, and pemphigus foliaceus, which is characterised by exclusive skin lesions. Pemphigus is diagnosed on the basis of either IgG or complement component 3 deposits (or both) at the keratinocyte cell membrane, detected by direct immunofluorescence microscopy of a perilesional biopsy, with serum anti-Dsg1 or anti-Dsg3 antibodies (or both) detected by ELISA. Corticosteroids are the therapeutic mainstay, which have recently been complemented by the anti-CD20 antibody rituximab in moderate and severe disease. Rituximab induces complete remission off therapy in 90% of patients, despite rapid tapering of corticosteroids, thus allowing for a major corticosteroid-sparing effect and a halved number of adverse events related to corticosteroids.

Pemphigus diseases are cutaneous and mucous membrane blistering diseases, related to the key antigens of desmoglein 1 and 3. This article reviews the topic, including diagnosis, and provides the physician with guidance on the treatment of these difficult to control disorders.

Background The BIOCHIP is a novel multiplex indirect immunofluorescence technique used in the serological diagnosis of bullous pemphigoid and pemphigus. The BIOCHIP method combines the screening of autoantibodies and target antigen-specific substrates in a single miniature incubation field. Objective To evaluate the diagnostic accuracy of the new immunofluorescence BIOCHIP multiplex tool in pemphigus and bullous pemphigoid. Methods For the validation of the BIOCHIP, sera from patients with BP (n = 38), PF (n = 8) and pemphigus vulgaris (PV) (n = 23) were used. In addition, sera from disease control patients (n = 63) and healthy volunteers (n = 39) were used. The multiplex BIOCHIP and direct immunofluorescence (DIF) were performed for all BP, PF and PV patients. Additional indirect immunofluorescence (IIF) was performed on patients with BP, and ELISA was performed on patients with pemphigus. Results The BIOCHIP mosaic showed a sensitivity of 86.8% and specificity of 85% for BP180 or BP230 being positive in BP. It demonstrated a sensitivity of 75% and specificity of 97.7% for Dsg1 in PF. The BIOCHIP was found to have a sensitivity of 60.9% and specificity of 73.6% for Dsg3 in PV. Conclusion The BIOCHIP mosaic-based immunofluorescence test is potentially a simple, time and effort saving test that can aid in the diagnosis and screening of BP, PV and PF. However, there is potential for interpretation bias and a learning curve that needs to be taken into consideration.

Palmoplantar keratoderma (PPK) is a heterogenous group of skin disorders characterized by a persistent thickening of the palms of the hands and sometimes soles of the feet. PPK can be classified into many types, including diffuse, transgradient, and focal or striate, where the areas of palmoplantar skin are alternatively thickened. Mutations in four main genes, keratin 9 (KRT9), keratin 1 (KRT1), desmoglein (DSG1), and desmoplakin (DSP), have been associated with PPK. Striate PPK (SPPK) is commonly caused by mutations in DSG1. However, DSP and KRT1 gene mutations have been identified in some cases. In this study, fragment and sequencing analysis were performed for a large Syrian family with dominant SPPK. Segregation analysis showed a linkage with DSG1 gene. Direct Sanger sequencing identified a new mutation c.dup165_168AGCA. This frameshift mutation was heterozygous in all affected family members and absent in all normal individuals.

Die Rolle von Interleukin(IL)-17 im Rahmen der Pemphiguserkrankung ist nicht hinreichend geklart. Sowohl der Pemphigus vulgaris (PV) als auch der Pemphigus foliaceus (PF) weisen intralasional IL-17-positive Zellen auf. Eine Patientin mit zunachst vermuteter koinzidenter Psoriasis pustulosa (PP) und einem PF wurde mit dem Anti-IL-17-Antikorper Secukinumab behandelt. Der klinische Hautbefund verbesserte sich deutlich und die Anti-Desmoglein-1-Antikorper fielen deutlich ab. Bei Verlangerung des Injektionsintervalls von Secukinumab wurde jedoch ein erneuter Anstieg der Antikorper beobachtet. Wir vermuten einen dosisabhangigen Effekt von Secukinumab auf die Autoantikorperbildung beim PF. Ruckblickend besteht die Moglichkeit eines neutrophilen dominierten PF, der unter einer IL-17-Blockade zu einer annahernd vollstandigen Abheilung gekommen ist.

Loss of the desmosomal cell–cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing epidermal growth factor receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2-binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation. Here, we provide evidence that restoring Dsg1 expression in cells derived from HNSCC suppresses invasion by decreasing the number of invadopodia and matrix degradation. Moreover, Dsg1 requires Erbin to downregulate EGFR/Erk signaling and to fully suppress invadopodia formation. Our findings indicate a novel role for Dsg1 in the regulation of invadopodia signaling and provide potential new targets for development of therapies to prevent invadopodia formation and therefore cancer invasion and metastasis. Implications: Our work exposes a new pathway by which a desmosomal cadherin called Dsg1, which is lost early in head and neck cancer progression, suppresses cancer cell invadopodia formation by scaffolding ErbB2 Interacting Protein and consequent attenuation of EGF/Erk signaling.

BACKGROUND Pemphigus foliaceus (PF) is an epidermal autoimmune disease, characterized by the presence of autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors contribute to PF, a complex disease that is endemic in Brazil and Colombia and neighbouring countries, and in Tunisia. Long noncoding RNAs (lncRNAs) may participate in gene regulation by interacting with DNA, proteins and other RNAs. Dysregulation of lncRNAs has recently been recognized as an important coplayer in the onset or progression of complex diseases. In addition, single-nucleotide polymorphisms (SNPs) located in lncRNA genes have been associated with differential risk to cancer, autoimmunity and infection. OBJECTIVES Here, we aimed to investigate whether SNPs in lncRNA genes are associated with differential susceptibility to endemic PF. MATERIALS AND METHODS We integrated data from the lncRNA SNP database with genome-wide genotype data obtained for 229 patients and 6681 controls. We tested the association between endemic PF and 2080 SNPs located in lncRNAs applying logistic regression. RESULTS The most significantly associated SNP was rs7144332 (OR = 1·63, P = 2·8 × 10-6 ), located in the lncRNA gene AL110292·1. Results for five other SNPs were suggestive of association (P < 0·001). In silico analysis indicated that five of the six SNPs impact transcription, three may influence lncRNA's secondary structure, and three may alter microRNA-lncRNA interactions. CONCLUSIONS We showed, for the first time, that variation in lncRNA genes may influence pemphigus pathogenesis. Our findings highlight the importance of lncRNA variation in autoimmune and possibly other complex diseases and suggest polymorphisms for functional validation.

Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell–cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.