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Masayuki Amagai - One of the best experts on this subject based on the ideXlab platform.
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Pemphigus
Nature Reviews Disease Primers, 2017Co-Authors: Michael Kasperkiewicz, Detlef Zillikens, Christoph T. Ellebrecht, Hayato Takahashi, Jun Yamagami, Aimee S. Payne, Masayuki AmagaiAbstract:Pemphigus is an autoimmune disorder characterized by blisters in the oral mucosa and epidermis. Acantholysis (loss of cell adhesion, which results in blisters) is caused by the presence of autoantibodies that target desmosomal proteins, in particular, desmoglein 1 and desmoglein 3. Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell–cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20^+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.
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Imaging and Force Spectroscopy on Desmoglein 1 Using Atomic Force Microscopy Reveal Multivalent Ca2+-Dependent, Low-Affinity Trans-Interaction
The Journal of membrane biology, 2007Co-Authors: Jens Waschke, Masayuki Amagai, Carlos Menendez-castro, Paola Bruggeman, Rainer Koob, Hermann J. Gruber, Detlev Drenckhahn, Werner BaumgartnerAbstract:Desmoglein 1 is a desmosomal member of the cadherin family expressed in stratified epithelia. Desmoglein 1 is the target adhesion molecule of severe blistering skin diseases such as pemphigus or bullous impetigo. However, despite this enormous pathological relevance, the molecular binding properties of desmoglein 1 are largely unknown. Using atomic force microscopic imaging, we found that desmoglein 1 molecules displayed Ca2+-dependent conformational changes of the extracellular domains. By single-molecule force-distance cycles, we provide evidence that desmoglein 1 undergoes Ca2+-dependent (K d = 0.8 mm Ca2+) homophilic trans-interaction, which is highly relevant for the contribution of desmoglein 1 homophilic binding to keratinocyte cohesion in distinct epidermal layers. Moreover, while the single-unit unbinding force is comparable to other cadherins (∼40 pN at retrace velocity of 300 nm/s), apparent differences with respect to multivalency of interaction and lifetime of single bonds (0.17 s) were observed. Thus, besides the biophysical characterization of desmoglein 1, a main outcome of the study is that desmoglein 1 differs from other members of the cadherin family in terms of some molecular binding properties.
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Imaging and Force Spectroscopy on Desmoglein 1 Using Atomic Force Microscopy Reveal Multivalent Ca^2+-Dependent, Low-Affinity Trans-Interaction
Journal of Membrane Biology, 2007Co-Authors: Jens Waschke, Masayuki Amagai, Carlos Menendez-castro, Paola Bruggeman, Rainer Koob, Hermann J. Gruber, Detlev Drenckhahn, Werner BaumgartnerAbstract:Desmoglein 1 is a desmosomal member of the cadherin family expressed in stratified epithelia. Desmoglein 1 is the target adhesion molecule of severe blistering skin diseases such as pemphigus or bullous impetigo. However, despite this enormous pathological relevance, the molecular binding properties of desmoglein 1 are largely unknown. Using atomic force microscopic imaging, we found that desmoglein 1 molecules displayed Ca^2+-dependent conformational changes of the extracellular domains. By single-molecule force-distance cycles, we provide evidence that desmoglein 1 undergoes Ca^2+-dependent ( K _d = 0.8 m m Ca^2+) homophilic trans -interaction, which is highly relevant for the contribution of desmoglein 1 homophilic binding to keratinocyte cohesion in distinct epidermal layers. Moreover, while the single-unit unbinding force is comparable to other cadherins (∼40 pN at retrace velocity of 300 nm/s), apparent differences with respect to multivalency of interaction and lifetime of single bonds (0.17 s) were observed. Thus, besides the biophysical characterization of desmoglein 1, a main outcome of the study is that desmoglein 1 differs from other members of the cadherin family in terms of some molecular binding properties.
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Staphylococcus hyicus exfoliative toxins selectively digest porcine desmoglein 1.
Microbial Pathogenesis, 2005Co-Authors: Yasuyuki Fudaba, Koji Nishifuji, Masayuki Amagai, Takayuki Yamaguchi, Lars Andresen, Hitoshi Komatsuzawa, Motoyuki SugaiAbstract:Virulent strains of Staphylococcus hyicus can cause exudative epidermitis in pigs. The major symptom of this disease is exfoliation of the skin in the upper stratum spinosum. Exfoliation of the skin is strongly associated with exfoliative toxin including ExhA, ExhB, ExhC, ExhD, SHETA, and SHETB. Recently, genes for ExhA, ExhB, ExhC and ExhD were cloned. Exfoliative toxins produced by S. aureus have been shown to selectively cleave human or mouse desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study, we attempted to identify the molecular target of Exhs in porcine skin. Each of recombinant Exhs injected in the skin of pigs caused superficial epidermal blisters or crust formation. Cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal porcine skin were incubated with one of Exhs suggesting that Exh selectively degrade porcine desmoglein 1. In vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 of human, mouse or canine origin demonstrated that only mouse desmogleins 1α and 1β were cleaved by ExhA and ExhC at high concentration. Furthermore, injection of ExhA and ExhC at high concentration caused superficial blisters in neonatal mice. These findings strongly suggest that Exhs cause blister formation of porcine skin by digesting porcine desmoglein 1 in a similar fashion to exfoliative toxins from S. aureus.
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Staphylococcus hyicus exfoliative toxins selectively digest porcine desmoglein 1.
Microbial pathogenesis, 2005Co-Authors: Yasuyuki Fudaba, Koji Nishifuji, Masayuki Amagai, Takayuki Yamaguchi, Lars Ole Andresen, Hitoshi Komatsuzawa, Motoyuki SugaiAbstract:Virulent strains of Staphylococcus hyicus can cause exudative epidermitis in pigs. The major symptom of this disease is exfoliation of the skin in the upper stratum spinosum. Exfoliation of the skin is strongly associated with exfoliative toxin including ExhA, ExhB, ExhC, ExhD, SHETA, and SHETB. Recently, genes for ExhA, ExhB, ExhC and ExhD were cloned. Exfoliative toxins produced by S. aureus have been shown to selectively cleave human or mouse desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study, we attempted to identify the molecular target of Exhs in porcine skin. Each of recombinant Exhs injected in the skin of pigs caused superficial epidermal blisters or crust formation. Cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal porcine skin were incubated with one of Exhs suggesting that Exh selectively degrade porcine desmoglein 1. In vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 of human, mouse or canine origin demonstrated that only mouse desmogleins 1alpha and 1beta were cleaved by ExhA and ExhC at high concentration. Furthermore, injection of ExhA and ExhC at high concentration caused superficial blisters in neonatal mice. These findings strongly suggest that Exhs cause blister formation of porcine skin by digesting porcine desmoglein 1 in a similar fashion to exfoliative toxins from S. aureus.
Luis A Diaz - One of the best experts on this subject based on the ideXlab platform.
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anti desmoglein 1 antibodies in onchocerciasis leishmaniasis and chagas disease suggest a possible etiological link to fogo selvagem
Journal of Investigative Dermatology, 2004Co-Authors: Luis A Diaz, Luis A Arteaga, Julio Hilariovargas, Jesus G Valenzuela, Ning Li, Simon Warren, Valeria Aoki, Gunter Hansfilho, Donald P Eaton, Vandir Dos SantosAbstract:Pemphigus foliaceus (PF) and the endemic form Fogo Selvagem (FS) are mediated by pathogenic antibodies to the EC1–2 domains of Desmoglein-1. There is a preclinical phase with antibodies to only EC5. Based on geographic clustering of cases, FS is thought to have an, as yet unidentified, environmental trigger. In this study we have searched for anti-Desmoglein-1 antibodies in sera from parasitic (leishmaniasis, Chagas, and onchocerciasis), and infectious diseases (leprosy and South American (SA) blastomycosis), which are prevalent in the same geographic regions of Brazil as FS. A specific and sensitive Desmoglein-1 ELISA detected antibodies in 34 of 41 onchocerciasis (83%), 38 of 88 leishmaniasis (43%), 18 of 31 Chagas disease (58%), 7 of 28 SA blastomycosis (25%), and 14 of 83 leprosy sera (17%). These sera recognized epitopes restricted to the EC5 domain. These findings identify several etiological factors for FS. It is hypothesized that a component of insect vector saliva, rather than the parasite itself may trigger an antibody response to EC-5. In persons with the known HLA susceptibility alleles and living in endemic areas, a response to the EC1–2 domains may subsequently develop by epitope spreading with associated clinical signs of FS.
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A Subset of Pemphigus Foliaceus Patients Exhibits Pathogenic Autoantibodies Against Both Desmoglein-1 and Desmoglein-3
The Journal of investigative dermatology, 2002Co-Authors: Luis A Arteaga, Luis A Diaz, Simon Warren, Zhi Liu, Philip S. Prisayanh, Mong Shang LinAbstract:In pemphigus vulgaris the major pathogenic antibody binds desmoglein-3, and mediates mucosal disease. Development of cutaneous disease is associated with acquisition of antibodies to Desmoglein-1. In pemphigus foliaceus, and its endemic form, fogo selvagem by contrast, the major pathogenic antibody recognizes Desmoglein-1 and mediates cutaneous disease only. In this study, we sought to determine the prevalence of antibodies to desmoglein-3 in patients with pemphigus foliaceus and fogo selvagem. We produced recombinant Desmoglein-1 and desmoglein-3, and used them in highly sensitive and specific enzyme-linked immunosorbent assays, as well as immunoprecipitation assays. We detected antibodies to desmoglein-3 in 19 of 276 patients with pemphigus foliaceus and fogo selvagem, who had cutaneous disease only. We showed that these antibodies to desmoglein-3 could be absorbed in a concentration-dependent manner by desmoglein-3 but not by Desmoglein-1. Also antibodies to Desmoglein-1 could be absorbed in a concentration-dependent manner by Desmoglein-1 but not desmoglein-3. This suggests that two separate species of antibody are present rather than one antibody capable of cross-reacting with both Desmoglein-1 and desmoglein-3. Finally, it was shown that affinity-purified antibodies to desmoglein-3 from patients with pemphigus foliaceus and fogo selvagem induced a pemphigus vulgaris-like skin disease in mice by passive transfer. These results suggest that a subset of patients with pemphigus foliaceus and fogo selvagem have antibodies to desmoglein-3 that may be involved in the pathogenesis of their cutaneous disease.
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The Prevalence of Antibodies against Desmoglein 1 in Endemic Pemphigus Foliaceus in Brazil
The New England journal of medicine, 2000Co-Authors: Simon Warren, Valeria Aoki, Vandir Dos Santos, George J. Giudice, Mong Shang Lin, Raymond G. Hoffmann, Gunter Hans-filho, Evandro A. Rivitti, Luis A DiazAbstract:Background Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies against desmoglein 1. The endemic form is thought to have an environmental cause. The Terena reservation of Limao Verde in Mato Grosso do Sul, Brazil, is a recently identified focus of the disease, with a prevalence of 3.4 percent in the population. We tested the hypothesis that normal subjects living in an endemic area have antibodies against desmoglein 1. Methods We used an enzyme-linked immunosorbent assay to detect antibodies against desmoglein 1 in serum samples from 60 patients with endemic pemphigus foliaceus (fogo selvagem) who lived in Limao Verde or elsewhere in Brazil, 372 normal subjects (without pemphigus foliaceus) from Limao Verde and surrounding locations, and 126 normal subjects from the United States and Japan. Results Antibodies against desmoglein 1 were detected in 59 of the 60 patients with fogo selvagem (98 percent) but in only 3 of the 126 normal subjects from the United States and Japan (2 perce...
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The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic.
The Journal of investigative dermatology, 1999Co-Authors: Xiang Ding, Luis A Diaz, Janet A. Fairley, George J. Giudice, Zhi LiuAbstract:Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.
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D - Penicillamine-induced pemphigus foliaceus with autoantibodies to Desmoglein-1 in a patient with mixed connective tissue disease
Journal of the American Academy of Dermatology, 1997Co-Authors: Pablo F. Peñas, Argelia Lopez, Guadalupe F Buezo, Inmaculada Carvajal, Esteban Daudén, Luis A DiazAbstract:Pemphigus is a bullous disease characterized by antidesmoglein autoantibodies. Desmogleins are members of the cadherin family of Ca++-depen dent cell adhesion molecules. Cadherins are subdivided into the classic and desmosomal cadherins. Desmogleins and desmocollins belong to the latter group and through desmoplakin and plakoglobin are the link to the intracellular network of keratin 1 intermediate filaments. Antibodies of patients with pemphigus vulgaris recognize desmoglein-3 (130 kd) and those with pemphigus foliaceus (PF) recognize Desmoglein-1 (160 kd). 1,2 Although spontaneous disease develops in most patients (idiopathic pemphigus), in some the disease is precipitated by drugs (induced pemphigus). 3 We describe a patient in whom, during treatment with D-penicillamine for mixed connective tissue disease, PF developed. CASE REPORT A 33-year-old woman had a 6-month history of diffuse hyperpigmentation, arthritis, sicca syndrome, cutaneous sclerosis, and Raynaud's phenomenon. Laboratory examination disclosed an antinuclear antibody titer of more than 1:10240 (nucleolar pattern), anti-double-stranded DNA titer of 1:132, and positive anti-SS-A. Antibodies to SS-B, ribonucleoprotein (RNP), Sin, Jo-1, centromere, and Scl-70 were not found. Esophageal manometry showed decreased peristalsis in the distal two thirds. No calcifications
Roger S. Buxton - One of the best experts on this subject based on the ideXlab platform.
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exon intron organization of the human type 2 desmocollin gene dsc2 desmocollin gene structure is closer to classical cadherins than to desmogleins
Genomics, 1997Co-Authors: Matthew D Greenwood, Catherine M.e. Cowley, Mark D. Marsden, Virender K Sahota, Roger S. BuxtonAbstract:Abstract The cadherins are a superfamily of calcium-dependent glycoproteins that are cell adhesion molecules. Two families of cadherins, the desmocollins (Dsc) and desmogleins (Dsg), are found only in the desmosome type of cell–cell junction. They are each present in at least three different isoforms with differing spatial and temporal distributions and are specified by two clusters of closely linked genes on human chromosome 18q12.1. The human DSC2 gene, coding for the most widely distributed form of the desmocollins, has been found to consist of more than 32 kb of DNA. By using PCR we have determined the exon–intron organization. The gene is arranged into 17 exons ranging in size from 46 to 258 bp; exon 16 is alternatively spliced, giving rise to the a and b forms of the protein. This has revealed a remarkable degree of conservation of intron position with other cadherins. The desmocollin exon–intron organization is more similar to the so-called classical cadherins than to the desmogleins, especially in the cytoplasmic domain. Intron 1 is the largest in DSC2, as it is in the desmogleins, in contrast to the classical cadherins, where intron 2 is extremely large; this latter intron is missing from the desmogleins.
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cloning and transcriptional analysis of the promoter of the human type 2 desmocollin gene dsc2
Gene, 1997Co-Authors: Mark D. Marsden, Jane E Collins, Matthew D Greenwood, Michael J Adams, Tom P Fleming, Anthony I Magee, Roger S. BuxtonAbstract:Abstract The desmocollins, together with the desmogleins, are members of the cadherin family and constitute the adhesive proteins of the desmosome type of cell-cell junction. Here we describe a study of the promoter of the human form of the DSC2 gene which is the equivalent of the first isoform expressed in the developing mouse embryo and that has the most widespread tissue distribution in epithelia and also in desmosome-bearing non-epithelial tissues. Analysis of the 5′ upstream region by DNA sequencing and Southern blotting suggested that it contained a CpG island, and a major site of transcription initiation 201 bp upstream of the translation start site was found by RNase protection and primer extension. There were no obvious CCAAT or TATA boxes present. Analysis of 1.9 kb upstream of the translation start site revealed consensus binding sites for transcription factors including Ap-2 and Sp-1, and motifs common to the promoters of other epithelially expressed genes such as keratin 14 and the desmoglein genes DSG1 and DSG3. Deletion derivatives defined a promoter of 525 bp which was active in epithelial cells and in mouse blastocysts with an intact epithelium. This promoter showed reduced expression in non-epithelial cells.
Detlef Zillikens - One of the best experts on this subject based on the ideXlab platform.
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Pemphigus
Nature Reviews Disease Primers, 2017Co-Authors: Michael Kasperkiewicz, Detlef Zillikens, Christoph T. Ellebrecht, Hayato Takahashi, Jun Yamagami, Aimee S. Payne, Masayuki AmagaiAbstract:Pemphigus is an autoimmune disorder characterized by blisters in the oral mucosa and epidermis. Acantholysis (loss of cell adhesion, which results in blisters) is caused by the presence of autoantibodies that target desmosomal proteins, in particular, desmoglein 1 and desmoglein 3. Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell–cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20^+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.
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Paraneoplastic pemphigus with anti-BP180 autoantibodies and Castleman's disease
British Journal of Dermatology, 2017Co-Authors: L. Maier, Enno Schmidt, A. Udvardi, Rudiger Eming, Michael Hertl, Detlef Zillikens, Beatrix Volc-platzerAbstract:Paraneoplastic pemphigus (PNP) is commonly associated with IgG-autoantibodies against desmoglein 1 and 3, plakins (desmoplakin I and II, envoplakin, periplakin), desmocollins 1-3, BP2301 and α2-macroglobulin-like-1 (A2ML1)2. The major autoantigen of bullous pemphigoid (BP), pemphigoid gestationis and lichen planus pemphigoides (LPP) is the NC16A domain of BP1803. This article is protected by copyright. All rights reserved.
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modern diagnosis of autoimmune blistering skin diseases
Autoimmunity Reviews, 2010Co-Authors: Enno Schmidt, Detlef ZillikensAbstract:Abstract The diagnostic gold standard of autoimmune bullous diseases is the detection of autoantibodies in skin or mucous membranes by direct immunofluorescence microscopy of a perilesional biopsy. The molecular characterisation of several target antigens within the last 10 years has, however, fostered the development of sensitive and specific diagnostic tools that allow the serological diagnosis in about 90% of patients. Based on the recombinant immunodominant portions of the target antigens, ELISA systems are commercially available for the detection of circulating antibodies against desmoglein 1, desmoglein 3, envoplakin, BP180, and BP230. Autoantibodies against the soluble ectodomain of BP180 (LAD-1), laminin 332, type VII collagen, and most recently, laminin γ1 can be detected by Western blotting with recombinant or cell-derived forms of these proteins. The definite differentiation between the various immunobullous disorders that comprise about a dozen entities is increasingly important since more diverse treatment options are employed. Exact diagnosis is also pivotal for the prognosis, since some autoimmune bullous diseases may indicate an underlying tumor. Association with a malignancy has been shown in paraneoplastic pemphigus (in 100%) and anti-laminin 332 mucous pemphigoid (in 25%) In pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid, autoantibodies to desmoglein 3, desmoglein 1, and BP180, respectively, have been shown to correlate with the disease activity. The detection of serum autoantibodies during the course of the disease may thus be helpful in guiding treatment decisions in these patients.
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IgA-Pemphigus – Vorkommen von Anti-Desmocollin-1-und Anti-Desmoglein-1-Antikörpern bei einem Patienten
Journal Der Deutschen Dermatologischen Gesellschaft, 2006Co-Authors: Tamara Kopp, Detlef Zillikens, Cassian Sitaru, Friederike Pieczkowski, Achim Schneeberger, Dagmar Födinger, Georg Stingl, Franz KarlhoferAbstract:Background: IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti-keratinocyte cell surface antibody reactivity. Two subtypes have been discerned: in the subcorneal pustular dermatosis type, desmocollin 1 has been identified as a targeted autoantigen, while in few cases of the intraepidermal neutrophilic type, IgA anti-desmoglein 1 or IgA anti-desmoglein 3 reactivity has been demonstrated. Patients and Methods: A 48-year-old white male presented with generalized large confluent pustules. Skin pathology was assessed by histology and direct immunofluorescence analysis. IgG/lgA autoantibodies against desmoglein 1/3 and desmocollin 1 were measured by ELISA and indirect immunofluorescence using desmocollin 1 cDNA-transfected COS7 cells, respectively. Results: Histopathology revealed subcorneal pustules and direct immunofluorescence microscopy exclusively showed in vivo bound IgA with an intercellular pattern in the epidermis. Desmocollin 1 was identified as a target of IgA autoantibodies by indirect immunofluorescence microscopy utilizing desmocollin 1 cDNA-transfected COS7 cells. In addition, IgA anti-desmoglein 1 reactivity was demonstrated by ELISA. Neither IgA anti-desmoglein 3 nor IgG anti-desmoglein 1/3 autoantibodies were present. Conclusions: Both desmocollin 1 and desmoglein 1 were autoantigens in this patient with IgA pemphigus and a distinct clinical presentation. To our knowledge, this is the first IgA pemphigus case with dual autoantibody reactivity.
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IgA pemphigus – Occurrence of anti-Desmocollin 1 and anti-Desmoglein 1 antibody reactivity in an individual patient
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2006Co-Authors: Tamara Kopp, Detlef Zillikens, Cassian Sitaru, Friederike Pieczkowski, Achim Schneeberger, Dagmar Födinger, Georg Stingl, Franz KarlhoferAbstract:Summary Background: IgA pemphigus is a rare pustular autoimmune disease with exclusive IgA anti-keratinocyte cell surface antibody reactivity. Two subtypes have been discerned: in the subcorneal pustular dermatosis type, desmocollin 1 has been identified as a targeted autoantigen, while in few cases of the intraepidermal neutrophilic type, IgA anti-desmoglein 1 or IgA anti-desmoglein 3 reactivity has been demonstrated. Patients and Methods: A 48-year-old white male presented with generalized large confluent pustules. Skin pathology was assessed by histology and direct immunofluorescence analysis. IgG/IgA autoantibodies against desmoglein 1/3 and desmocollin 1 were measured by ELISA and indirect immunofluorescence using desmocollin 1 cDNA-transfected COS7 cells, respectively. Results: Histopathology revealed subcorneal pustules and direct immunofluorescence microscopy exclusively showed in vivo bound IgA with an intercellular pattern in the epidermis. Desmocollin 1 was identified as a target of IgA autoantibodies by indirect immunofluorescence microscopy utilizing desmocollin 1 cDNA-transfected COS7 cells. In addition, IgA anti-desmoglein 1 reactivity was demonstrated by ELISA. Neither IgA anti-desmoglein 3 nor IgG anti-desmoglein 1/3 autoantibodies were present. Conclusions: Both desmocollin 1 and desmoglein 1 were autoantigens in this patient with IgA pemphigus and a distinct clinical presentation. To our knowledge, this is the first IgA pemphigus case with dual autoantibody reactivity. Zusammenfassung Hintergrund: Der IgA Pemphigus ist eine seltene pustulose Autoimmunerkrankung, die sich durch IgA Antikorperreaktivitat gegen Oberflachenmolekule an Keratinozyten auszeichnet.Man unterscheidet zwei Subtypen: den subkornealpustulosen Dermatose-Typ, bei dem Desmocollin 1 das Autoantigen ist, und den intraepidermal-neutrophilen Typ, bei dem in einigen Fallen IgA-anti-Desmoglein-1- oder IgA-anti-Desmoglein-3-Reaktivitat gefunden wurde. Patienten und Methodik: Wir berichten uber einen 48-jahrigen kaukasischen Mann, der sich mit generalisiert auftretenden konfluierenden Pusteln prasentierte. Die zugrunde liegende kutane Immunpathologie wurde mittels histologischer Untersuchung und direkter Immunfluoreszenz analysiert.IgG/IgA-Autoantikorper gegen Desmoglein 1/3 und gegen Desmocollin 1 wurden mittels ELISA und indirekter Immunofluoreszenz an Desmocollin-1-cDNA-transfizierten COS7-Zellen bestimmt. Ergebnisse: Histopathologisch zeigten sich subkorneale Pusteln. In der direkten Immunofluoreszenz waren ausschlieslich in vivo gebundene IgA-Autoantikorper mit einem Interzellularmuster in der Epidermis nachweisbar. Desmocollin 1 wurde mittels indirekter Immunofluoreszenz an Desmocollin-1-cDNA-transfizierten COS7-Zellen als Zielstruktur der IgA-Autoantikorper identifiziert. Zusatzlich konnte IgA-anti-Desmoglein-1-Reaktivitat im ELISA nachgewiesen werden. Weder IgA-anti-Desmoglein-3- noch IgG-anti-Desmoglein-1/3-Autoantikorper waren detektierbar. Schlussfolgerungen: Zusammenfassend identifizieren diese Daten Desmocollin 1 und Desmoglein 1 als Autoantigene bei diesem Patienten. Soweit uns bekannt ist, ist dies der erste Fall eines IgA-Pemphigus mit dualer Autoantikorper-Reaktivitat.
John R Stanley - One of the best experts on this subject based on the ideXlab platform.
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Desmoglein-1, differentiation, and disease
The Journal of clinical investigation, 2013Co-Authors: Christoph M. Hammers, John R StanleyAbstract:Desmoglein-1 (DSG1), a desmosomal protein, maintains the structure of epidermis through its adhesive function. However, heterozygous mutations in DSG1 in humans result in abnormal differentiation, as does downregulation of DSG1 in human skin organ culture, suggesting that it may have important signaling functions. In this issue of the JCI, Harmon et al. elucidate how the binding of the DSG1 cytoplasmic tail to the scaffolding protein Erbin decreases signaling through the Ras-Raf pathway to promote stratification and differentiation of keratinocytes in the epidermis.
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Calcium-Dependent Conformation of Desmoglein 1 Is Required for its Cleavage by Exfoliative Toxin
The Journal of investigative dermatology, 2003Co-Authors: Yasushi Hanakawa, Trevor Selwood, Denise Woo, Chenyan Lin, Norman M. Schechter, John R StanleyAbstract:In bullous impetigo, Staphylococcus aureus spreads under the stratum corneum of skin by elaboration of exfoliative toxin, which hydrolyzes only one peptide bond in a highly structured calcium-binding domain of desmoglein 1, resulting in loss of its function. We investigated the basis of this exquisite specificity. Exfoliative toxin cannot cleave desmoglein 1 pretreated at 56°C or higher or at low or high pH, suggesting that the proper conformation of desmoglein 1 is critical for its cleavage. Because cleavage occurs in an area of desmoglein 1 stabilized by calcium, we determined if the conformation necessary for cleavage is calcium-dependent. Depletion of calcium from desmoglein 1 completely inhibited its cleavage by exfoliative toxin, even after calcium was added back. A change in conformation of desmoglein 1 by calcium depletion was shown, with immunofluorescence and enzyme-linked immunoassay, by loss of binding of PF sera, which recognize conformational epitopes. This change in conformation was confirmed by tryptophan fluorometry and circular dichroism, and was irreversible with repletion of calcium. These data suggest that the specificity of exfoliative toxin cleavage of desmoglein 1 resides not only in simple amino acid sequences but also in its calcium-dependent conformation.
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Expression of Desmoglein 1 Compensates for Genetic Loss of Desmoglein 3 in Keratinocyte Adhesion
The Journal of investigative dermatology, 2002Co-Authors: Yasushi Hanakawa, Norihisa Matsuyoshi, John R StanleyAbstract:The desmoglein compensation hypothesis, namely that one desmoglein can compensate for loss of function of another, has been proposed to explain the tissue specificity of the autoantibody-induced loss of cell adhesion in pemphigus. To validate this hypothesis genetically, we used desmoglein-3 knockout mice (DSG3–/–) that lose their telogen hair prematurely due to loss of adhesion between keratinocytes of the telogen hair club and the outer root sheath, where the only desmoglein expressed in normal mice is desmoglein-3. To determine if Desmoglein-1 could substitute for the function of desmoglein-3 in telogen hair, we produced transgenic mice that express Desmoglein-1 driven off the keratin 14 promoter, and then bred the transgene (TG) into DSG3–/– mice. Immunoblotting showed transgene expression in skin, and immunofluorescence showed Desmoglein-1 in the telogen club of DSG3–/–TG+ but not DSG3–/–TG– mice. DSG3–/–TG– mice lost telogen hair with each wave of telogen, whereas DSG3–/–TG+ mice had markedly delayed and decreased hair loss. DSG3–/– mice also show low weights due to blisters in the oral mucosa. Surprisingly, DSG3–/–TG+ mice showed similar low weights, because the transgene, although expressed in skin, was not well expressed in oral mucous membranes. These studies show that Desmoglein-1 can compensate for loss of desmoglein-3-mediated adhesion, and provide genetic evidence confirming the desmoglein compensation hypothesis.
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Staphylococcal Exfoliative Toxin B Specifically Cleaves Desmoglein 1
The Journal of investigative dermatology, 2002Co-Authors: Masayuki Amagai, Koji Nishifuji, Motoyuki Sugai, Takayuki Yamaguchi, Yasushi Hanakawa, John R StanleyAbstract:Staphylococcal scalded skin syndrome and its localized form, bullous impetigo, show superficial epidermal blister formation caused by exfoliative toxin A or B produced by Staphylococcus aureus. Recently we have demonstrated that exfoliative toxin A specifically cleaves desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study we determine the target molecule for exfoliative toxin B. Exfoliative toxin B injected in neonatal mice caused superficial epidermal blisters, abolished cell surface staining of desmoglein 1, and degraded desmoglein 1 without affecting desmoglein 3 or E-cadherin. When adenovirus-transduced cultured keratinocytes expressing exogenous mouse desmoglein 1 or desmoglein 3 were incubated with exfoliative toxin B, desmoglein 1, but not desmoglein 3, was cleaved. Furthermore, cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal human skin were incubated with exfoliative toxin B, suggesting that living cells were not necessary for exfoliative toxin B cleavage of desmoglein 1. Finally, in vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 with exfoliative toxin B demonstrated that both mouse and human desmoglein 1, but not desmoglein 3, were directly cleaved by exfoliative toxin B in a dose-dependent fashion. These findings demonstrate that exfoliative toxin A and exfoliative toxin B cause blister formation in staphylococcal scalded skin syndrome and bullous impetigo by identical molecular pathophysiologic mechanisms.
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postnatal lethality of p cadherin desmoglein 3 double knockout mice demonstration of a cooperative effect of these cell adhesion molecules in tissue homeostasis of stratified squamous epithelia
Journal of Investigative Dermatology, 2000Co-Authors: Jennifer M Lenox, Peter J Koch, My G Mahoney, Melanie Lieberman, John R Stanley, Glenn L RadiceAbstract:To investigate the cooperativity of different cell adhesion molecules in maintaining the structural integrity of the epidermis, we have generated mice deficient for both a classical cadherin, P-cadherin, and a desmosomal cadherin, desmoglein 3. In epithelial cells, P-cadherin is localized to the adherens junction, whereas desmoglein 3 is found in desmosomes. Previous studies have shown that these two junctional complexes are important for keratinocyte cell-cell adhesion. Both P-cadherin and desmoglein 3 expression are restricted to the basal and most immediate suprabasal cells of the epidermis, whereas both proteins are found throughout the oral mucosal epithelium. Although P-cadherin mutant mice have no apparent defect in epithelial cell adhesion, the desmoglein 3 mutant phenotype resembles that of patients with the autoimmune disease pemphigus vulgaris, in that the mice develop spontaneous mucous membrane blisters and trauma-induced skin blisters. The oral lesions in DSG3–/– mice reduce their food intake, resulting in a runted phenotype; however, most animals recover and live past weaning age. In contrast, animals mutant for both P-cadherin and desmoglein 3 die before weaning. The majority of the double mutant animals die around 1 wk after birth, apparently due to malnutrition. These studies suggest that loss of P-cadherin leads to a more severe desmoglein 3 mutant phenotype in the double knockout mice. This is the first in vivo evidence of possible synergism between a classical and desmosomal cadherin.