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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 erythematosus (PE) is a rare disorder that belongs to a group of chronic autoimmune blistering diseases. It is a form of pemphigus with an overlapping clinical and immunological presentation of pemphigus foliaceus and lupus erythematosus, mediated by autoantibodies targeting desmoglein 1. It has a broad clinical spectrum, and severe cases can result in multi-organ compromise. To date, there is no established treatment for severe cases of PE. We describe a case of a previously healthy patient with a 4-month clinical course of generalized painful erythematous desquamative plaques and blisters, associated with a 10 kg weight loss. The clinical and histopathological findings were consistent with PE. An adjusted rituximab protocol was used, achieving disease remission within 20 days. Rituximab is the mainstay of therapy and a well-known effective treatment for pemphigus vulgaris with a prolonged remission; nevertheless, there are no established protocols and limited evidence in PE. [ABSTRACT FROM AUTHOR]

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]

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.

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.

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. [ABSTRACT FROM AUTHOR]

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.

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling.

Pemphigus foliaceus (PF) is part of a group of rare and serious autoimmune diseases, which is mediated by autoantibodies directed against cellular adhesion proteins present in the skin and is characterized histologically by acantholysis and clinically by the presence of blisters and cutaneous crusts. We report a case of PF in a 22-year-old woman presenting with widespread blisters and crusts, without mucosal involvement, and a sui generis smell. The diagnosis is later confirmed by the findings of histopathology and direct immunofluorescence and, due to demographic characteristics, endemic PF or fogo selvagem is inferred. [ABSTRACT FROM AUTHOR]

Abstract: Fogo selvagem or endemic pemphigus foliaceus is an autoimmune acantholytic anti-cadherin bullous disease that primarily affects seborrheic areas, which might disseminate. Brazil has the world's largest number of patients, mainly in the Central-West region, but the disease has also been reported in other South American countries. It affects young people and adults who have been exposed to rural areas, with occurrence of familial cases. Anti-desmoglein-1 autoantibodies are directed against desmosomal structures, with loss of adhesion of the upper layers of the epidermis, causing superficial blisters. The etiology is multifactorial and includes genetic, immune, and environmental factors, highlighting hematophagous insect bites; drug-related factors are occasionally involved. Flaccid blisters readily rupture to yield erosive-crusty lesions that sometimes resemble seborrheic dermatitis, actinic keratosis, and chronic cutaneous lupus erythematosus. The clinical presentation varies from localized to disseminated lesions. Clinical suspicion should be confirmed with histopathological and immunofluorescence tests, among others. The progression is usually chronic, and therapy varies according to clinical presentation, but generally requires systemic corticosteroid therapy associated with adjuvant immunosuppressive treatment to decrease the adverse effects of corticosteroids. Once the disease is under control, many patients remain stable on low-dose medication, and a significant proportion achieve remission.

Pemphigus foliaceus (PF) is one of the two main forms of pemphigus and is characterized by circulating IgG to the desmosomal cadherin desmoglein 1 (DSG1) and by subcorneal blistering of the skin. The pathomechanism of blister formation in PF is unknown. Previously we have shown that PF IgG induces aggregation of DSG1, plakoglobin (PG), and IgG outside of desmosomes, what in immunofluorescence of PF patient skin visualizes as a granular IgG deposition pattern with a limited number of coarse IgG aggregates between cells. Here we have investigated the fate of these aggregates in skin and found that these are cleared by endocytosis. We performed double immunofluorescence staining on snap-frozen skin biopsies of six PF patients for the following molecules: IgG, the desmosomal proteins DSG1 and DSG3, desmocollins 1 and 3, PG, desmoplakin and plakophilin 3, and for the endosomal marker early endosomal antigen 1 and the lysosomal markers cathepsin D and lysosomal-associated membrane protein 1. Endosomes were present in all cells but did not make contact with the aggregates in the basal and suprabasal layers. In the higher layers they moored to the aggregates, often symmetrically from two adjacent cells, and IgG, DSG1, and PG were taken up. Finally these endosomes became localized perinuclear. Endocytosis was only observed in perilesional or lesional skin but not in non-lesional skin. Older immunoelectron microscopic studies have suggested that in PF skin endocytosis of detached desmosomes takes place but we found no other desmosomal proteins to be present in these endosomes. Double staining with cathepsin D and LAMP-1 revealed no overlap with IgG, DSG1, or PG suggesting that lysosomes have no role in the clearing process. Collectively, our results show that endocytosis is part of the pathogenic process in PF but that no detached desmosomes are taken up but instead the deposited IgG is taken up together with DSG1 and PG.

Pemphigus foliaceus (PF) is one of the two main forms of pemphigus and is characterized by circulating IgG to the desmosomal cadherin desmoglein 1 (DSG1) and by subcorneal blistering of the skin. The pathomechanism of blister formation in PF is unknown. Previously we have shown that PF IgG induces aggregation of DSG1, plakoglobin (PG), and IgG outside of desmosomes, what in immunofluorescence of PF patient skin visualizes as a granular IgG deposition pattern with a limited number of coarse IgG aggregates between cells. Here we have investigated the fate of these aggregates in skin and found that these are cleared by endocytosis. We performed double immunofluorescence staining on snap-frozen skin biopsies of six PF patients for the following molecules: IgG, the desmosomal proteins DSG1 and DSG3, desmocollins 1 and 3, PG, desmoplakin and plakophilin 3, and for the endosomal marker early endosomal antigen 1 and the lysosomal markers cathepsin D and lysosomal-associated membrane protein 1. Endosomes were present in all cells but did not make contact with the aggregates in the basal and suprabasal layers. In the higher layers they moored to the aggregates, often symmetrically from two adjacent cells, and IgG, DSG1, and PG were taken up. Finally these endosomes became localized perinuclear. Endocytosis was only observed in perilesional or lesional skin but not in non-lesional skin. Older immunoelectron microscopic studies have suggested that in PF skin endocytosis of detached desmosomes takes place but we found no other desmosomal proteins to be present in these endosomes. Double staining with cathepsin D and LAMP-1 revealed no overlap with IgG, DSG1, or PG suggesting that lysosomes have no role in the clearing process. Collectively, our results show that endocytosis is part of the pathogenic process in PF but that no detached desmosomes are taken up but instead the deposited IgG is taken up together with DSG1 and PG. [ABSTRACT FROM AUTHOR]

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Abstract: Bullous pemphigoid is a blistering autoimmune disease characterized by two hemidesmosomal proteins (anti-BP180 and 230). Pemphigus, by contrast, is characterized by two autoantibodies (anti-desmoglein 1 and 3). Coexistence of autoantibodies of bullous pemphigoid and pemphigus in a patient is rare. A 25-year-old male patient was admitted to our hospital, reporting a 3-month history of multiple papules, vesicles, and erosions over an extensive erythema on the entire body. Laboratory tests showed high levels of serum IgE, anti-BP180 antibodies, and anti-desmoglein 1 and 3. Histopathologic and immunopathologic features were characterized by bullous pemphigoid. No improvement was seen with systemic corticosteroid therapy, however, pulse corticosteriod therapy combined with methylprednisolone, immunosuppressants, immunomodulators, and plasmapheresis led to the recovery of his condition with numerous milia.

Pemphigus vulgaris lesions have a tendency to localize around natural body orifices. The aim here was to analyze the involvement of nail apparatus in pemphigus vulgaris. Sixty seven ethnic Poles suffering from pemphigus vulgaris on photographic files archiving initial presentation were retrospectively evaluated. Pemphigus vulgaris was diagnosed using combination of clinical data, H+E histology, direct immunofluorescence of plucked scalp hair and/or perilesional tissue also for IgG1 and IgG4 deposits evaluation, indirect immunofluorescence on mosaic substrate and/or monkey esophagus, mono-analyte ELISA with desmoglein 1/3 or multi-analyte ELISA. The nail apparatus involvement was found in 9 of 67 patients (13.4%; 3 females and 6 males). Periungual fingernail lesions were found in 6 patients (2 females, 4 males), whereas periungual toenail lesions in just 3 patients (1 female, 2 males). Our patients nail apparatus changes included, by order of frequency, paronychia, nail discoloration, onychorrhexis, Beau lines, periungual hemorrhages, onychomadesis, cross-ridging, onycholysis, and trachyonychia. The average time between the onset, as recalled by patients, and the diagnosis of pemphigus vulgaris with direct immunofluorescence was not statistically different in PV patients with and without nail apparatus lesions. In this article the molecular and immunological rationale for of periungual involvement is discussed. Our single-center study suggests that nail apparatus involvement is infrequent in pemphigus vulgaris in ethnic Poles. Due to the fact that nail apparatus lesions in pemphigus vulgaris may clinically resemble onychomycosis, giving the proper diagnosis can be difficult particularly when other lesions are overlooked or misinterpreted.

Desmosomes and corneodesmosomes are the most important adhering junctions, providing strength for the epidermal sheet structure made of living keratinocytes and enucleated stratum corneum corneocytes, respectively. These junctions are connected directly with transmembrane desmosomal cadherins, desmogleins (Dsgs), and desmocollins (Dscs); mainly Dsg1/Dsc1 and Dsg3/Dsc3 in desmosomes, and Dsg1/Dsc1 with corneodesmosin in corneodesmosomes. Dsgs and Dscs are associated with several proteins at their inner cytoplasmic domains to anchor keratin intermediate filaments. Desmosomes are not static, but dynamic units that undergo regular remodeling to allow for keratinocyte outward-migration in the epidermis. In corneodesmosomes, this dynamic nature of desmosomes is lost by fixing desmosomal cadherins with corneodesmosin at the intercellular domain of desmosomes and possibly with the formation of peptide bonds by activation of transglutaminase-1 at the intracellular face of desmosomes. Immediately after formation, corneodesmosomes normally commit to degradation, which is complicatedly regulated by proteolytic cleavage of their respective extracellular portions, via kallikrein-regulated peptidases and cathepsins. This proteolytic activity is in turn controlled by a variety of inhibitory agents, including protease inhibitors, cholesterol sulfate, and an acidic gradient. The impairment of protease control causes keratinization disorders. This review focuses on the regulation of corneodesmosome remodeling in relation to disorders of the stratum corneum.

Abstract: Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life‐threatening inherited condition caused by bi‐allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome‐causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits. [ABSTRACT FROM AUTHOR]

BACKGROUND: Trichoscopy is becoming increasingly popular in diagnosing hair and scalp diseases. Scalp involvement in pemphigus is common. The scalp may be the first or only site of clinical manifestation of the disease. OBJECTIVE: The aim of this study was to analyze whether trichoscopy may be useful in aiding differential diagnosis of scalp lesions in patients with pemphigus vulgaris and pemphigus foliaceus. METHODS: Trichoscopy was performed in 19 patients with scalp lesions in the course of pemphigus (9 patients with pemphigus vulgaris and 10 with pemphigus foliaceus). In all patients, the diagnosis of scalp pemphigus was confirmed by histopathology. The working magnification was 20-fold and 70-fold. RESULTS: The most frequently observed trichoscopy features of pemphigus lesions were: extravasations (18/19; 94.7%) and yellow hemorrhagic crusts (11/19; 57.9%). Yellow dots with whitish halo were observed in 6/19 (31.6%) patients with pemphigus. White polygonal structures were observed in pemphigus foliaceus (6/10; 60%), but not in pemphigus vulgaris. Vascular abnormalities were more frequent in pemphigus vulgaris, when compared to pemphigus foliaceus, and were associated with a severe course of disease. Linear serpentine vessels were the most frequent vascular abnormality in patients with pemphigus vulgaris and pemphigus foliaceus (77.8% and 30%, respectively). CONCLUSION: Trichoscopy may serve as a useful supplementary method in the differential diagnosis of pemphigus, especially in cases of desquamative or exudative lesions limited to the scalp. Extravasations, yellow hemorrhagic crusts, yellow dots with whitish halo, white polygonal structures and linear serpentine vessels are trichoscopy features which may suggest the diagnosis of pemphigus.

Background Pemphigus foliaceus (PF) is an autoimmune blistering disease caused by autoantibodies (Abs) against desmoglein 1 (Dsg1). PF sera contain polyclonal Abs which are heterogeneous mixture of both pathogenic and non-pathogenic Abs, as shown by isolation of monoclonal Abs (mAbs). Objective To investigate how pathogenic and non-pathogenic anti-Dsg1 Abs contribute to blister formation in PF. Methods Using organ-cultured human skin, we compared the effect of a single pathogenic anti-Dsg1 IgG mAb, a single non-pathogenic anti-Dsg1 IgG mAb, and their mixture on blister formation as analyzed by histology, subcellular localization of IgG deposits and desmosomal proteins by confocal microscopy, and desmosomal structure by electron microscopy. In addition, we measured keratinocyte adhesion by an in vitro dissociation assay. Results 24 h after injection, a single pathogenic anti-Dsg1 IgG caused a subcorneal blister with IgG and Dsg1 localized linearly on the cell surface of keratinocytes. A single non-pathogenic anti-Dsg1 IgG bound linearly on the keratinocytes but did not induce blisters. A pathogenic and a non-pathogenic IgG mAb injected together caused an aberrant granular pattern of IgG and Dsg1 in the lower epidermis with blister formation in the superficial epidermis. Electron microscopy demonstrated that the mixture of mAbs shortened desmosomal lengths more than a single mAb in the basal and spinous layers. Furthermore, although Dsg1 clustering required both cross-linking of Dsg1 molecules by the non-pathogenic IgG plus a pathogenic antibody, the latter could be in the form of a monovalent single chain variable fragment, suggesting that loss of trans-interaction of Dsg1 is required for clustering. Finally, a p38MAPK inhibitor blocked Dsg1 clustering. When pathogenic strength was measured by the dissociation assay, a mixture of pathogenic and non-pathogenic IgG mAbs disrupted keratinocyte adhesion more than a single pathogenic mAb. This pathogenic effect was only partially suppressed by the p38MAPK inhibitor. Conclusion These findings indicate that a polyclonal mixture of anti-Dsg1 IgG antibodies enhances pathogenic activity for blister formation associated with p38MAPK-dependent Dsg1 clustering and that not only pathogenic antibodies but also non-pathogenic antibodies coordinately contribute to blister formation in PF. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV), pemphigus foliaceus (PF), and paraneoplastic pemphigus (PNP) are a group of rare and fatal blistering diseases involving autoantibodies that target desmosomal proteins. The pathogenesis of pemphigus involves the production of activated B-cells and IgG with stimulation by IL-4 by T-helper 2 cells. Clinically these diseases present most often with epidermal erosions of the mucosae and skin caused by rapid rupturing of flaccid bullae. These lesions correlate histologically with splits forming in the epidermis, leaving a blister roof composed of a few cell layers. Standard treatment of pemphigus involves oral corticosteroids, often with the addition of adjuvant therapies, to improve disease control, minimize corticosteroids side-effects, and increase the odds of remission. [ABSTRACT FROM AUTHOR]

Desmosomes and corneodesmosomes are the most important adhering junctions, providing strength for the epidermal sheet structure made of living keratinocytes and enucleated stratum corneum corneocytes, respectively. These junctions are connected directly with transmembrane desmosomal cadherins, desmogleins (Dsgs), and desmocollins (Dscs); mainly Dsg1/Dsc1 and Dsg3/Dsc3 in desmosomes, and Dsg1/Dsc1 with corneodesmosin in corneodesmosomes. Dsgs and Dscs are associated with several proteins at their inner cytoplasmic domains to anchor keratin intermediate filaments. Desmosomes are not static, but dynamic units that undergo regular remodeling to allow for keratinocyte outward-migration in the epidermis. In corneodesmosomes, this dynamic nature of desmosomes is lost by fixing desmosomal cadherins with corneodesmosin at the intercellular domain of desmosomes and possibly with the formation of peptide bonds by activation of transglutaminase-1 at the intracellular face of desmosomes. Immediately after formation, corneodesmosomes normally commit to degradation, which is complicatedly regulated by proteolytic cleavage of their respective extracellular portions, via kallikrein-regulated peptidases and cathepsins. This proteolytic activity is in turn controlled by a variety of inhibitory agents, including protease inhibitors, cholesterol sulfate, and an acidic gradient. The impairment of protease control causes keratinization disorders. This review focuses on the regulation of corneodesmosome remodeling in relation to disorders of the stratum corneum. [ABSTRACT FROM AUTHOR]

Although the role that Autoimmune Regulator (Aire) plays in the induction of central tolerance is well known, the precise cellular and molecular mechanisms are still unclear and debated. In the prevailing view, Aire serves mainly as a direct inducer of tissue-specific antigens (TSAs). However, there is a growing amount of evidence suggesting that Aire modulates the differentiation program of medullary thymic epithelial cells (mTECs), which may directly contribute to the negative selection of self-reactive thymocytes. In addition, Aire has been shown to regulate the expression of many intrathymic chemokines that are required for the proper localization of thymocytes and dendritic cells (DCs), and thus are potentially important for direct and indirect self-antigen presentation in the thymic medulla. Further, recent evidence suggests that the induction of certain antigen-specific Tregs that translocate to tumors and peripheral tissues can be Aire dependent and may contribute to tissue-specific tolerance. This review summarizes the current understanding of the effects of Aire on these alternative mechanisms for the induction of Aire-induced central tolerance.

The epidermis forms during the course of a complex differentiation process known as cornification, which culminates with the formation of the epidermal barrier. The epidermal barrier serves as a vital line of defense against the environment and mainly consists of 3 elements: intracellular keratin filaments, intercellular lipids, and the cornified cell envelope. Adequate epidermal barrier function is also critically dependent on normal shedding of terminally differentiated keratinocytes, a process termed desquamation, which requires the dissolution of cell-cell junctions in the upper granular layers. Although much has been learned about epidermal differentiation through the deciphering of the molecular basis of various cornification disorders, less is currently known about the mechanisms regulating epidermal desquamation and disorders resulting from disruption of this process. Netherton syndrome, peeling skin syndrome type B, and skin dermatitis—multiple severe allergies—metabolic wasting syndrome are 3 autosomal recessive conditions resulting from aberrant regulation of epidermal desquamation. The deciphering of their pathogenesis has not only broadened our understanding of this process but has also shed new light on clinical and mechanistic links between allergic reactions and abnormal desquamation, substantiating the notion that allergic manifestations might, under some circumstances, be the sole consequence of a primary epidermal defect. [ABSTRACT FROM AUTHOR]

Background The twin goals of long-term disease control and minimizing toxicities related to immunosuppression necessitate efforts to find effective steroid-sparing agents in the management of patients with autoimmune bullous diseases. Pemphigus especially requires a long view, because the disease can persist throughout a patient's lifetime, yet few clinical trial reports exist to guide the practitioner. Objectives We review the response of pemphigus patients to tetracycline, doxycycline, or minocycline plus niacinamide (TCN/NAM) as steroid-sparing therapy and to determine the effects of TCN/NAM on autoantibody levels during the long-term treatment of pemphigus. Methods This was a retrospective chart review in a private medical dermatology practice setting of all pemphigus patients treated between 1993 and 2013. Clinical responses to TCN/NAM therapy after initial high-dose steroid induction therapy and pemphigus antibody levels were recorded over the course of disease flares and treatment cycles along with any related side effects. Anti-desmoglein 1 and 3 titers were compared in a subset of patients over time, and a statistical analysis was performed to correlate the clinical response with antibody levels. Results Fifty-one pemphigus patients (43 with pemphigus vulgaris, 7 with pemphigus foliaceous, and 1 with pemphigus erythematosus) received at least 3 months of TCN/NAM, and 16 patients with pemphigus vulgaris had 1 set of pemphigus antibody titers correlating to a baseline/flare and clinical remission. TCN/NAM was associated with disease control in 43 of 51 patients, with a duration of response ranging from 1 to 13 years (mean, 3.14 ± 2.97 years). Thirteen of 51 patients needed no additional treatment for complete disease control, while 33 of 51 needed intermittent topical clobetasol or short courses of oral steroids for long-term management. There were 5 nonresponders. Antidesmoglein titers trended lower in TCN/NAM responders, but only desmoglein 3 approached statistical significance (anti-desmoglein 1, P = .21; anti-desmoglein 3, P = .02). Limitations This is a retrospective analysis from a single practice. A lack of serial autoantibody titers limited statistical analyses. Conclusion TCN/NAM may be useful as a steroid-sparing therapy for pemphigus. [ABSTRACT FROM AUTHOR]

The patient was a 47-year-old female who presented with skin and oral mucosal lesions. Edematous erythema and pigmentation with crusts were observed on the sinciput, precordium and upper back, and gingival erosion and redness were seen in the oral cavity. Clinically, pemphigus vulgaris (PV) was suspected. However, blood examination results were positive for antidesmoglein 1 antibody, but negative for anti-Dsg 3 antibody. Histopathological examination and direct immunofluorescence microscopic observation revealed superficial vesicular formation and IgG and C3 deposits in the epithelial cell membranes. A diagnosis of pemphigus foliaceus (PF) was made. Regarding the gingival lesions, histopathological cleavage of the suprabasal cell layer was detected, and direct immunofluorescence microscopy found intercellular IgG and C3 deposits in almost the entire epithelial cell layer. These findings were compatible with PV. As there was a contradiction between the clinical features and laboratory data, we further performed immunoblotting analysis. Autoantibodies against periplakin and C-terminal of the 180-kDa bullous pemphigoid antigen (BP 180) were detected. However, these autoantibodies were not considered to pathogenic. We report a rare case of anti-Dsg 1 antibody-positive and anti-Dsg 3 negative pemphigus with oral mucosal lesions. [ABSTRACT FROM AUTHOR]

مقدمه: پمفیگوس فولیاسه، یکی از بیماریهای پوستی اتوایمیون است که بوسیله حضور آنتی بادیهای آنتیمیگردد. تصور میشود تشکیل این آنتی بادیها، از طریق وکتورهای بیماریهای انگلی مانند لیشمانیازیس که در مناطق آندمیک پمفیگوس فولیاسه شیوع فراوانتری دارند واسطه گری میشود. از آنجا که انواع غیر پاتولوژیک این آنتی بادی در بیماران مبتلا به اینگونه بیماریهای انگلی در مناطق آندمیک پمفیگوس فولیاسه یافت شده است، این نظریه می‌تواند توسط یافتن این آنتی بادی در بیماران مبتلابه بیماریهای انگلی در مناطق غیر آندمیک پمفیگوس فولیاسه تایید گردد. بنابر این مطالعهجهت ارزیابی وجود این آنتی بادی در بیماران مبتلا به لیشمانیوز جلدی در شهر اصفهانبه عنوان منطقه اندمیک لیشمانیوز پوستی و منطقه غیر آندمیک پمفیگوس فولیاسه طراحی گردید. روش‌ها: :سرم خون بیماران مبتلا به لیشمانیوز پوستی که توسط علائم بالینی و اسمیر مستقیم تایید شده بود، جدا شده و وجود آنتی بادی توسط تکنیک تشخیصی الایزا مورد ارزیابی قرار گرفت. یافته‌ها: 56 بیمار از 58 بیمار مورد مطالعه ما از نظر وجود این آنتی بادی منفی بودند. یک بیمار از نظر وجود این آنتی بادی به میزان حدواسط و یک بیمار در حد مثبت ارزیابی شد. نتیجه‌گیری: نتایج این مطالعه، نظریه نقش ناقل بیماری انگلی لیشمانیوز پوستی را در تشکیل این آنتی بادی Anti-DSG1 را تایید نمی کند.احتمال دخالت سایر عوامل مانند حضور پشه‌های سیمولیوم نیگریمانوم را در تشکیل این آنتی بادیقابل طرح می‌باشد.

Many skin infections are caused by Staphylococcus aureus, a bacterial pathogen that produces virulence factors associated with these conditions such as exfoliative toxins A and B (ETA, ETB) and the leukotoxin Panton–Valentine leukocidin (PVL). Herein, we examine the potential of skin-infecting S. aureus to produce virulence factors and their impact on the local immune response. Toxin gene profiles were generated from 188 S. aureus isolated as single infecting organisms from skin lesions and demonstrated a higher potential to express ETA, ETB, and PVL than community isolates ( p < 0.001). Within the study isolate group, the prevalence of genes encoding PVL was higher among methicillin-resistant S. aureus (MRSA; n = 49), while genes encoding ETs were more prevalent in methicillin-susceptible S. aureus (MSSA; n = 139). When lesion-associated white blood cell (WBC) counts were dichotomized into high- or low-WBC-count-associated bacteria, the gene for ETA was found to be associated with a low WBC count among MSSA ( p = 0.001). The ETA-induced mouse model of staphylococcal scalded skin syndrome was used to investigate the link between ETA and cytokine production. Elevated IL-6 levels in the serum and increased expression of IL-6 mRNA in the skin were detected in response to ETA exposure. These findings were recapitulated in vitro using primary human keratinocytes. Thus, S. aureus may influence the local immune response via ETA cleavage of desmoglein 1 and the induction of cutaneous IL-6 expression. [ABSTRACT FROM AUTHOR]

Abstract: Background: Desmoglein 1 (Dsg1), the pemphigus foliaceus (PF) antigen, is produced as a precursor (preDsg1) and is transported to the cell surface as the mature form (matDsg1). Recent studies show that B cells from North American individuals without pemphigus can potentially produce anti-preDsg1 IgG antibodies, but ELISA screening of large numbers of normal people in North America and Japan hardly ever shows circulating antibodies against preDsg1 or matDsg1. In contrast, in Tunisia, where PF is endemic, anti-Dsg1 IgGs are frequently detected in healthy individuals. Objective: To characterize these anti-Dsg1 antibodies from normal individuals in Tunisia. Methods: Sera from 16 healthy individuals and 9 PF patients in the endemic PF area in Tunisia, and sera from Japanese non-endemic PF patients were analyzed by immunoprecipitation-immunoblotting using recombinant proteins of preDsg1, matDsg1, and domain-swapped Dsg1/Dsg2 molecules. Results: Sera from normal Tunisian individuals reacted to preDsg1 alone (8/16) or more strongly to preDsg1 than to matDsg1 (7/16), while those from all Tunisian PF patients and Japanese non-endemic PF patients reacted similarly to preDsg1 and matDsg1, or preferentially to matDsg1. The epitopes recognized by anti-Dsg1 IgGs from normal Tunisian individuals were more frequently found in the C-terminal extracellular domains (EC3 to EC5), while those in Tunisian endemic PF patients were more widely distributed throughout the extracellular domains, suggesting IgGs against EC1 and EC2 developed during disease progression. Conclusions: These findings indicate that IgG autoantibodies against Dsg1 are mostly raised against preDsg1 and/or C-terminal domains of Dsg1 in healthy Tunisians in the endemic area of PF. [Copyright &y& Elsevier]

There is mounting evidence that Th2 cytokines adversely affect skin barrier functions and contribute to the pathogenesis of atopic dermatitis ( AD). AD is also characterized by abnormal cohesion in the stratum corneum ( SC). However, the contribution of Th2 cytokines to this abnormality remains unknown. This study examined the effects of IL-4, a prototypic Th2 cytokine, on the cohesion of the SC. Structural and physiological assessments revealed that repeated intradermal injections of IL-4 compromised the cohesion of the SC of normal hairless mice. Two potential mechanisms were explored to account for the altered cohesion. First, IL-4 decreased the amount of corneodesmosomes and down-regulated the expression of desmoglein 1, but not of corneodesmosin ( CDSN) or loricrin expression, in murine skin and in cultured human keratinocytes ( KC). IL-4 did not affect the skin surface p H, and in situ zymography revealed no net change in total serine protease activity in the IL-4-treated SC. Yet, IL-4 enhanced expression of kallikrein ( KLK)7, while simultaneously down-regulating KLK5 and KLK14. Finally, IL-4 did not alter the expression of the lympho-epithelial Kazal-type inhibitor ( LEKTI) in KC. This study suggests that IL-4 abrogates the cohesion of SC primarily by reducing epidermal differentiation. [ABSTRACT FROM AUTHOR]

Fogo selvagem is an endemic form of pemphigus foliaceus with its own demographic characteristics. It presents in children and teenagers and it is characterized by subcorneal blisters due to auto-antibodies against desmoglein 1. We report two patients from the Colombian Amazon region with this diagnosis. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is a life-threatening, autoimmune blistering disease of the mucocutaneous surfaces. Intraepidermal suprabasilar blistering and acantholysis in PV is caused by bound and circulating IgG autoantibodies against keratinocyte cell-surface antigens, namely desmosomal desmoglein 3 and desmoglein 1. A patient taking ramipril with chancre of pemphigus, i.e. single initial persistent lesion, which in this patient was localized on the scalp and heralded further PV mucosal lesions for 8 months is described. Direct immunofluorescence on perilesional skin revealed IgG(+), IgG1(+/-), IgG4(++) and C3(+/-) pemphigus deposits in the follicular and extrafollicular epithelium. Indirect immunofluorescence on monkey oesophagus revealed IgG and IgG4 antibodies directed against desmosomal proteins of keratinocytes. ELISA demonstrated elevated serum levels of IgG autoantibodies directed against desmoglein 3, but not desmoglein 1. Both the symptoms and progression of mucosal dominant PV may vary widely. Controlled trials on the treatment of autoimmune blistering dermatoses are still scarce. Individual approach in identifying and subsequent elimination of the plausible triggering or/and disease sustaining factors should be a common practice. [ABSTRACT FROM AUTHOR]

To maintain stratum corneum integrity while simultaneously desquamating at a steady rate, degradation of corneodesmosomes must proceed in a controlled manner. It is unknown why corneodesmosomes are present only at the cell periphery in the upper stratum corneum. To explore this, we studied distributions of three major corneodesmosomal components, corneodesmosin, desmoglein 1 and desmocollin 1 in normal adult human epidermis. Immunofluorescent microscopy studies of skin surface corneocytes detected all three components only at the cell edges. Immunoelectron microscopy revealed selective loss of these components at the central areas starting from the deep cornified layers. We hypothesized that tight junctions (TJs) formed in the superficial granular layer may prevent protease access by functioning as a barrier between the peripheral and the central intercellular spaces in the stratum corneum. Ultrastructural examination demonstrated TJs up to the junctions between the seventh and the eighth deepest cornified layers. Immunoelectron microscopy also detected clusters of occludin and claudin-1 immunolabels at the cell periphery, and kallikrein 7 immunolabels outside of TJs in the lower cornified layers. With colloidal lanthanum nitrate perfusion assay of stripped stratum corneum, the tracer was excluded from TJ domains. Taken together, we propose that TJs inhibit access of proteases to the peripheral corneodesmosomes forming the structural basis for the basket-weave-like appearance of the stratum corneum. [ABSTRACT FROM AUTHOR]

The corneodesmosomes in the stratum corneum are critical for the maintenance of stratum corneum integrity. To evaluate the normal and diseased keratinization states in the epidermis, we studied the distribution of desmoglein 1 (DSG1), a major component of corneodesmosomes, in samples of the stratum corneum obtained by tape stripping, a non-invasive method. Samples were collected from lesional skin of four patients with psoriasis and three with lichen planus, and from non-lesional skin of three volunteers. Upper stratum corneum cells were obtained by tape stripping and skin biopsies were obtained from adjacent sites. Tape-stripped samples were examined by immunofluorescence microscopy using anti-DSG1 monoclonal antibody, in combination with histopathology of skin biopsies. In normal human stratum corneum, which shows basket-woven orthokeratosis, DSG1-containing fluorescent dots were distributed on the lateral cell-cell contact areas of plasma membrane, but not on the dorsal/ventral plasma membrane, and formed a well-ordered hexagonal network structure. In psoriatic stratum corneum, fluorescent dots were distributed throughout the cell membrane at ventral aspects of corneocytes as well as at the lateral cell-cell contacts. In lichen planus, fluorescent dots were distributed homogeneously and/or heterogeneously on the ventral surface in some cells. Adjacent cells lacked DSG1 at the lateral cell-cell contacts, but were instead separated by distinctive black-gap lines. These results suggest that the intercellular adhesion by DSG1 may depend on the lateral plasma membrane in normal human stratum corneum, on the dorsal/ventral plasma membrane in lichen planus, and on both lateral and dorsal/ventral plasma membranes in psoriatic stratum corneum. Tape stripping and DSG1 immunofluorescence visualizes adhesion features of corneocytes and has considerable potential for evaluation of abnormal keratinization and the process of healing in response to treatment. [ABSTRACT FROM AUTHOR]

Background Pemphigus foliaceus (PF) is a blistering skin disease mediated by antibodies to desmoglein (Dsg) 1. The two major subtypes are nonendemic and endemic PF. A previous study in endemic PF demonstrated that changes in antibody epitope could modulate disease relapse and remission. Objectives To characterize the frequency of immunoreactivity to various Dsg1 extracellular (EC) domains in nonendemic PF and to study if there is any change in epitope profile across various activity stages. Methods Sera from 34 patients with nonendemic PF were selected. To map the conformational epitopes by immunoprecipitation-immunoblotting, we constructed five Dsg1/Dsg2 domain-swapped molecules, with each molecule representing one EC domain of Dsg1 on a backbone of Dsg2. Results Dsg1 EC1, EC2, EC3, EC4 and EC5 domains were recognized by 88%, 50%, 13%, 22% and 0% of active PF sera, respectively. Immunoreactivity to EC3 or EC4 often cosegregated with that to either EC1 or EC2. Longitudinal follow-up of 21 patients with PF for a median of 16 months revealed that, in most cases, immunoreactivity to the amino-terminus of Dsg1 persisted across various activity stages; only two patients lost their EC1 reactivity upon remission and changed their major epitope(s) to EC2 ± EC3. Conclusions Most of the anti-Dsg1 antibodies in nonendemic PF bind to the amino-terminus of Dsg1, a region critical for intercellular adhesion of cadherins, and this skewed amino-terminal immunoreactivity prevails across various activity stages in most patients, even upon remission. These findings are valuable for understanding the biology of Dsg-mediated cellular adhesion as well as for the development of epitope-based monitoring and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Recent developments in molecular genetics may lead to re-examination of the histopathology of inherited palmoplantar keratodermas (PPKs) based on more precise groupings of the various entities and syndromes. Objective: We sought to characterize the histopathological findings in PPKs associated with mutations in DSG1, which encodes desmoglein 1. Methods: We studied the histopathology of 3 cases of keratosis palmoplantaris striata type I and one case of diffuse PPK, all associated with autosomal-dominant mutations in DSG1. Our cases for comparison included 4 cases with Mal de Meleda PPK associated with autosomal-recessive SLURP1 mutations, one case with pachyonychia congenita type II PPK associated with an autosomal-dominant KRT17 mutation, and one case with focal PPK associated with an autosomal-dominant KRT16 mutation. Results: The distinguishing histopathological features of the 3 keratosis palmoplantaris striata type I cases and the diffuse PPK case associated with DSG1 mutation were: varying degrees of widening of the intercellular spaces and partial disadhesion of keratinocytes in the mid and upper epidermal spinous cell layers, often extending to the granular cell layer. These findings, which are associated with haploinsufficiency of desmoglein 1, were not observed in any of the other 6 PPK cases. Mild perinuclear eosinophilic condensations and cytoplasmic vacuolizations were observed in the spinous cell layer keratinocytes of the pachyonychia congenita type II PPK and the nonspecified focal PPK cases. Limitations: There were a limited number of patients and control patients with hereditary PPKs. Conclusion: Widening of the intercellular spaces and disadhesion of epidermal keratinocytes may serve as a histologic clue to PPKs caused by DSG1 mutations. [Copyright &y& Elsevier]

Background Pemphigus foliaceus is an autoimmune blistering skin disease characterized by the production of pathogenic IgG autoantibodies directed against desmoglein 1. Aim To determine the prevalence of anti-desmoglein 1 antibodies in healthy subjects and their distribution in the different regions of Tunisia and to better identify endemic areas of pemphigus foliaceus. Methods We tested, by enzyme-linked immunoserbent assay, sera of 270 normal subjects recruited from different Tunisian areas and 203 related healthy relatives to 90 Tunisian pemphigus foliaceus patients. Results Seventy-six patients (84.4%), 20 healthy controls (7.4%), and 32 relatives (15.76%) had anti-desmoglein 1 antibodies. In southern regions where pemphigus foliaceus is associated with a significant sex ratio imbalance (9 female : 1 male in the south vs. 2.3 : 1 in the north) and a lower mean age of disease onset (33.5 in the south vs. 45 years in the north), a higher prevalence of anti-desmoglein 1 antibodies in healthy controls was observed (9.23% vs. 5.71% in the north). Interestingly, the highest prevalence of anti-desmoglein 1 antibodies in healthy relatives (up to 22%) was observed in the most rural southern localities. More than half anti-desmoglein 1–positive healthy controls were living in rural conditions with farming as occupation, which suggests that this activity may expose the subjects to particular environmental conditions. Conclusion These results show that the endemic features of Tunisian pemphigus foliaceus are focused in these southern areas more than in other areas and that both environmental and genetic factors contribute to the disease. Conflicts of interest None declared. [ABSTRACT FROM AUTHOR]

Mucositis is a frequent problem after irradiation of the oral mucosa. To study the early effects of irradiation on the desmosomal adhesion complex, explants of keratinized oral mucosa were exposed to a single dose of 2 Gy gamma irradiation. Biopsies were obtained from the upper dental arch of nine young healthy non-smoking women undergoing minor oral surgery. The biopsies were incubated in a Transwell culture system and, after irradiation, fixed in formalin 24 h later. Morphometric measurements of epithelial thickness revealed that it was unaffected by exposure to ionizing rays. Immunofluorescence analysis of desmosomal cadherin expression (desmoglein 1/desmoglein 3) demonstrated that the distribution of desmoglein 1 was not affected, whereas the expression of desmoglein 3 decreased in the suprabasal layers of irradiated samples. It is suggested that this has consequences for the mechanical integrity of the mucosa and promotes the development of radiation mucositis. [ABSTRACT FROM AUTHOR]

Summary: Background: Striate palmoplantar keratoderma (SPPK; OMIM #148700) is a rare autosomal dominant genodermatosis characterized by linear hyperkeratosis on the digits and hyperkeratosis on the palms and soles. SPPK is known to be caused by heterozygous mutations in either the desmoglein 1 (DSG1), desmoplakin (DSP), or keratin 1 (KRT1) genes. Objective: To define the molecular basis of SPPK in five Pakistani families showing a clear autosomal dominant inheritance pattern of SPPK. Methods: Based on previous reports of DSG1 mutations in SPPK, we performed direct sequencing of the DSG1 gene of all five families. Results: Mutation analysis resulted in the identification of one recurrent mutation (p.R26X) and four novel mutations (c.Ivs4-2A>G, c.515C>T, c.Ivs9-3C>G, and c.1399delA) in the DSG1 gene. Each mutation is predicted to cause haploinsufficiency of DSG1 protein. Conclusion: The results of our study further underscore the significance of the desmoglein gene family in diseases of epidermal integrity. [Copyright &y& Elsevier]

Anti-desmoglein 3 and 1 autoantibodies are involved in the pathogenesis of pemphigus diseases. Our objective was to assess the value of ELISA in the diagnosis of pemphigus and its correlation with the severity of pemphigus vulgaris. Based on clinical presentation and histopathologic confirmation for the diagnosis of the pemphigus, 38 patients took part in the study. Sera of the patients were tested by desmoglein 1 and desmoglein 3 ELISA. Also, direct immunofluorescence was performed for all patients which revealed positive results in 36 patients (94.7%). ELISA was positive in 37 of 38 pemphigus patients (Sensitivity: 97.3%). The relationship between desmoglein 1 index values and skin severity was statistically significant (p<0.05). Desmoglein 3 index values increased with oral severity although this was not statistically significant. Iranian patients similar to Indian patients had higher positive anti-desmoglein 1 autoantibodies. Desmoglein-ELISA test is appropriate in the diagnosis of pemphigus. Desmoglein 1 index value is statistically correlated with the severity of pemphigus vulgaris. [ABSTRACT FROM AUTHOR]

Desmoglein (Dsg) 1 is a transmembrane glycoprotein of the desmosome allowing cell–cell adhesion between keratinocytes, whose expression is restricted to stratified squamous epithelia-like epidermis. Dsg1 is the target autoantigen of pathogenic autoantibodies produced by pemphigus foliaceus and 50% of pemphigus vulgaris patients in a Dsg1-specific T-cell-dependent pathway. Herewith, we show that mRNA of the DSG1 gene is present in normal human thymus and show by quantitative real-time polymerase chain reaction analysis that the expression of DSG1 transcript increases with age. Although immunoblot analysis on human thymus extracts using different anti-Dsg1 antibodies did not allow to detect the protein, we show by double-immunofluorescence assay that Dsg1 is expressed at protein level by CD19+ CD63+ cells located in the medulla. These data provide another illustration of the thymic expression of a tissue-specific autoantigen involved in an organ-specific autoimmune disease, which may participate in the tolerance acquisition and/or regulation of Dsg1-specific T cells. [ABSTRACT FROM AUTHOR]

Summary: Background: Striate keratodermas (PPKS) are a group of rare autosomal dominant palmoplantar keratodermas, characterized by a thickening of the skin on the palms and soles. PPKS is characterized by hyperkeratosis extending along the length of each finger and on the palm of the hand, as well as by patches of hyperkeratosis on the soles. Objective: We report a four-generation Pakistani kindred in which 11 members were affected with PPKS. Methods: Based on previous reports of DSG1 mutations in PPKS, we performed direct DNA sequencing analysis. Results: Clinically, these patients presented with hyperkeratotic palms and with linear hyperkeratosis on the fingers. Additionally, focal hyperkeratosis was seen on the sole of the toes as well as the ball and heel of the foot. DNA sequencing analysis revealed a heterozygous G-to-T transversion in the 3′ splice acceptor site of intron 11 of the DSG1 gene designated 1688 −1 G>T. We predict that this mutation will lead to the skipping of exon 12 which is out of frame (134nt), subsequent degradation of the mutant mRNA by non-sense mediated RNA decay, and haploinsufficiency for DSG1. Conclusion: We report a novel splice site mutation in the DSG1 gene in PPKS, which further underscores the significance of the desmoglein gene family in diseases of epidermal integrity. [Copyright &y& Elsevier]

Background Fogo selvagem (FS) has been described in several regions of Brazil, including the Western regions of the state of Parana. In 1990, Empinotti et al. reported case studies of 213 patients with FS that were collected from 1976 to 1988. The same author (J.C.E.) has observed that the frequency of cases in these regions of Parana has decreased. Objectives The purpose of this study was to clinically and serologically evaluate a small group of the patients originally reported in 1990 and compare data with a group of control individuals. These patients were treated at the onset of the disease with systemic steroids. Patients and methods Patients with FS, their unaffected relatives ( n = 80) and genetically unrelated controls ( n = 15) were identified during a field study from 1 May 2001 to 30 June 2002. Sera from nine patients with FS and six normal controls that were collected in the 1976–1988 evaluation were available for this study. The sera were tested by indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation using recombinant human desmoglein 1 (Dsg1). Results Only 16 of the originally identified 213 patients with FS were found during the field studies. Thirteen of the 16 patients were in clinical and serological remission; 20% of normal controls (19 of 95) were positive in the Dsg1 ELISA. The majority of these subjects (17 of 19) were genetically related to FS patients. Six normal controls that were positive in the Dsg1 ELISA in the original survey were found to be negative or weakly positive in this evaluation. Conclusion The reduced frequency of positive serological markers of disease in patients and normal controls from Western Parana, as well as the absence of recurrent disease in previously identified patients, suggest that environmental antigenic stimulation of the population at risk may have decreased in recent years. [ABSTRACT FROM AUTHOR]

In neonatal rat stratum corneum (SC), pH declines from pH 6.8 at birth to adult levels (pH 5.0–5.5) over 5–6 d. Liver X receptor (LXR) activators stimulate keratinocyte differentiation, improve permeability barrier homeostasis, and accelerate the in utero development of the SC. In this manuscript we determined the effect of LXR activators on SC acidification in the neonatal period and whether these activators correct the functional abnormalities in permeability barrier homeostasis and SC integrity/cohesion. Formation of the acid SC-buffer system was accelerated by topically applying the LXR activator, 22( R)-hydroxycholesterol, and non-oxysterol activators of LXR, TO-901317, and GW-3965. A sterol which does not activate LXR had no effect. LXR activation increased secretory phospholipase A2 (sPLA2) activity and conversely, inhibition of sPLA2 activity prevented the LXR induced increase in SC acidification, suggesting that increasing sPLA2 accounts in part, for the LXR stimulation of acidification. LXR activation resulted in an improvement in permeability barrier homeostasis, associated with an increased maturation of lamellar membranes attributable to an increased β-glucocerebrosidase activity. SC integrity cohesion also normalized in LXR-activator-treated animals and was associated with an increase in corneodesmosomes and in desmoglein 1 expression. These results demonstrate that LXR activators stimulate the formation of an acidic SC and improve both permeability barrier homeostasis and SC integrity/cohesion. [ABSTRACT FROM AUTHOR]

Background Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal-type-related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation. Objectives To identify pathogenic mutations in two Japanese siblings with NS, and further to investigate the consequences of the mutations at the protein level. Methods To screen for mutations in the SPINK5 gene, all of its exons and splice junctions were amplified by polymerase chain reaction and directly sequenced. In addition, immunohistochemical staining of LEKTI, desmoglein (Dsg) 1 and elafin was performed with their specific antibodies. Results Mutation analysis resulted in the identification of compound heterozygous mutations, Q713X and R790X, in the SPINK5 gene of both patients. The former one is a novel mutation. Immunohistochemical studies in one patient demonstrated a complete absence of LEKTI and a strong expression of elafin in the patient's skin. Dsg1 was normally expressed in our patient. Conclusions In this report, we describe compound heterozygous mutations in the SPINK5 gene in two Japanese siblings with NS. The result of immunohistochemistry shows LEKTI deficiency and upregulation of elafin in the skin of one patient. Furthermore, our data indicate that degradation of Dsg1 does not always occur in NS. [ABSTRACT FROM AUTHOR]

Purpose: To report the involvement of eyelid skin in a patient with pemphigus foliaceus.Methods: Retrospective, interventional case report of a patient with pemphigus foliaceus involving both eyelids. The diagnosis of pemphigus foliaceus was based on histopathology and confirmed by direct immunofluorescence and immunoblot. Failure to respond to conventional immunosuppressive therapy, including high-dose corticosteroids, methotrexate, azathioprine, dapsone, and mycophenolate mofetil, necessitated the use of intravenous immunoglobulin (IVIg) therapy.Results: After successful treatment with IVIg, no change in visual acuity or other sequelae secondary to ocular pemphigus foliaceus were observed. Normal ocular architecture was maintained. Clinical remission was observed after successful therapy.Conclusions: Pemphigus foliaceus involves the skin of the eyelid and does not involve the conjunctiva. The patient did not respond to conventional immunosuppressive therapy. The use of IVIg as mono-therapy resulted in long-term clinical remission. [ABSTRACT FROM AUTHOR]