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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]

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]

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: 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 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]

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]

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 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]

At birth, neonatal stratum corneum (SC) pH is close to neutral but acidifies with maturation, which can be ascribed, in part, to secretory phospholipase A2 and sodium/hydrogen antiporter 1 (NHE1) activities. Here we assessed the functional consequences of a neutral SC pH in a newborn rat model. While basal transepidermal water loss rates are near normal, barrier recovery (BR) rates after acute barrier disruption were delayed in newborn animals. The abnormality in barrier homeostasis could be improved by topical applications of an acidic buffer, indicating that barrier abnormality is primarily due to high SC pH. The delay in BR correlated with incompletely processed lamellar membranes and decreased activity of beta-glucocerebrosidase. Inhibition of NHE1 delayed BR after acute barrier perturbation. SC integrity was abnormal in newborn animals. Electron microscopy demonstrated decreased corneodesmosomes (CD) in newborn animals with decreased expression of desmoglein 1 and corneodesmosin. Serine protease activation appears to be responsible for CD degradation in newborn animals, because serine protease activity is increased in the SC and it can be reduced by acidification of the SC. The delay in acidification of neonatal SC results in abnormalities in permeability barrier homeostasis and SC integrity and are likely due to pH-induced modulations in enzyme activity. [ABSTRACT FROM AUTHOR]

Abstract: Pemphigus erythematosus, initially described as a combination of pemphigus with lupus erythematosus, and pemphigus foliaceus are now frequently considered localized and generalized variants of superficial pemphigus. Yet diagnostic criteria for pemphigus erythematosus remain controversial. Distinct from pemphigus foliaceus, pemphigus erythematosus displays immune depositions at the dermal-epidermal junction, which suggests additional immunopathological mechanisms. We present three patients with clinical and histopathologic signs of superficial pemphigus, who all exhibited an immunomorphology characteristic of pemphigus erythematosus. Complement depositions in a granular-linear fashion were consistently found at the dermal-epidermal junction besides in vivo bound and circulating antikeratinocyte cell-surface autoantibodies. Histopathology showed subcorneal acantholysis, and all sera contained antidesmoglein 1 but not antidesmoglein 3 autoantibodies detected by enzyme-linked immunosorbent assays (ELISA). Additional autoantibodies against a 230-kDa protein and against a 190-kDa protein comigrating with bullous pemphigoid antigen 1 (BP230) and periplakin, respectively, were present in all the patients' sera. As two sera specifically reacted with BP230 by ELISA, the presence of BP230-specific autoantibodies could be associated with dermal-epidermal immune staining in these patients. In pemphigus erythematosus, dermal–epidermal immune staining is generally attributed to the deposition of immune complexes, while the presence of BP230-specific autoantibodies has not been reported in this disease previously. Perhaps, the unique autoantibody profile of the patients in the study permits discrimination between patients with superficial pemphigus that display additional dermal-epidermal immune staining from those with conventional pemphigus foliaceus on a molecular basis. Further studies will be required to substantiate the frequency of this occurrence and to unravel its pathogenic significance. [ABSTRACT FROM AUTHOR]

ABSTRACT Tufted hair folliculitis (THF) is a rare disease which is characterized by the emergence of multiple hairs from widely dilated follicular orifices surrounded by an inflammatory infiltrate resulting in scarring alopecia. The pathogenesis is not yet fully understood. Although colonization with Staphylococcus aureus could not always be detected and systemic treatment with antibiotics alone is not sufficient, this microorganism is considered to play an important role. Around 30 patients with THF have been reported since the first publication. We present a patient with pemphigus vulgaris who developed THF. To our knowledge, this is the fourth case with an association of these two entities. Amongst other causing mechanisms, the autoimmune reaction may play an important role for the development of THF. [ABSTRACT FROM AUTHOR]

The desmoglein plays an important part in the formation of desmosomes. We constructed recombinant adenoviruses containing desmoglein 1 and desmoglein 3 derivatives partly lacking the extracellular domain (desmoglein 1ΔEC and desmoglein 3ΔEC, respectively), and full-length desmoglein 1 and desmoglein 3 and studied the involvement of desmoglein 1 and desmoglein 3 in desmosome formation. During low-level expression of desmoglein 3ΔEC in transduced HaCaT cells, keratin insertion at cell–cell contact sites was only partially inhibited and desmoplakin was partially stained at cell–cell contact sites. Low-level expression of desmoglein 1ΔEC, however, resulted in complete inhibition of keratin insertion at the cell–cell contact sites, and desmoplakin was stained in perinuclear dots. These results indicate the dominant-negative effect of desmoglein 1ΔEC on desmosome formation was stronger than that of desmoglein 3ΔEC. Desmoglein 1ΔEC coprecipitated plakoglobin to approximately the same extent as desmoglein 3ΔEC. Therefore, we conclude that the dominant-negative effect of desmoglein 1ΔEC is not simply due to plakoglobin sequestration. On the other hand, during low-level expression of full-length desmoglein 3 and desmoglein 1, they both colocalized with desmoplakin. During high-level expression, however, keratin insertion at cell–cell contact sites was inhibited in desmoglein 1 but not in desmoglein 3, and desmoplakin was stained at cell–cell contact sites in desmoglein 3 but not in desmoglein 1. These data suggest desmoglein 1 and desmoglein 3 expressed at low level were incorporated into desmosome but at high-level expression, desmoglein 1 disrupted desmosomes but desmoglein 3 did not. Our findings provide biologic evidence that desmoglein 1 and desmoglein 3 play a different functional role in cell–cell adhesion of keratinocytes. [ABSTRACT FROM AUTHOR]

Pemphigus foliaceus (PF) is an autoimmune skin disease characterized by the presence of a pathogenic autoantibody to desmoglein 1, an epidermal cadherin molecule. Antibody titers to the desmoglein 1 protein can be used to monitor disease activity and severity in patients with PF. The purpose of this study is to report the influence of IVIg therapy on anti-desmoglein 1 antibody titers, in eight patients with severe PF, over a period of 18 consecutive months on each patient. This prospective study consisted of eight patients with severe widespread active PF at the time of entry into the study. The levels of autoantibody to desmoglein 1 were measured by an ELISA, at monthly intervals. Sera of all eight had high titers of the autoantibody to desmoglein 1, prior to initiating of IVIg therapy. A statistically significant reduction in the autoantibody titer index to desmoglein 1 was seen after 4 months of IVIg therapy. All eight patients were observed to have a progressive decline in autoantibody titer index while they were receiving IVIg. Patients on IVIg therapy had nondetectable titers after a mean period of 13 months and continued to remain in a serological remission for an additional observation period of 5 months. In the context of this study, autoantibody titers to desmoglein 1 can be used to monitor the serological response to treatment in patients with PF. Patients receiving IVIg therapy achieve serological remission. [Copyright &y& Elsevier]

We describe four patients with generalized scaly and pustular skin lesions showing extensive neutrophilic infiltration in the subcorneal region of the epidermis. Immunofluorescence, immunoblot and enzyme-linked immunosorbent assay analyses detected IgG antibodies reacting exclusively with desmoglein 1, the pemphigus foliaceus antigen. This study indicates that pemphigus foliaceus may show prominent neutrophilic pustular skin lesions. [ABSTRACT FROM AUTHOR]

Background Pemphigus vulgaris (PV) and foliaceus (PF) are characterized by antibodies to the desmosomal proteins desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. Past studies using indirect immunofluorescence (IIF) as a measure of pemphigus antibody levels have failed to demonstrate consistently a relationship between disease severity and IIF titres. However, IIF is not able to measure separately Dsg1 and 3 antibodies, unlike enzyme-linked immunosorbent assays (ELISA), which utilize recombinant proteins. Objectives To compare independently Dsg1 and 3 antibody levels with the severity of both cutaneous and oral involvement in PV and PF. Patients and methods Four hundred and twenty-four serum samples were analysed from 80 subjects with PV and 24 with PF. IgG antibodies to Dsg1 and 3 were measured by ELISA. For every sample analysed, the associated severity of skin and oral disease were graded from 0 to 3; quiescent, mild, moderate and severe. Results A relationship between Dsg1 antibodies and skin severity was demonstrated such that a 10-unit increase in Dsg1 ELISA value was associated with a 34% chance of having a higher severity score [95% confidence interval (CI), 25–45%, P < 0·0005]. This was observed in both PV and PF. Oral severity was associated with Dsg3 antibody levels and a 10-unit increase in the Dsg3 ELISA value was associated with a 25% chance of a higher oral severity score (CI 17–33%, P < 0·0005). We were unable to demonstrate a relationship between Dsg1 antibodies and oral severity, even after adjusting for the effect of Dsg3 antibodies. Similarly, there was no relationship between Dsg3 antibodies and skin severity. Conclusions This study suggests that the clinical phenotype of pemphigus, in particular the balance of skin and oral disease, is determined principally by the quantities of Dsg1 and 3 autoantibodies, respectively. [ABSTRACT FROM AUTHOR]

Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous blistering disease characterized by IgG autoantibodies that bind to various epithelia and immunoprecipitate a complex of 250, 230, 210, 190 and 170 kDa proteins. A recent study has suggested that PNP patients have antidesmoglein (Dsg) 3 autoantibody and that the antibody plays a pathogenic role in PNP. We report a 72-year-old woman with PNP associated with thymoma and adenocarcinoma of the lung. Diagnosis of PNP was made by the characteristic clinical, histological and immunopathological findings, as well as immunoprecipitation of characteristic 230, 210 and 190 kDa proteins. Using enzyme-linked immunosorbent assay with baculovirus-expressed recombinant proteins, the patient’s serum was negative against both Dsg 3 and Dsg 1. This finding is unusual, and it suggests that the target antigen, which is involved in acantholysis, may be other than Dsg 3 in this case. [ABSTRACT FROM AUTHOR]

Background Pemphigus vulgaris (PV) is characterized by pathogenic autoantibodies to desmoglein (Dsg) 3, but additional antibodies to Dsg1, the pemphigus foliaceus antigen, are detectable in some cases. Objectives To investigate the clinical significance of the presence of both Dsg 1 and 3 antibodies. Methods In 79 subjects with PV, enzyme-linked immunosorbent assays were used to detect IgG autoantibodies reactive with the ectodomain of Dsg1 and Dsg3. Results There was a clear association between the clinical phenotype and the Dsg antibody profile. All subjects had Dsg3 autoantibodies and 61% had coexisting Dsg1 antibodies (Dsg3+/Dsg1+). PV limited entirely to the mucosal surfaces was seen only in Dsg3+/Dsg1– patients, while additional Dsg1 antibodies (Dsg3+/Dsg1+) predicted cutaneous in addition to mucosal involvement. Although minor cutaneous involvement was observed in most Dsg3+/Dsg1– patients, severe cutaneous involvement was seen only in Dsg3+/Dsg1+ patients. Dsg1 antibodies were detectable early in the course of disease and their appearance did not relate to the use of systemic therapy. The proportion of Dsg1+ patients was higher in those of Indian origin compared with white northern Europeans (P < 0·05). Conclusions These data suggest that the presence of Dsg1 antibodies is predictive of a potentially more severe disease and that genetic factors may determine the Dsg antibody profile. [ABSTRACT FROM AUTHOR]

Pemphigoid nodularis is a rare variant of bullous pemphigoid. We report a 49-year-old Japanese male with clinical and histopathological features of pemphigoid nodularis including circulating and in vivo-bound IgG antibasement membrane zone antibodies and IgA anti-intercellular antibodies. Although the precise molecular target of the IgG autoantibodies could not be determined, intriguingly, immunoblotting showed that the IgA in the patient’s serum reacted with the intracellular domain of desmoglein 1, the target antigen in cases of pemphigus foliaceus. However, the IgA did not react with the extracellular domain of desmoglein 1 in sensitive enzyme-linked immunosorbent assay studies using a baculovirus system. These results suggest therefore that these IgA antibodies may possibly not be pathogenic. The mechanism for the production of different autoantibodies is unknown, but this case provides further illustration of the atypical skin immunoreactants often seen in this unusual subtype of bullous pemphigoid. [ABSTRACT FROM AUTHOR]

The article discusses the study which examines the familial feature of pemphigus foliaceus (PF) which is endemic in southern Tunisia. Subjects of the study include 32 Tunisian families with 40 affected members with PF. The study suggests that young farmers from southern Tunisia exposed to the local ecology in the endemic areas are the main individuals at risk.

The article presents a study on striate palmoplantar keratoderma (SPPK), which is mainly characterized by linear hyperkeratosis of the fingers' volar aspects. Study shows strong evidence that SPPK is caused by defects in desmosomes, conferring the strength and rigidity to tissues which will experience high mechanical stress. It is also noted that the light microscopy of affected plantar epidermis is likely to show acanthosis.

Epidermal desquamation involves a finely-tuned proteolytic cascade ensuring the regulated cleavage of desmosomes that releases old stratum corneum outermost layers. Although the roles of desmosomes in normal physiology are well-established, their putative involvement in cancer remains unexplored. The KLK5 protease is thought of having fundamental roles in epidermal proteolysis and homeostasis, and its aberrant activity has been linked to skin pathologies. We found that deletion of Klk5 results in significantly higher numbers of lengthier desmosomes and enhanced skin strength. Klk5 − / − mice retained normal skin barrier function and are resistant to chemically-induced skin tumorigenesis. The resistance to tumorigenesis was not due to inhibition of inflammation, and on the contrary, absence of Klk5 increased the TPA-induced inflammatory skin response. We found that increased desmosomes and reduced proteolysis prevent oncogenic signaling by capturing β-catenin into the cytoplasm and facilitate epidermal keratinocyte apoptosis, thus, inhibiting tumor initiation. We highlight that the skin ultrastructure affects early neoplastic transformation by modulating intracellular signaling and suggest that tissue reinforcement provides a novel mode of tumor suppression. • The epidermis of Klk5 − / − mice displays increased number of desmosomes and enhanced mechanical strength. • The Klk5 − / − mice are resistant to chemically-induced skin tumorigenesis. • Desmosomal reinforcement inhibits β-catenin oncogenic signaling. • Tissue reinforcement is a new mode of tumor suppression. [ABSTRACT FROM AUTHOR]

Discusses the case of a 42-year-old woman who developed allergy to thiurams from contact with rubber gloves worn by her carer. Allergic contact dermatitis from thiurams with pemphigus-like autoantibodies; Case report; Clinical, histological and serological description.