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The neonatal Fc receptor (FcRn) is important for numerous cellular processes that involve antibody recycling and trafficking. A major function of FcRn is IgG recycling and half-life prolongation, and FcRn blockade results in a reduction of autoantibodies in IgG-mediated autoimmune diseases. In epithelial cells, FcRn functions in processes different from IgG recycling, such as antibody transcytosis in intestinal cells. In pemphigus vulgaris, an autoimmune disease of the epidermis, IgG autoantibodies directed against desmosomal adhesion proteins, especially desmoglein-3 and -1, cause loss of keratinocyte adhesion. We have previously demonstrated that FcRn blockade with efgartigimod, a human Fc fragment with enhanced FcRn binding, significantly reduces the keratinocyte monolayer fragmentation caused by anti-desmoglein-3 antibodies. This points to a direct function of FcRn in keratinocytes, beyond IgG recycling, but the mechanisms have not yet been elucidated in detail. Here, we show that FcRn binding is required for the full pathogenicity of recombinant anti-desmoglein-3 antibodies in keratinocytes, and that antibodies that exhibit enhanced or reduced FcRn affinity due to targeted substitutions in their Fc region, as well as F(ab')2 fragments not binding to FcRn display different degrees of pathogenicity. Blockade of FcRn by efgartigimod only shows a protective effect on keratinocyte adhesion against antibodies capable of binding to FcRn. Furthermore, antibody-induced degradation of desmoglein-3 in keratinocytes does not depend on FcRn, demonstrating that desmoglein-3 degradation and acantholysis are functionally disconnected processes. Our data suggest that the role of FcRn in autoimmune diseases is likely to be versatile and cell-type dependent, thus stressing the importance of further studies on FcRn function in autoimmune diseases. [ABSTRACT FROM AUTHOR]

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Summary: Background and objectives: Oral lichen planus (OLP) is a T cell driven disorder that significantly impairs patients' quality of life. Previous reports suggest that both cellular and humoral activities against desmoglein (dsg) 1 and 3 may be involved in OLP pathogenesis. Here, we aim to analyze the frequency of occurrence and pathological significance of anti‐dsg antibodies in a large cohort of OLP patients. Materials and methods: OLP patients were screened for anti‐dsg antibodies by enzyme‐linked immunosorbent assay in three tertiary referral centers. OLP sera with anti‐dsg antibodies were further analyzed by Western blot and dispase‐based keratinocyte dissociation assay (DDA) to identify the targeted dsg ectodomains and to assess their pathogenicity. Results: Of 151‐screened individuals with OLP, only four patients (2.6%) with erosive OLP showed serum IgG against dsg1/3. Western blot analysis with recombinant dsg3 ectodomains revealed preferential recognition of the extracellular domain 5. By DDA with spontaneously immortalized human keratinocytes, none of the sera from these four patients induced acantholysis. Conclusions: Activation of humoral immunity occurs prevalently in patients with erosive OLP, probably due to epitope spreading. OLP serum antibodies are unable to induce loss of intercellular adhesion in vitro, strongly suggesting that they are not disease causing but rather an epiphenomenon. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-desmoglein (Dsg)1 is produced in pemphigus foliaceus (PF), affecting exclusively the skin. Pemphigus vulgaris (PV) shows the production of anti-Dsg3 in the mucosal form, and anti-Dsg1 and 3 in the mucocutaneous form. Anti-Dsg3 autoantibodies have been rarely reported in PF. Objectives To determine the factors associated with the production and pathogenicity of anti-Dsg3 in PF. Methods Comparative analytical study of three patients groups: 16 PF-anti-Dsg3+, and 42 PF-anti-Dsg3(-) and 22 PV treatment-naïve cases. Serum was used in the anti-Dsg1 and 3 ELISA, and in immunoblotting (IB) with human epidermis extract. The expression of Dsg1 and 3 in paraffin sections was analyzed by immunohistochemistry (IHC). HLA-DRB1 alleles were compiled from a database. Results In the PF-anti-Dsg3+ group: age range similar to that of the PV group (p > 0.9999); predominance of the generalized form of PF (p = 0.002); anti-Dsg3 titers lower than those of PV (p < 0.0001); IB confirmed Dsg3 identification in one (8.33%) of 12 patients; IHC showed exclusive cytoplasmic internalization of Dsg1; HLA-DRB1 alleles of susceptibility to PF, with the absence of alleles associated with PV, in the five typed patients. Study limitations Most of the patients in the PF-anti-Dsg3+ group were undergoing treatment. Conclusion The presence of anti-Dsg3 antibodies in PF was related to older age (comparable to that of PV) and the generalized form of PF. The non-pathogenicity of anti-Dsg3 antibodies in PF can be attributed to the low serum anti-Dsg3 titers, the lack of Dsg3 internalization as detected by IHC, and the absence of PV-associated HLA-DRB1 alleles.

Pemphigus vegetans and pemphigus foliaceus are rare autoimmune blistering diseases characterized by the disruption of desmosomal adhesion proteins, particularly desmoglein 3 and desmoglein 1. We report the case of a 62-year-old male who presented initially with scaly red plaques posing several diagnostic challenges. A histopathological examination revealed subcorneal acantholysis, matching the suspected clinical diagnosis of pemphigus foliaceus. The patient progressed, developing vegetating plaques, and a new biopsy was performed. The new histopathological and direct immunofluorescence exams were consistent with pemphigus vegetans. This case highlights the diagnostic challenges posed by the transition of pemphigus foliaceus to its vegetating form. We discuss the role of desmogleins in the pathogenesis of pemphigus and explore potential therapeutic strategies targeting these specific autoantigens.

Background: Pemphigus is a chronic potentially fatal autoimmune bullous disorder. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are the two common subtypes. PV is the most common and aggressive type characterized by oral mucosal erosions and cutaneous lesions. PF presents with blisters on the scalp, face, and upper trunk, and spares the mucosae. Direct immunofluorescence (DIF) is the gold standard for diagnosis. Immunohistochemistry (IHC) is an emerging alternate diagnostic tool. In this study, our objectives were to identify the staining patterns of desmoglein 1 (dsg 1) and desmoglein 3 (dsg 3) IHC and to correlate the same with autoantibody levels and clinical severity in patients with PV and PF. Methods: Forty‐nine clinically, histologically, and DIF‐confirmed cases of pemphigus were included in the study. The IHC patterns were scored from 0 to 3+ with 3+ dsg 1 IHC exhibiting intense membranous staining in the upper layers of the epidermis and 3+ dsg 3 IHC showing intense basal layer staining. Enzyme‐linked immunosorbent assay (ELISA) for anti‐dsg 1 and 3 antibodies was performed in 38 cases where serum samples were available. The pemphigus disease activity index system was utilized for clinical scoring. Results: A 0 to 1+ score was observed for dsg 1 IHC in 100% of PF cases. A score of 0 to 1+ was observed for dsg 3 IHC in 97.3% of PV cases. One hundred percent of cases with PF and 83.9% of patients with PV tested positive for ELISA anti‐dsg 1 and 3 antibody titers, respectively. Anti‐dsg 1 and 3 ELISA titers significantly correlated with the dsg 1 and dsg 3 IHC scores. The mucosal scores showed a significant association with both dsg 1 and 3 IHC (p < 0.001). The cutaneous scores showed a significant association with the dsg 3 IHC (p < 0.001). Conclusion: The IHC patterns for dsg 1 and 3 proved reliable in giving concordant results with the ELISA antibody titers and clinical severity. [ABSTRACT FROM AUTHOR]

Introduction: Pemphigus is a potentially life‐threatening autoimmune blistering disease. To date, studies assessing the association of histopathology with clinical phenotype are lacking. We sought to evaluate the main histopathologic findings and, also, the potential links between cutaneous inflammatory infiltrates and clinical characteristics in pemphigus. Methods: We conducted a retrospective cohort study in patients diagnosed with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) in a referral center for autoimmune blistering diseases. Results: A total of 124 patients were included in the study (97 had PV and 27 had PF). On biopsy specimens, PV was more frequently associated with the "row of tombstones" feature (36.1% vs. 11.1%, p = 0.013), and PF was associated with acanthosis (44.4% vs. 23.7%, p = 0.034). Acantholysis was found in the upper half of the epidermis in PF (96.3% vs. 5.15%, p < 0.001), as opposed to the lower half in PV (75.2% vs. 0%, p = 0.002). Patients with lymphocyte‐predominant inflammatory infiltrates in lesional skin specimens presented with a higher frequency of the mucosal‐dominant phenotype (25.5% vs. 9.1%, p = 0.014), higher‐density cellular infiltrate (100% vs. 41.6%, p < 0.001), and more frequent acantholytic cells (42.6% vs. 23.4%, p = 0.025). Neutrophil‐predominant infiltrates in specimens from lesional skin were linked to a milder disease based on median Pemphigus Disease Area Index (38.9% vs. 13.2%, p = 0.036) and Autoimmune Bullous Skin Disorder Intensity Score (20.2 vs. 36.3, p = 0.019), while eosinophil‐predominant inflammatory infiltrates were more often associated with eosinophilic spongiosis (100% vs. 23.1%, p = 0.014). Conclusions: Lymphocyte‐predominant infiltrates in lesional skin specimens of pemphigus patients predict a mucosal‐dominant phenotype, while neutrophil‐predominant infiltrates are associated with a milder disease. [ABSTRACT FROM AUTHOR]

Background: Carcinogenesis is a complex multistep process involving alterations at the cellular level. Alteration in cell-to-cell adhesion of oral epithelium plays an important role in carcinogenesis and metastasis. The alterations in the role of desmosomal components due to autoantibodies to desmoglein 1 (DSG 1) and desmoglein 3 (DSG 3) may cause the detachment of the cells due to altered adhesiveness leading to initiation and metastasis. The exact role of autoantibodies in DSG 1 and 3 and their role in oral carcinogenesis remains unclear. Objectives: A pilot study was undertaken to evaluate autoantibodies to DSG 1 and 3 oral cancer (OC), Oral potentially malignant disorder (OPMDs) patients, and healthy controls. Materials and Methods: A total of 25 cases (15 OC, 5 OPMDs, and 5 healthy controls) were selected. Serum and tissue biopsies were taken and evaluated for autoantibodies to DSG 1 and 3 by enzyme-linked immunosorbent assay (ELISA) and was confirmed with direct immunofluorescence (DIF). Results: The DSG 1 and 3 values obtained were way below the positive value of 20 RU/ml for autoantibody levels for either DSG 1 or DSG 3 in serum. Direct immunofluorescence (DIF) of tissues also failed to demonstrate the presence of antibodies in all three groups. Conclusion: Though the results were not encouraging, they suggest a possible role of desmosomal components, DSG 1 and 3, in oral carcinogenesis and metastasis.

Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing this devastating disease. Here, we observed that non-desmoglein (Dsg) AuAbs in the sera of patients with Dsg1/3 AuAb-negative acute PV are pathogenic, because IgGs from these individuals induced skin blistering in neonatal mice caused by suprabasal acantholysis. Serum levels of AuAbs to desmocollin 3 (Dsc3), M3 muscarinic acetylcholine receptor (M3AR), and secretory pathway Ca2+/Mn2+-ATPase isoform 1 (SPCA1) correlated with the disease stage of PV. Moreover, AuAb absorption on recombinant Dsc3, M3AR, or SPCA1 both prevented skin blistering in the passive transfer of AuAbs model of PV in BALB/c mice and significantly decreased the extent of acantholysis in a neonatal mouse skin explant model. Although acantholytic activities of each of these immunoaffinity-purified AuAbs could not induce a PV-like phenotype, their mixture produced a synergistic effect manifested by a positive Nikolskiy sign in the skin of neonatal mice. The downstream signaling of all pathogenic non-Dsg AuAbs involved p38 mitogen-activated protein kinase (MAPK)-mediated phosphorylation and elevation of cytochrome c release and caspase 9 activity. Anti-Dsc3 and anti-SPCA1 AuAbs also activated SRC proto-oncogene, nonreceptor tyrosine kinase (SRC). Of note, although a constellation of non-Dsg AuAbs apparently disrupted epidermal integrity, elimination of a single pathogenic AuAb could prevent keratinocyte detachment and blistering. Therefore, anti-Dsg1/3 AuAb-free PV can be a model for elucidating the roles of non-Dsg antigen-specific AuAbs in the physiological regulation of keratinocyte cell-cell adhesion and blister development.

Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease. Patients develop non-healing erosions and blisters due to cell-cell detachment of keratinocytes (acantholysis), with subsequent suprabasal intraepidermal splitting. Identified almost 30 years ago, desmoglein-3 (Dsg3), a Ca2+-dependent cell adhesion molecule belonging to the cadherin family, has been considered the "primary" autoantigen in PV. Proteomic studies have identified numerous autoantibodies in patients with PV that have known roles in the physiology and cell adhesion of keratinocytes. Antibodies to these autoantibodies include desmocollins 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes, mitochondrial proteins, human leukocyte antigen molecules, thyroid peroxidase, and hSPCA1-the Ca2+/Mn2+-ATPase encoded by ATP2C1, which is mutated in Hailey-Hailey disease. Several studies have identified direct pathogenic roles of these proteins, or synergistic roles when combined with Dsg3. We review the role of these direct and indirect mechanisms of non-desmoglein autoantibodies in the pathogenesis of PV.

The neonatal Fc receptor (FcRn) is important for numerous cellular processes that involve antibody recycling and trafficking. A major function of FcRn is IgG recycling and half-life prolongation, and FcRn blockade results in a reduction of autoantibodies in IgG-mediated autoimmune diseases. In epithelial cells, FcRn functions in processes different from IgG recycling, such as antibody transcytosis in intestinal cells. In pemphigus vulgaris, an autoimmune disease of the epidermis, IgG autoantibodies directed against desmosomal adhesion proteins, especially desmoglein-3 and -1, cause loss of keratinocyte adhesion. We have previously demonstrated that FcRn blockade with efgartigimod, a human Fc fragment with enhanced FcRn binding, significantly reduces the keratinocyte monolayer fragmentation caused by anti-desmoglein-3 antibodies. This points to a direct function of FcRn in keratinocytes, beyond IgG recycling, but the mechanisms have not yet been elucidated in detail. Here, we show that FcRn binding is required for the full pathogenicity of recombinant anti-desmoglein-3 antibodies in keratinocytes, and that antibodies that exhibit enhanced or reduced FcRn affinity due to targeted substitutions in their Fc region, as well as F(ab')2 fragments not binding to FcRn display different degrees of pathogenicity. Blockade of FcRn by efgartigimod only shows a protective effect on keratinocyte adhesion against antibodies capable of binding to FcRn. Furthermore, antibody-induced degradation of desmoglein-3 in keratinocytes does not depend on FcRn, demonstrating that desmoglein-3 degradation and acantholysis are functionally disconnected processes. Our data suggest that the role of FcRn in autoimmune diseases is likely to be versatile and cell-type dependent, thus stressing the importance of further studies on FcRn function in autoimmune diseases., Competing Interests: RT has received research funding from argenx within a bilateral Research Collaboration Agreement. KV, MS and MB are employees of argenx, and their role in this study was as required from eligible coauthors. These aforementioned argenx coworkers generated some of the data, participated in the design of the study and in the writing of the manuscript as coauthors. The argenx coworkers and the funders had no role beyond their role as coauthors in the interpretation of the data or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zakrzewicz, Vanderheyden, Galaly, Feldhoff, Sips, Brinkhaus and Tikkanen.)

Background: Anti-desmoglein (Dsg)1 is produced in pemphigus foliaceus (PF), affecting exclusively the skin. Pemphigus vulgaris (PV) shows the production of anti-Dsg3 in the mucosal form, and anti-Dsg1 and 3 in the mucocutaneous form. Anti-Dsg3 autoantibodies have been rarely reported in PF., Objectives: To determine the factors associated with the production and pathogenicity of anti-Dsg3 in PF., Methods: Comparative analytical study of three patients groups: 16 PF-anti-Dsg3+, and 42 PF-anti-Dsg3(-) and 22 PV treatment-naïve cases. Serum was used in the anti-Dsg1 and 3 ELISA, and in immunoblotting (IB) with human epidermis extract. The expression of Dsg1 and 3 in paraffin sections was analyzed by immunohistochemistry (IHC). HLA-DRB1 alleles were compiled from a database., Results: In the PF-anti-Dsg3+ group: age range similar to that of the PV group (p > 0.9999); predominance of the generalized form of PF (p = 0.002); anti-Dsg3 titers lower than those of PV (p < 0.0001); IB confirmed Dsg3 identification in one (8.33%) of 12 patients; IHC showed exclusive cytoplasmic internalization of Dsg1; HLA-DRB1 alleles of susceptibility to PF, with the absence of alleles associated with PV, in the five typed patients., Study Limitations: Most of the patients in the PF-anti-Dsg3+ group were undergoing treatment., Conclusion: The presence of anti-Dsg3 antibodies in PF was related to older age (comparable to that of PV) and the generalized form of PF. The non-pathogenicity of anti-Dsg3 antibodies in PF can be attributed to the low serum anti-Dsg3 titers, the lack of Dsg3 internalization as detected by IHC, and the absence of PV-associated HLA-DRB1 alleles., (Copyright © 2024 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

The Hippo-YAP pathway serves as a central signalling hub in epithelial tissue generation and homeostasis. Yes-associated protein (YAP) is an essential downstream transcription cofactor of this pathway, with its activity being negatively regulated by Hippo kinase-mediated phosphorylation, leading to its cytoplasmic translocation or degradation. Our recent study showed phospho-YAP complexes with Desmoglein-3 (Dsg3), the desmosomal cadherin known to be required for junction assembly and cell–cell adhesion. In this study, we show that YAP inhibition by Verteporfin (VP) caused a significant downregulation of desmosomal genes and a remarkable reduction in desmosomal proteins, including the Dsg3/phospho-YAP complex, resulting in attenuation of cell cohesion. We also found the desmosomal genes, along with E-cadherin, were the YAP-TEAD transcriptional targets and Dsg3 regulated key Hippo components, including WWTR1/TAZ, LATS2 and the key desmosomal molecules. Furthermore, Dsg3 and phospho-YAP exhibited coordinated regulation in response to varied cell densities and culture durations. Overexpression of Dsg3 could compensate for VP mediated loss of adhesion components and proper architecture of cell junctions. Thus, our findings suggest that Dsg3 plays a crucial role in the Hippo network and regulates junction configuration via complexing with phospho-YAP. [ABSTRACT FROM AUTHOR]

Desmogleins (DSGs), with the ability to link adjacent cells, have been shown to participate in the development of malignancy. DSG3 was up-regulated in various cancers, including lung, head and neck, and esophagus squamous cell carcinoma, which contributed to the tumor progression. The role of DSG3 in pancreatic ductal adenocarcinoma (PDAC) still remains elusive. Here, the expression of DSG3 was found to be enhanced in pancreatic cancer cell lines in vitro. Functional assays showed that shRNA-mediated knockdown of DSG3 decreased cell viability of pancreatic cancer cells and retarded the cell proliferation, migration and invasion. However, pcDNA-mediated over-expression of DSG3 exhibited reversed effect on pancreatic cancer cell progression. In addition, the in vivo assay demonstrated that transfection of shDSG3 lentiviruses into pancreatic cancer cells repressed the tumorigenicity of PDAC after the cancer cells were transplanted into mice subcutaneously. Elevated DSG3 expression promoted the phosphorylation of Src (p-Src), focal adhesion kinase (p-FAK) and AKT (p-AKT) in vitro, while silence of DSG3 reduced the expression of p-Src, p-FAK and p-AKT both in vitro and in vivo. In conclusion, DSG3, as an oncogene, contributed to the tumorigenicity of PDAC through activating Src–FAK signaling.

Introduction: We studied the distribution and in vitro pathogenicity of anti-DSG3 IgG subclasses during the course of pemphigus vulgaris (PV). Methods: We longitudinally studied the distribution of anti-DSG3 IgG subclasses (before versus after treatment) in sera from PV patients, using an addressable-laser bead immunoassay (ALBIA). The in vitro pathogenicity of corresponding sera was tested using keratinocyte dissociation and immunofluorescence assays. Results: Sixty-five sera were assessed at baseline (33 from patients treated with rituximab and 32 with corticosteroids). Sixty-three percent of these baseline sera contained 2 or more anti-DSG3 IgG subclasses versus 35.7% of sera from patients in complete remission (CR) and 75.0% of sera from patients with persistent disease activity after treatment. IgG4 was the most frequently detected anti-DSG3 IgG subclass, both in patients with disease activity and in those in CR. The presence of three or more anti-DSG3 IgG subclasses was predictive of relapse, in particular when it included IgG3, with a positive predictive value of 62.5% and a negative predictive value of 92%. While anti-DSG3 IgG4 Abs from sera collected before treatment were most often pathogenic, anti-DSG3 IgG4 from sera collected after treatment were pathogenic only after adjusting their titer to the one measured before treatment. The IgG3 fraction containing anti-DSG3 Abs also had an in vitro pathogenic effect. The disappearance of the pathogenic effect of some sera after removal of anti-DSG3 IgG3 suggested an additional effect of this IgG subclass. Conclusion: The serum levels and number of anti-DSG3 IgG subclasses drive the pathogenic effect of pemphigus sera and may predict the occurrence of relapses. [ABSTRACT FROM AUTHOR]

IntroductionWe studied the distribution and in vitro pathogenicity of anti-DSG3 IgG subclasses during the course of pemphigus vulgaris (PV).MethodsWe longitudinally studied the distribution of anti-DSG3 IgG subclasses (before versus after treatment) in sera from PV patients, using an addressable-laser bead immunoassay (ALBIA). The in vitro pathogenicity of corresponding sera was tested using keratinocyte dissociation and immunofluorescence assays.ResultsSixty-five sera were assessed at baseline (33 from patients treated with rituximab and 32 with corticosteroids). Sixty-three percent of these baseline sera contained 2 or more anti-DSG3 IgG subclasses versus 35.7% of sera from patients in complete remission (CR) and 75.0% of sera from patients with persistent disease activity after treatment. IgG4 was the most frequently detected anti-DSG3 IgG subclass, both in patients with disease activity and in those in CR. The presence of three or more anti-DSG3 IgG subclasses was predictive of relapse, in particular when it included IgG3, with a positive predictive value of 62.5% and a negative predictive value of 92%. While anti-DSG3 IgG4 Abs from sera collected before treatment were most often pathogenic, anti-DSG3 IgG4 from sera collected after treatment were pathogenic only after adjusting their titer to the one measured before treatment. The IgG3 fraction containing anti-DSG3 Abs also had an in vitro pathogenic effect. The disappearance of the pathogenic effect of some sera after removal of anti-DSG3 IgG3 suggested an additional effect of this IgG subclass.ConclusionThe serum levels and number of anti-DSG3 IgG subclasses drive the pathogenic effect of pemphigus sera and may predict the occurrence of relapses.

During differentiation, keratinocytes acquire a strong, hyper-adhesive state, where desmosomal cadherins interact calcium ion independently. Previous data indicate that hyper-adhesion protects keratinocytes from pemphigus vulgaris autoantibody-induced loss of intercellular adhesion, although the underlying mechanism remains to be elucidated. Thus, in this study, we investigated the effect of hyper-adhesion on pemphigus vulgaris autoantibody-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 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 extracellular domain 1 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. In addition, heterophilic DSC3-DSG3 and DSG2-DSG3 interactions did not cause reduced susceptibility to direct inhibition under hyper-adhesive condition in wild-type keratinocytes. Taken together, the data suggest that hyper-adhesion reduces susceptibility to autoantibody-induced direct inhibition in dependency on autoantibody-targeted extracellular domain but also demonstrate that further mechanisms are required for the protective effect of desmosomal hyper-adhesion in pemphigus vulgaris., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The role for 1,25-dihydroxyvitamin D3 and/or calcium in hair follicle cycling is not clear despite their impact on keratinocyte differentiation. We found that calbindin-D9k null (knockout) pups generated from calbindin-D9k knockout females fed a vitamin D-deficient, low-calcium (0.47%) diet develop transient alopecia. The pups appear phenotypically normal until 13 days of age, after which the hair progressively sheds in a caudocephalic direction, resulting in truncal alopecia totalis by 20-23 days, with spontaneous recovery by 28 days. Histological studies showed markedly dystrophic hair follicles, loss of hair shafts with increased apoptosis, and hyperplastic epidermis during this time. Ha1 expression is lost during catagen in all mice but recovers more slowly in the knockout pups on the vitamin D-deficient, low-calcium diet. Keratin 1 expression is reduced throughout days 19-28. The expressions of involucrin, loricrin, and cathepsin L is initially increased by day 19 but subsequently falls below those of controls by day 23, as does that of desmoglein 3. Feeding the mothers a high-vitamin D/high-calcium (2%)/lactose (20%) diet lessens the phenotype, and knockout pups fostered to mothers fed a normal diet do not develop alopecia. Our results show that in calbindin-D9k knockout pups, a maternal vitamin D-deficient/low-calcium diet leads to transient noncicatricial alopecia.

Systemic autoimmune diseases such as lupus affect multiple organs, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the "local" immune cells play a role in regulating tissue specificity in relation to disease heterogeneity in systemic autoimmune diseases. In this study, we used skin as a model to determine the role of tissue-resident dendritic cells (DCs) in local and systemic involvement within a systemic lupus disease model. Skin-resident DCs, namely, Langerhans cells (LCs), have been implicated in regulating tolerance or autoimmunity using elegant transgenic models, however, their role in local versus systemic immune regulation is unknown. We demonstrate that although lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Fas(lpr/lp) (r) (MRL-lpr) mice react spontaneously to a physiological skin self-Ag desmoglein-3, epicutaneous applications of desmoglein-3 induced tolerance that is dependent on LCs. Inducible ablation of LCs in adult preclinical MRL-lpr and MRL/MpJ-Fas(+/+) mice resulted in increased autoantibodies against skin Ags and markedly accelerated lupus dermatitis with increased local macrophage infiltration, but had no effect on systemic autoantibodies such as anti-dsDNA Abs or disease in other organs such as kidneys, lung, and liver. Furthermore, skin-draining lymph nodes of LC-ablated MRL-lpr mice had significantly fewer CD4(+) T cells producing anti-inflammatory cytokine IL-10 than LC-intact controls. These results indicate that a skin-resident DC population regulates local tolerance in systemic lupus and emphasize the importance of the local immune milieu in preventing tissue-specific autoimmunity, yet have no effect on systemic autoimmunity.

A method for the analysis of the epitope specificity of auto-reactive antibodies to desmoglein 3 (Dsg3) using competitive ELISA has been developed. It is based on a two-stage solid-phase ELISA with initial "depletion" of auto-reactive antibodies against the studied epitope and subsequent quantitative assessment of antibodies against full-length extracellular domain Dsg3. The proposed approach for assessing the specificity of the autoimmune response in patients with pemphigus vulgaris can provide in the future the possibility to personalize the therapy using plasmapheresis by preliminary selection of the antigenic composition of the extracorporeal immunosorbent. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death in the world. Despite developments in personalized treatment, lung cancer is still problematic for therapy due to resistance and metastasis. Moreover, heterogeneity of lung cancers makes treatment difficult. Therefore, there is an urgent need to find novel prognostic and diagnostic markers. Desmosomal proteins seem to be a good candidate to be acknowledged due to their function in the cell. Desmosomal proteins are known to be responsible for accurate cell-to-cell adhesion in physiological conditions. In cancer cells, the destabilization of desmosomes by the loss of proteins promotes the process of epithelial-mesenchymal transition, which is strongly connected to metastasis. Desmoglein 3 is one of the desmosomal proteins often deregulated in cancer, including lung cancer. Taking the above, our goal was to analyze the results on DSG3 function and its clinical implications in lung cancer. [ABSTRACT FROM AUTHOR]

Desmogleins (DSGs), with the ability to link adjacent cells, have been shown to participate in the development of malignancy. DSG3 was up-regulated in various cancers, including lung, head and neck, and esophagus squamous cell carcinoma, which contributed to the tumor progression. The role of DSG3 in pancreatic ductal adenocarcinoma (PDAC) still remains elusive. Here, the expression of DSG3 was found to be enhanced in pancreatic cancer cell lines in vitro. Functional assays showed that shRNA-mediated knockdown of DSG3 decreased cell viability of pancreatic cancer cells and retarded the cell proliferation, migration and invasion. However, pcDNA-mediated over-expression of DSG3 exhibited reversed effect on pancreatic cancer cell progression. In addition, the in vivo assay demonstrated that transfection of shDSG3 lentiviruses into pancreatic cancer cells repressed the tumorigenicity of PDAC after the cancer cells were transplanted into mice subcutaneously. Elevated DSG3 expression promoted the phosphorylation of Src (p-Src), focal adhesion kinase (p-FAK) and AKT (p-AKT) in vitro, while silence of DSG3 reduced the expression of p-Src, p-FAK and p-AKT both in vitro and in vivo. In conclusion, DSG3, as an oncogene, contributed to the tumorigenicity of PDAC through activating Src–FAK signaling. [ABSTRACT FROM AUTHOR]

Abstract Pemphigus vulgaris (PV) is an autoimmune, blistering disease that affects the mucosa and skin. The current theory favors the concept that anti‐desmoglein (Dsg) 3 autoimmunity is the only pathogenic event needed to induce acantholysis. However, a few cases of active PV in the oral cavity had no detectable anti‐Dsg 3 antibody. The aim of this study was to evaluate the differences in clinical and laboratory findings, whether or not the anti‐Dsg 3 antibodies were present. This study was based on a retrospective review of 10 PV cases. The evaluation of the circulating autoantibody titers to Dsg 3 was conducted by using enzyme‐linked immunosorbent assay (ELISA). An index value of 20 or more was used as the cutoff for a positive reaction. Only five of the 10 PV cases had a positive Dsg 3 ELISA. There were no differences in clinical, cytological, histopathological, and direct immunofluorescence findings, whether or not the anti‐Dsg 3 antibodies were present. Of the five patients with a negative reaction at the time of diagnosis, the Dsg 3 ELISA became positive in the follow‐up period in three cases. In the remaining two cases, the Dsg 3 ELISA was consistently negative for 18 months. Dsg 3 ELISA was negative early in some PV cases. Therefore, PV acantholysis may precede the elevation of circulating anti‐Dsg 3 antibody levels. The diagnosis of PV should be considered based on comprehensive clinical, histopathological, and immunofluorescent criteria.

Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and oral mucous membrane. Tongue involvement occurs when most of the other common sites are concurrently affected or when the patient is in remission. PV is an autoimmune disease that may affect the invasive capacity of tongue tumors. An association between PV and cervical lymph node metastasis (CLNM) has been rarely reported in tongue cancer. Herein, we report a rare case of a 46-year-old man with early invasive squamous cell carcinoma (SCC) arising from PV of the tongue who presented with delayed CLNM. A 46-year-old male was referred to our Department of Oral and Maxillofacial Surgery from the Department of Dermatology with a chief complaint of pain due to tongue erosion. The history of the patient revealed the presence of severe PV. A biopsy confirmed the diagnosis of concomitant PV with microinvasive SCC in the tongue. Despite a T1 stage tongue tumor, the patient developed delayed CLNM with extranodal extension two months after the primary surgery. The present case underlines the association between PV, a chronic inflammatory disease of the oral cavity, and tongue SCC, and indicates the need for careful follow-up of patients with such inflammatory diseases. Furthermore, a biopsy should be performed in patients with PV of the tongue due to the potential for malignancy. Our findings indicate that PV may contribute to the invasion of SCCs and the promotion of lymph node metastasis. [ABSTRACT FROM AUTHOR]

The Hippo-YAP pathway serves as a central signalling hub in epithelial tissue generation and homeostasis. Yes-associated protein (YAP) is an essential downstream transcription cofactor of this pathway, with its activity being negatively regulated by Hippo kinase-mediated phosphorylation, leading to its cytoplasmic translocation or degradation. Our recent study showed phospho-YAP complexes with Desmoglein-3 (Dsg3), the desmosomal cadherin known to be required for junction assembly and cell–cell adhesion. In this study, we show that YAP inhibition by Verteporfin (VP) caused a significant downregulation of desmosomal genes and a remarkable reduction in desmosomal proteins, including the Dsg3/phospho-YAP complex, resulting in attenuation of cell cohesion. We also found the desmosomal genes, along with E-cadherin, were the YAP-TEAD transcriptional targets and Dsg3 regulated key Hippo components, including WWTR1/TAZ, LATS2 and the key desmosomal molecules. Furthermore, Dsg3 and phospho-YAP exhibited coordinated regulation in response to varied cell densities and culture durations. Overexpression of Dsg3 could compensate for VP mediated loss of adhesion components and proper architecture of cell junctions. Thus, our findings suggest that Dsg3 plays a crucial role in the Hippo network and regulates junction configuration via complexing with phospho-YAP.

• Acute thymic involution (ATI) occurs during imiquimod-induced dermatitis. • Desmoglein 3+ thymic epithelial cells decrease in number in imiquimod-induced ATI. • Desmoglein 3-specific thymic tolerance is impaired in imiquimod-induced ATI. The thymus plays an essential role in removing autoreactive T cells. Autoantigen-expressing thymic epithelial cells (TECs) contribute to the tolerogenic process. The thymus transiently shrinks as an acute thymic involution (ATI) under various inflammatory conditions. However, whether ATI occurs during local skin inflammation remains unclear, as does its influence on thymic immune tolerance. We investigated whether imiquimod-induced dermatitis causes ATI and impairs thymic immune tolerance against desmoglein 3 (Dsg3), an epidermal autoantigen of pemphigus vulgaris. 5% imiquimod cream was applied daily, at 62.5 mg/day (high dose group) or 31.25 mg/day (low dose group), for 1 week on the back of wild-type mice, and to wild-type mice that had undergone bone-marrow transplantation from Dsg3-specific T-cell receptor (TCR) transgenic- Rag2 −/− mice. Next, thymocytes, TECs and other immune cells were analyzed by flow cytometry. TEC-associated Dsg3 expression was also analyzed by immunofluorescence staining. Thymus weight and thymocyte number in all developmental stages decreased in a dose-dependent manner under imiquimod-induced dermatitis. The number of total TECs, specifically medullary, but not cortical, TECs, decreased in high and low dose groups. Accordingly, the number of Dsg3-experssing UEA-1+keratin 5+mTEC decreased in the thymus during imiquimod-induced dermatitis. Although Dsg3-sepcific transgenic thymocytes was usually deleted in the thymus under physiological condition by central tolerance, Dsg3-sepcific transgenic CD4+CD8− thymocytes significantly increased in number under imiquimod-induced dermatitis. These findings indicate a crosstalk between skin and thymus in adult mice and suggest that skin inflammation may impair thymic tolerance to autoantigens, such as Dsg3. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets. Methods RNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed. Results Ninety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung. Conclusion We identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung.

Aim of the study : Despite advances in surgical and radiotherapy techniques, the presence of lymph node metastasis drastically decreases the survival rate of patients with primary oral squamous cell carcinoma (OSCC). Thus the accurate pathological staging of the neck is critical. Desmoglein 3 (DSG3), a desmosomal cadherin protein is said to be highly expressed in head and neck squamous cell carcinoma (HNSCC) and in metastatic cervical lymph nodes, but absent in non-invaded nodes. With an aim to improve the sensitivity of tumour cell detection, we investigated the potential of DSG3 as an immunohistochemical marker for the detection of occult lymph node metastasis in patients with primary OSCC. Material and methods : Forty-seven lymph node specimens from 10 patients who underwent neck dissection for primary OSCC were immunostained with DSG3. Results : The DSG3 positivity was noted in the six positive lymph nodes. However, when using DSG3 as an immunohistochemical marker, no additional micrometastatic deposits were evident in the histologically negative nodes. Interestingly, tumour marker DSG3-positive macrophages could be identified within the subcapsular sinuses, medullary sinuses, and the interfollicular areas. Conclusions : Our findings suggest that although DSG3 is overexpressed in HNSCC, it is not specific and may not prove to be a potent immunohistochemical marker to detect micrometastasis. The role of tumour marker-positive macrophages within the lymph nodes needs to be investigated further.

Objective: To investigate the effects of desmoglein 3 (DSG3) gene mediating epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling pathway on inflammatory response and immune function of anaphylactic rhinitis (AR). Methods: Ten of the seventy male BALB/c mice were randomly selected as the normal control group, and the remaining 60 were used to construct the AR mice model. AR model mice were divided into 6 groups: model group (instilled with 5 μL saline), empty vector group (instilled with 5 μL of liposome and empty vector mixture), siRNA-DSG3 group (instilled with 5 μL of liposome and siRNA-DSG3 carrier mixture), AG1478 group (instilled with 5 μL of EGF/EGFR inhibitor AG1478), siRNA-DSG3+AG1478 group (instilled with 5 μL of liposome and siRNA-DSG3 carrier and EGF/EGFR inhibitor AG1478 mixture) and oe-DSG3 group, 10 in each group. After taking serum, each group of mice was sacrificed to get nasal mucosa tissues. HE staining was used to observe the pathological changes of nasal mucosa tissues in each group. The expression levels of DSG3, EGF and EGFR in nasal mucosa tissues of mice in each group were detected by qRT-PCR and western blot methods respectively. TUNEL staining was used to observe the apoptosis of nasal mucosa cells in mice. The expression of IgE, INF-γ, TNF-α, IL-2, IL-4 and IL-6 in serum of mice was determined by ELISA method. The immune adhesion function of red blood cells was detected by complement sensitization yeast hemagglutination method. Results: All the mice with AR showed different degrees of nasal mucosa injury and inflammatory cell infiltration, and silencing DSG3 or inhibiting the activity of EGF signaling pathway could alleviate the nasal mucosa injury. Compared with control group, the INF-γ and IL-2 levels of serum in AR model mice were significantly decreased; IgE, TNF-α, IL-4 and IL-6 levels were significantly increased (all P

Pemphigus vulgaris (PV) is a rare blistering disease caused by IgG autoantibodies against the epidermal adhesion molecules desmoglein (Dsg)3 and Dsg1 providing a well-characterized paradigm of an antibody-mediated organ-specific autoimmune disease. In PV patients who have achieved clinical remission after B cell-depleting therapy, relapses often coincide with a reoccurrence of B cells and Dsg-specific autoantibodies. Here, we analyzed Dsg3-specific B cell subpopulations (i.e., total CD19+ B cells, CD19+CD27−B cells, CD19+CD27+ memory B cells, and CD19+CD27hiCD38hi plasmablasts) in peripheral blood of both PV patients (n = 14) at different stages of disease and healthy individuals (n = 14) by flow cytometry using fluorescently labeled recombinant human Dsg3 protein. Applying this approach, Dsg3-specific B cells could be detected at low frequencies (0.11–0.53% of CD19+ B cells) and numbers of Dsg3-specific memory B cells were significantly increased in PV patients in clinical remission receiving minimal immunosuppressive therapy. Finally, we confirmed in vitro that Dsg3-reactive memory B cells were able to produce anti-Dsg3 IgG autoantibodies upon ex vivo activation. Thus, monitoring of Dsg3-specific B cells in PV is of particular interest to further characterize the immunopathogenesis of PV.

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve from both Dsg-autoreactive and non-binding precursors. We observe an altered distribution of CD4 + T cell subsets within pemphigus lesions, including an imbalance of Th17/Th2 cells. Significantly, we identify a distinct subpopulation of Th17 cells expressing CXCL13 and IL-21 within pemphigus lesions, implying its pivotal role in B cell recruitment and local production of autoantibodies. Furthermore, we characterize multiple clonally expanded CD8 + subpopulations, including effector GMZB + and GMZK + subsets with augmented cytotoxic activities, within pemphigus lesions. Chemokine-receptor mapping uncovers cell-type-specific signaling programs involved in the recruitment of T/B cells within pemphigus lesions. Our findings significantly contribute to advancing the understanding of the heterogeneous immune microenvironment and the pathogenesis of pemphigus cutaneous lesions, thereby providing valuable insights for potential therapeutic interventions in this disease., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: To assess the correlation between the levels of anti-desmoglein-1 and anti-desmoglein-3 autoantibodies and disease severity in pemphigus patients., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-β stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).

Chronic rhinosinusitis (CRS) is a common disease characterized by inflammation of the nose and paranasal sinuses lasting over 12 weeks. This study aims to evaluate the effect of desmoglein 3 (DSG3) on inflammatory response and goblet cell mucin secretion in a mouse model of CRS. The CRS-related differentially expressed genes and disease genes were screened using microarray-based gene expression analysis. Subsequently, CRS mouse models were established. The levels of pro-inflammatory factors TNF-α, IL-6, and IL-8 were measured by ELISA. In addition, loss-of-function experiment was conducted using siRNAs targeting DSG3 and β-catenin. The secretion of mucins MUC5B and MUC5AC in goblet cells was detected, and the apoptosis of goblet cells was assessed. The regulatory effect of DSG3 on the Wnt/β-catenin signaling pathway was analyzed by determining the mRNA and protein levels of DSG3, Wnt, β-catenin, and GSK3β. DSG3 was identified to be an upregulated gene in CRS, which was further documented in CRS mice models. Elevated inflammation and mucin production were noted in CRS mice models. Also, it was found that DSG3 or β-catenin silencing could decrease the levels of TNF-α, IL-6, and IL-8, and the positive rates of MUC5B and MUC5AC while enhancing goblet cell apoptosis. The Wnt/β-catenin signaling pathway was blocked by DSG3, evidenced by downregulated Wnt and β-catenin as well as upregulated GSK3β mRNA and protein levels. Overall, this study provides evidence that silencing DSG3 could inhibit the activation of the Wnt/β-catenin signaling pathway, thus alleviating CRS. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is a rare blistering disease caused by IgG autoantibodies against the epidermal adhesion molecules desmoglein (Dsg)3 and Dsg1 providing a well-characterized paradigm of an antibody-mediated organ-specific autoimmune disease. In PV patients who have achieved clinical remission after B cell-depleting therapy, relapses often coincide with a reoccurrence of B cells and Dsg-specific autoantibodies. Here, we analyzed Dsg3-specific B cell subpopulations (i.e., total CD19+ B cells, CD19+CD27−B cells, CD19+CD27+ memory B cells, and CD19+CD27hiCD38hi plasmablasts) in peripheral blood of both PV patients (n = 14) at different stages of disease and healthy individuals (n = 14) by flow cytometry using fluorescently labeled recombinant human Dsg3 protein. Applying this approach, Dsg3-specific B cells could be detected at low frequencies (0.11–0.53% of CD19+ B cells) and numbers of Dsg3-specific memory B cells were significantly increased in PV patients in clinical remission receiving minimal immunosuppressive therapy. Finally, we confirmed in vitro that Dsg3-reactive memory B cells were able to produce anti-Dsg3 IgG autoantibodies upon ex vivo activation. Thus, monitoring of Dsg3-specific B cells in PV is of particular interest to further characterize the immunopathogenesis of PV. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is an autoimmune, blistering disease that affects the mucosa and skin. The current theory favors the concept that anti‐desmoglein (Dsg) 3 autoimmunity is the only pathogenic event needed to induce acantholysis. However, a few cases of active PV in the oral cavity had no detectable anti‐Dsg 3 antibody. The aim of this study was to evaluate the differences in clinical and laboratory findings, whether or not the anti‐Dsg 3 antibodies were present. This study was based on a retrospective review of 10 PV cases. The evaluation of the circulating autoantibody titers to Dsg 3 was conducted by using enzyme‐linked immunosorbent assay (ELISA). An index value of 20 or more was used as the cutoff for a positive reaction. Only five of the 10 PV cases had a positive Dsg 3 ELISA. There were no differences in clinical, cytological, histopathological, and direct immunofluorescence findings, whether or not the anti‐Dsg 3 antibodies were present. Of the five patients with a negative reaction at the time of diagnosis, the Dsg 3 ELISA became positive in the follow‐up period in three cases. In the remaining two cases, the Dsg 3 ELISA was consistently negative for 18 months. Dsg 3 ELISA was negative early in some PV cases. Therefore, PV acantholysis may precede the elevation of circulating anti‐Dsg 3 antibody levels. The diagnosis of PV should be considered based on comprehensive clinical, histopathological, and immunofluorescent criteria. [ABSTRACT FROM AUTHOR]

Desmoglein (DSG) 3 is overexpressed in oral squamous cell carcinoma (OSCC). Epidermal growth factor receptor (EGFR) inhibitor cetuximab is widely used for OSCC treatment. Several evidences suggest a correlation between DSG3 and EGFR in epidermal keratinocytes. EGFR inhibition has been shown to enhance cell‐cell adhesion and induce terminal differentiation in epidermal cells. Thus, here we investigated the DSG3‐EGFR interaction in OSCC and its effect on cetuximab treatment. Cell lines established from the primary tumor and metastatic lymph nodes of four OSCC patients and three commercial OSCC cell lines were used for the experiments. Cells from metastatic lymph nodes of each patient expressed increased DSG3 and EGFR than cells from the primary tumor in the same patient. Cetuximab treatment increased DSG3 expression by up to 3.5‐fold in seven of the 11 cell lines. A high calcium concentration increased the expression of DSG3 and EGFR in a dose‐dependent manner. Strikingly, a high calcium‐associated DSG3 induction enhanced cetuximab efficacy by up to 23% increase in cetuximab‐low‐sensitive cell lines. Our findings also suggest a correlation between DSG3 and EGFR in OSCC, and this affects cetuximab treatment efficacy. [ABSTRACT FROM AUTHOR]