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Luis A Diaz - One of the best experts on this subject based on the ideXlab platform.

  • The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)
    2013
    Co-Authors: Gunter Hans-filho, Ro A. Rivitti, Luis A Diaz
    Abstract:

    We report here a relationship between intramolecular epitope spreading and the clinical onset of the endemic form of pemphigus foliaceus in a Brazilian community with a high prevalence and incidence of the disease. Also known as Fogo Selvagem (FS), this disease is characterized by severe skin blistering and pathogenic anti–desmoglein-1 (Dsg1) autoantibodies. These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment, the hallmark of FS. We show that (a) sera from FS patients in the preclinical stage recognized epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergence of antibodies specific for epitopes on the NH2-terminal EC1 and EC2 domains, (c) all sera from FS patients with active disease recognized the EC1 and/or EC2 domains, and (d) sera from FS patients in remission showed reactivity restricted to EC5. These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading toward epitopes on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset. Moreover, intramolecular epitope spreading may also modulate remissions and relapses of FS. Key words: autoimmunity • autoantibodies • desmogleins • epitope spreading • pemphigu

  • historical profile of the immunopathogenesis of endemic pemphigus foliaceus fogo selvagem perfil historico da imunopatogenia do penfigo foliaceo endemico fogo selvagem
    2005
    Co-Authors: Evandro A. Rivitti, Gunter Hansfilho, Luis A Diaz
    Abstract:

    5 Abstract: Fogo selvagem, or endemic pemphigus foliaceus, is an organ-specific disease, where IgG autoantibodies, especially from the IgG4 subclass are directed against the ectodomains of desmoglein 1, culminating in acantholysis. Genetic and environmental influ- ences modulate this specific autoimmune response; individuals with a determined sequence of alleles (LLEQRRAA) in the positions 67-74 of the third hypervariable region of the HLA-DRB1, or those exposed to hematophagous insects, especially Simulium nigrimanum, are more sus- ceptible to develop the disease. A possible explanation for the development of the autoim- mune process would be antigenic mimicry, initiated by environmental stimuli in those genet- ically predisposed individuals. Keywords: Autoimmunity; Fluorescent antibody technique; Epitope Mapping; Pemphigus Resumo: O fogo selvagem, ou penfigo foliaceo endemico, e doenca orgao-especifica, em que auto-anticorpos IgG, especialmente da subclasse IgG4, se dirigem contra ectodominios da desmogleina 1, culminando no processo de acantolise. Influencias geneticas e ambientais modulam essa resposta auto-imune especifica; nota-se maior susceptibilidade ao penfigo foliaceo endemico nos individuos que apresentam uma determinada sequencia de alelos (LLE- QRRAA) nas posicoes 67-74 da terceira regiao hipervariavel do HLA-DRB1, e naqueles expostos a insetos hematofagos, em especial o Simulium nigrimanum. Uma possivel explicacao para o desencadeamento do processo auto-imune seria o mimetismo antigenico, iniciado por esti- mulos ambientais, nos individuos geneticamente predispostos. Palavras-chave: Auto-imunidade; Imunofluorescencia; Mapeamento de Epitopos; Penfigo

  • anti desmoglein 1 antibodies in onchocerciasis leishmaniasis and chagas disease suggest a possible etiological link to fogo selvagem
    Journal of Investigative Dermatology, 2004
    Co-Authors: Luis A Diaz, Luis A Arteaga, Julio Hilariovargas, Jesus G Valenzuela, Ning Li, Simon Warren, Gunter Hansfilho, Donald P Eaton, Vandir Dos Santos
    Abstract:

    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.

  • A Subset of Pemphigus Foliaceus Patients Exhibits Pathogenic Autoantibodies Against Both Desmoglein-1 and Desmoglein-3
    The Journal of investigative dermatology, 2002
    Co-Authors: Luis A Arteaga, Luis A Diaz, Simon Warren, Zhi Liu, Philip S. Prisayanh, Mong Shang Lin
    Abstract:

    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.

  • The Prevalence of Antibodies against Desmoglein 1 in Endemic Pemphigus Foliaceus in Brazil
    The New England journal of medicine, 2000
    Co-Authors: Simon Warren, Vandir Dos Santos, George J. Giudice, Mong Shang Lin, Raymond G. Hoffmann, Gunter Hans-filho, Evandro A. Rivitti, Luis A Diaz
    Abstract:

    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...

Kathleen J Green - One of the best experts on this subject based on the ideXlab platform.

  • Abstract LB-32: The unique region of a desmosomal cadherin, desmoglein 2, regulates internalization via tail-tail interactions
    Molecular and Cellular Biology, 2012
    Co-Authors: Jing Chen, Evangeline V Amargo, Bhushan V. Desai, Jodi L. Klessner, Dipal M. Patel, Kathleen J Green
    Abstract:

    Desmogleins and desmocollins are desmosomal cadherins that make up the adhesive core of desmosomes, intercellular junctions specialized for helping cells withstand mechanical stress. Desmoglein 2 (Dsg2) is the most widely expressed member of the Dsg subfamily and misregulation of Dsg2 has been reported in many types of cancer. While endocytosis is known to be a critical determinant in regulating cell surface levels of classic cadherins during tissue remodeling and cancer progression, less is known about the regulation of desmosomal cadherins. The trafficking of transmembane proteins is frequently dictated by the presence of specific sequences in their cytoplasmic tails. The cytoplasmic tail of Dsg contains a membrane proximal region, which is conserved in classic cadherins, and a desmoglein unique region (DUR), which is only present in the Dsg family. To determine the contribution of the Dsg2 tail to its endocytosis, we generated a series of mutants with progressive truncations of the cytoplasmic tail. A time course to track the internalized pool of Dsg2 mutants following cell surface biotinylation demonstrated that the DUR attenuates Dsg2 internalization. Analysis of a series of chimeric molecules in which variable lengths of the Dsg2 tail were fused with interleukin-2 ecto- and transmembrane domains showed that this function of the DUR is independent of the status of the Dsg2 ectodomain. With or without the DUR, internalization of the Dsg2 mutants exhibited the same dependence on cholesterol and dynamin, suggesting that the DUR inhibits Dsg29s entry into a common pathway(s). Detergent solubility and sucrose gradient fractionation assays indicated that the presence of the DUR alters the Dsg2 protein complex profile, even though there was no change in the interaction of Dsg2 mutants with known desmoglein binding partners, plakoglobin and plakophilin 3. To test whether the DUR controls the formation of Dsg2 complexes by affecting the oligomeric status of the Dsg2 cytoplasmic domain, we carried out in situ proximity ligation and yeast two hybrid analyses. The data suggest that Dsg2 inter- but not intra-molecular interactions occur, and that these are mediated through the DUR. To investigate whether DUR-dependent inhibition of internalization and mediation of tail-tail interactions are mechanistically linked, one copy of a dimerization motif was fused to the C-terminus of a Dsg2 construct lacking the DUR. Forced dimerization of this mutant using a cell-permeable bivalent compound led to its decreased internalization. Collectively, our studies demonstrate for the first time that the Dsg2 DUR mediates intermolecular interactions between the Dsg2 cytoplasmic domains, and that this function is linked to the inhibition of Dsg2 internalization. This discovery has important implications for normal tissue remodeling and homeostasis, in addition to the pathogenesis of diseases such as cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-32. doi:1538-7445.AM2012-LB-32

  • Desmoglein-2: Ein neuer Regulator der Apoptose im intestinalen Epithel
    Chirurgisches Forum 2008, 2008
    Co-Authors: Med. Mike G. Laukötter, Oskar Laur, Kirsten Gerner-smidt, Ann M. Hopkins, Porfirio Nava, Kathleen J Green, Charles A. Parkos, Asma Nusrat
    Abstract:

    Intestinal epithelial intercellular junctions regulate barrier properties, and have been linked to epithelial differentiation and programmed cell death (apoptosis). However, mechanisms regulating these processes are poorly defined. Desmosomes are critical elements of intercellular junctions; they are punctate structures made up of transmembrane desmosomal cadherins termed Desmoglein-2 (Dsg2) and desmocollin-2 (Dsc2) that affiliate with the underlying intermediate filaments via linker proteins to provide mechanical strength to epithelia. In the present study, we generated an antibody, AH12.2, which recognizes Dsg2. We show that Dsg2 but not another desmosomal cadherin, Dsc2, is cleaved by cysteine proteases during the onset of intestinal epithelial cell (IEC) apoptosis. Small interfering RNA-mediated down-regulation of Dsg2 protected epithelial cells from apoptosis. Moreover, we report that a C-terminal fragment of Dsg2 regulates apoptosis and Dsg2 protein levels. Our studies highlight a novel mechanism by which Dsg2 regulates IEC apoptosis driven by cysteine proteases during physiological differentiation and inflammation. (Supported by grants from the German Research Foundation — La 2359/1-1, the NIH — DK-55679, DK — 61379 (A.N) and the CCFA — fellowship award to A.M.H. and P.N.D).

  • The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes.
    The Journal of biological chemistry, 2005
    Co-Authors: Rachel L. Dusek, Evangeline V Amargo, Spiro Getsios, Feng Chen, Jung K. Park, Vincent L. Cryns, Kathleen J Green
    Abstract:

    Abstract Although a number of cell adhesion proteins have been identified as caspase substrates, the potential role of differentiation-specific desmosomal cadherins during apoptosis has not been examined. Here, we demonstrate that UV-induced caspase cleavage of the human desmoglein 1 cytoplasmic tail results in distinct 17- and 140- kDa products, whereas metalloproteinase-dependent shedding of the extracellular adhesion domain generates a 75-kDa product. In vitro studies identify caspase-3 as the preferred enzyme that cleaves desmoglein 1 within its unique repeating unit domain at aspartic acid 888, part of a consensus sequence not conserved among the other desmosomal cadherins. Apoptotic processing leads to decreased cell surface expression of desmoglein 1 and re-localization of its C terminus diffusely throughout the cytoplasm over a time course comparable with the processing of other desmosomal proteins and cytoplasmic keratins. Importantly, whereas classic cadherins have been reported to promote cell survival, short hairpin RNA-mediated suppression of desmoglein 1 in differentiated keratinocytes protected cells from UV-induced apoptosis. Collectively, our results identify desmoglein 1 as a novel caspase and metalloproteinase substrate whose cleavage likely contributes to the dismantling of desmosomes during keratinocyte apoptosis and also reveal desmoglein 1 as a previously unrecognized regulator of apoptosis in keratinocytes.

  • Assembly of desmosomal cadherins into desmosomes is isoform dependent
    Journal of Investigative Dermatology, 2001
    Co-Authors: Ken Ishii, Leslie J Bannon, Suzanne M. Norvell, Lauren T. Pascoe, Evangeline V Amargo, Kathleen J Green
    Abstract:

    Desmosomes are intercellular adhesive junctions that exhibit cell- and differentiation-specific differences in their molecular composition. In complex epithelia, desmosomes contain multiple representatives of the desmosomal cadherin family, which includes three desmogleins and three desmocollins. Rules governing the assembly of desmosomal cadherin isoforms into desmosomes of different cell types are unknown. Here we compared the assembly properties of desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2), which are widely expressed, with Dsg1 and Dsc1, which are expressed in the differentiated layers of complex epithelia, by introducing myc-tagged forms into simple and squamous epithelial cells that do not express Dsg1 or Dsc1. Dsc2.myc and Dsg2.myc assembled efficiently into desmosomes in every cell type in spite of significant shifts in the stoichiometric relationship between desmogleins and desmocollins. In contrast, Dsc1a.myc, Dsc1b.myc, and Dsg1.myc did not stably incorporate into desmosomes in any line. Coexpression of Dsc1a.myc or Dsc1b.myc and Dsg1.myc did not lead to their colocalization and failed to enhance incorporation of either cadherin into desmosomes. Dsg1.myc, but not Dsc1a, Dsc1b, disrupted desmosome assembly in a cell-type-specific manner, and disruption correlated with the recruitment of Dsg1.myc, but not Dsc1a or Dsc1b, into a Triton-insoluble pool. The plakoglobin:E-cadherin ratio decreased in Dsg1-expressing cells with disrupted desmosomes, but a decrease was also observed in a Dsc1a line. Thus, a modest reduction of plakoglobin associated with E-cadherin is apparently not sufficient to disrupt desmosome assembly. Our results demonstrate that desmosome assembly tolerates large shifts in cadherin stoichiometry, but is sensitive to isoform-specific differences exhibited by desmogleins and desmocollins.

  • analysis of desmosomal cadherin adhesive function and stoichiometry of desmosomal cadherin plakoglobin complexes
    Journal of Investigative Dermatology, 1996
    Co-Authors: Andrew P Kowalczyk, Jeffrey E Borgwardt, Kathleen J Green
    Abstract:

    Desmosomes are intercellular adhesive junctions that associate with the intermediate filament cytoskeleton. The two major classes of transmembrane desmosomal glycoproteins, desmogleins and desmocollins, are widely considered to function as adhesion molecules. This assumption is based in part on their homology to the cadherin family of calcium-dependent homophilic adhesion molecules. In addition, autoantibodies from pemphigus patients bind directly to desmoglein family members and are thought to cause epidermal blistering by inhibiting the function of these cadherins. To directly test the ability of the desmosomal cadherins to mediate adhesion, desmoglein-1 (Dsg1), desmocollin-2 (Dsc2a) and plakoglobin were expressed in mouse L cell fibroblasts. Similar to catenin:classical cadherin complexes, plakoglobin:Dsc2a complexes exhibited an ∼ 1:1 stoichiometry; however, plakoglobin:Dsg1 complexes exhibited a 6:1 stoichiometry. When L cells expressing the desmosomal cadherins were tested for the ability to aggregate in suspension, L cells expressing E-cadherin exhibited extensive aggregation, but L cells expressing Dsg1 or Dsc2a did not aggregate. In addition, L cells co-expressing Dsg1, Dsc2a, and plakoglobin failed to aggregate. The cytoplasmic domain of E-cadherin is thought to play a central role in the adhesive function of E-cadherin by providing a link to the actin cytoskeleton. Therefore, two chimeric cadherins comprising the cytoplasmic domain of E-cadherin and the extracellular domain of either Dsg1 or Dsc2a were expressed in L cells. Both chimeras formed a complex with α - and β -catenin. Nevertheless, neither of these chimeras supported aggregation of L cells when expressed individually or when co-expressed. These data suggest that the extracellular domains of the desmosomal cadherins exhibit functional properties distinct from those of the classical cadherins, such as E-cadherin.

Detlef Zillikens - One of the best experts on this subject based on the ideXlab platform.

  • Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins.
    Experimental dermatology, 2014
    Co-Authors: Jana Langenhan, Detlef Zillikens, Jenny Dworschak, Sandra Saschenbrecker, Lars Komorowski, Wolfgang Schlumberger, Winfried Stöcker, Jürgen Westermann, Andreas Recke, Enno Schmidt
    Abstract:

    Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are life-threatening autoimmune blistering skin diseases. They are characterized by circulating autoantibodies which bind to the ectodomains of desmoglein (Dsg) 1 and Dsg3. These antibodies induce acantholysis in skin and mucous membranes. In severe cases of pemphigus, immunoadsorption is applied to remove total IgG from patient plasma using protein A or other ligands. To develop a specific adsorber for anti-Dsg antibodies, epitope mapping studies of Dsg1 and Dsg3 ectodomains were conducted. Dsg variants were expressed on the surface of HEK-293 cells and analysed for reactivity with pemphigus and control sera by indirect immunofluorescence technique. For Dsg1, a construct consisting of domain 1 directly fused to domain 5, seemed to be suitable for specific immunoadsorption of anti-Dsg1 antibodies. The recognized epitopes were mainly conformation-dependent. However, adsorption of pemphigus foliaceus IgG using this protein coupled to a Sepharose matrix did not completely remove pathogenicity from the sera, as proven by a keratinocyte dissociation assay. In contrast, full-length Dsg1 and Dsg3 ectodomains were able to specifically adsorb anti-Dsg antibodies and to efficiently eliminate pathogenicity. Therefore, the complete and correctly folded ectodomains of both desmogleins are required for therapeutic immunoadsorption.

  • iga pemphigus vorkommen von anti desmocollin 1 und anti desmoglein 1 antikorpern bei einem patienten
    Journal Der Deutschen Dermatologischen Gesellschaft, 2006
    Co-Authors: Tamara Kopp, Detlef Zillikens, Cassian Sitaru, Friederike Pieczkowski, Achim Schneeberger, Dagmar Födinger, Georg Stingl, Franz Karlhofer
    Abstract:

    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.

  • iga pemphigus occurrence of anti desmocollin 1 and anti desmoglein 1 antibody reactivity in an individual patient
    Journal Der Deutschen Dermatologischen Gesellschaft, 2006
    Co-Authors: Tamara Kopp, Detlef Zillikens, Cassian Sitaru, Friederike Pieczkowski, Achim Schneeberger, Dagmar Födinger, Georg Stingl, Franz Karlhofer
    Abstract:

    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.

  • rapid response of iga pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin
    Journal of The American Academy of Dermatology, 2000
    Co-Authors: Claudia Gruss, M Kroiss, Markus Landthaler, T. Vogt, T Hashimoto, Detlef Zillikens, W Stolz
    Abstract:

    Abstract Diagnosing IgA pemphigus and distinguishing between its 2 subtypes, intraepidermal neutrophilic IgA dermatosis type and subcorneal pustular dermatosis type, is important because treatment of IgA pemphigus has to be different from treatment of other blistering autoimmune dermatoses. We present a patient with subcorneal pustular dermatosis type of IgA pemphigus who rapidly responded to systemic treatment with isotretinoin. Specific diagnosis was established by detecting IgA serum activity to desmocollin 1 by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1. No IgA or IgG serum reactivity was found to recombinant forms of desmogleins 1 and 3 by an antigen-specific enzyme-linked immunosorbent assay. The disease was not effectively controlled by conventional therapeutic regimens. Systemic treatment with isotretinoin 20 mg daily led to complete clearance of skin lesions within 3 weeks. Assaying IgA serum reactivity to desmocollin 1, desmoglein 1, and desmoglein 3 as a valuable method for establishing the diagnosis and differentiating the 2 subtypes of IgA pemphigus. Isotretinoin was an effective drug in the treatment of subcorneal pustular dermatosis type of IgA pemphigus in this patient. (J Am Acad Dermatol 2000;43:923-6.)

  • rapid response of iga pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin
    Journal of The American Academy of Dermatology, 2000
    Co-Authors: M Kroiss, T Hashimoto, Detlef Zillikens, Masayuki Amagai, Claus Gruss
    Abstract:

    Diagnosing IgA pemphigus and distinguishing between its 2 subtypes, intraepidermal neutrophilic IgA dermatosis type and subcorneal pustular dermatosis type, is important because treatment of IgA pemphigus has to be different from treatment of other blistering autoimmune dermatoses. We present a patient with subcorneal pustular dermatosis type of IgA pemphigus who rapidly responded to systemic treatment with isotretinoin. Specific diagnosis was established by detecting IgA serum activity to desmocollin 1 by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1. No IgA or IgG serum reactivity was found to recombinant forms of desmogleins 1 and 3 by an antigen-specific enzyme-linked immunosorbent assay. The disease was not effectively controlled by conventional therapeutic regimens. Systemic treatment with isotretinoin 20 mg daily led to complete clearance of skin lesions within 3 weeks. Assaying IgA serum reactivity to desmocollin 1, desmoglein 1, and desmoglein 3 as a valuable method for establishing the diagnosis and differentiating the 2 subtypes of IgA pemphigus. Isotretinoin was an effective drug in the treatment of subcorneal pustular dermatosis type of IgA pemphigus in this patient.

John R Stanley - One of the best experts on this subject based on the ideXlab platform.

  • desmoglein as a target in skin disease and beyond
    Journal of Investigative Dermatology, 2012
    Co-Authors: Masayuki Amagai, John R Stanley
    Abstract:

    Much of the original research on desmosomes and their biochemical components was through analysis of skin and mucous membranes. The identification of desmogleins 1 and 3, desmosomal adhesion glycoproteins, as targets in pemphigus, a fatal autoimmune blistering disease of the skin and mucous membranes, provided the first link between desmosomes, desmogleins, and human diseases. The clinical and histological similarities of staphylococcal scalded skin syndrome or bullous impetigo and pemphigus foliaceus led us to identify desmoglein 1 as the proteolytic target of staphylococcal exfoliative toxins. Genetic analysis of striate palmoplantar keratoderma and hypotrichosis identified their responsible genes as desmogleins 1 and 4, respectively. More recently, these fundamental findings in cutaneous biology were extended beyond the skin. Desmoglein 2, which is expressed earliest among the four isoforms of desmoglein in development and found in all desmosome-bearing epithelial cells, was found to be mutated in arrythmogenic right ventricular cardiomyopathy and has also been identified as a receptor for a subset of adenoviruses that cause respiratory and urinary tract infections. The story of desmoglein research illuminates how dermatological research, originally focused on one skin disease, pemphigus, has contributed to understanding the biology and pathophysiology of many seemingly unrelated tissues and diseases.

  • desmosomes and disease pemphigus and bullous impetigo
    Current Opinion in Cell Biology, 2004
    Co-Authors: Aimee S Payne, Masayuki Amagai, Yasushi Hanakawa, John R Stanley
    Abstract:

    Desmosomal cadherins are the pathophysiologic targets of autoimmune or toxin-mediated disruption in the human diseases pemphigus and bullous impetigo (including its generalized form, called staphylococcal scalded skin syndrome). Experiments exploiting the production of both pathogenic and nonpathogenic antidesmoglein antibodies in pemphigus patients' sera have afforded data that make an invaluable contribution towards identifying the functional domains of the desmogleins involved in intercellular adhesion. Conformational epitopes of antidesmoglein autoantibodies in pemphigus patients' sera and the specific cleavage site of desmoglein 1 by exfoliative toxin have been identified, implicating the N-terminal extracellular domains of the desmogleins as critical regions for controlling intercellular adhesion. Furthermore, the development of active autoimmune mouse models for pemphigus allows in vivo characterization of the disease and its pathogenesis. These studies offer new insight into the potential mechanisms of acantholysis in pemphigus and staphylococcal-associated blistering disease, with implications for the role of desmogleins in desmosomal structure and function.

  • desmoglein isotype expression in the hair follicle and its cysts correlates with type of keratinization and degree of differentiation
    Journal of Investigative Dermatology, 2003
    Co-Authors: John R Stanley, George Cotsarelis
    Abstract:

    Within stratified squamous epithelia, such as the epidermis, desmogleins are generally expressed in a differentiation-specific manner. Similar to the epidermis, the hair follicle is compartmentalized into a hierarchy of cell types based on their level of differentiation. Relatively undifferentiated stem cells in the bulge can generate epidermis, sebaceous gland, and hair bulb matrix cells. The latter give rise to at least six different cell types that keratinize as they move up the hair shaft and inner root sheath. Here, we examined expression patterns of the desmoglein isotypes, desmogleins 1, 2, and 3 in the cutaneous epithelium, and discovered that desmoglein 1 and 2 expression correlated with the state of differentiation of defined populations within the hair follicle. Desmoglein 2 was highly expressed by the least differentiated cells of the cutaneous epithelium, including the hair follicle bulge of the fetus and adult, bulb matrix cells, and basal layer of the outer root sheath. In contrast, desmoglein 1 defined more differentiated cell populations, and was expressed in epidermal suprabasal cells, the inner root sheath, and the innermost layers of the outer root sheath. We found that the expression pattern of desmoglein 3 correlated with different types of keratinization. In areas of trichilemmal keratinization in the follicle, and in cysts arising from these areas, desmoglein 3 was expressed throughout all layers of the outer root sheath and cyst wall. In areas of epidermal-like keratinization, such as in the infundibulum and in epidermal inclusion cysts, desmoglein 3 expression was limited mainly to the basal layer. We conclude that desmoglein expression patterns define compartments of cells in similar states of differentiation within the cutaneous epithelium, and reveal a hierarchy of differentiation among these compartments.

  • Calcium-Dependent Conformation of Desmoglein 1 Is Required for its Cleavage by Exfoliative Toxin
    The Journal of investigative dermatology, 2003
    Co-Authors: Yasushi Hanakawa, Trevor Selwood, Denise Woo, Chenyan Lin, Norman M. Schechter, John R Stanley
    Abstract:

    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.

  • Staphylococcal Exfoliative Toxin B Specifically Cleaves Desmoglein 1
    The Journal of investigative dermatology, 2002
    Co-Authors: Takayuki Yamaguchi, Koji Nishifuji, Motoyuki Sugai, Yasushi Hanakawa, John R Stanley
    Abstract:

    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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  • desmoglein as a target in skin disease and beyond
    Journal of Investigative Dermatology, 2012
    Co-Authors: Masayuki Amagai, John R Stanley
    Abstract:

    Much of the original research on desmosomes and their biochemical components was through analysis of skin and mucous membranes. The identification of desmogleins 1 and 3, desmosomal adhesion glycoproteins, as targets in pemphigus, a fatal autoimmune blistering disease of the skin and mucous membranes, provided the first link between desmosomes, desmogleins, and human diseases. The clinical and histological similarities of staphylococcal scalded skin syndrome or bullous impetigo and pemphigus foliaceus led us to identify desmoglein 1 as the proteolytic target of staphylococcal exfoliative toxins. Genetic analysis of striate palmoplantar keratoderma and hypotrichosis identified their responsible genes as desmogleins 1 and 4, respectively. More recently, these fundamental findings in cutaneous biology were extended beyond the skin. Desmoglein 2, which is expressed earliest among the four isoforms of desmoglein in development and found in all desmosome-bearing epithelial cells, was found to be mutated in arrythmogenic right ventricular cardiomyopathy and has also been identified as a receptor for a subset of adenoviruses that cause respiratory and urinary tract infections. The story of desmoglein research illuminates how dermatological research, originally focused on one skin disease, pemphigus, has contributed to understanding the biology and pathophysiology of many seemingly unrelated tissues and diseases.

  • desmosomes and disease pemphigus and bullous impetigo
    Current Opinion in Cell Biology, 2004
    Co-Authors: Aimee S Payne, Masayuki Amagai, Yasushi Hanakawa, John R Stanley
    Abstract:

    Desmosomal cadherins are the pathophysiologic targets of autoimmune or toxin-mediated disruption in the human diseases pemphigus and bullous impetigo (including its generalized form, called staphylococcal scalded skin syndrome). Experiments exploiting the production of both pathogenic and nonpathogenic antidesmoglein antibodies in pemphigus patients' sera have afforded data that make an invaluable contribution towards identifying the functional domains of the desmogleins involved in intercellular adhesion. Conformational epitopes of antidesmoglein autoantibodies in pemphigus patients' sera and the specific cleavage site of desmoglein 1 by exfoliative toxin have been identified, implicating the N-terminal extracellular domains of the desmogleins as critical regions for controlling intercellular adhesion. Furthermore, the development of active autoimmune mouse models for pemphigus allows in vivo characterization of the disease and its pathogenesis. These studies offer new insight into the potential mechanisms of acantholysis in pemphigus and staphylococcal-associated blistering disease, with implications for the role of desmogleins in desmosomal structure and function.

  • rapid response of iga pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin
    Journal of The American Academy of Dermatology, 2000
    Co-Authors: M Kroiss, T Hashimoto, Detlef Zillikens, Masayuki Amagai, Claus Gruss
    Abstract:

    Diagnosing IgA pemphigus and distinguishing between its 2 subtypes, intraepidermal neutrophilic IgA dermatosis type and subcorneal pustular dermatosis type, is important because treatment of IgA pemphigus has to be different from treatment of other blistering autoimmune dermatoses. We present a patient with subcorneal pustular dermatosis type of IgA pemphigus who rapidly responded to systemic treatment with isotretinoin. Specific diagnosis was established by detecting IgA serum activity to desmocollin 1 by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1. No IgA or IgG serum reactivity was found to recombinant forms of desmogleins 1 and 3 by an antigen-specific enzyme-linked immunosorbent assay. The disease was not effectively controlled by conventional therapeutic regimens. Systemic treatment with isotretinoin 20 mg daily led to complete clearance of skin lesions within 3 weeks. Assaying IgA serum reactivity to desmocollin 1, desmoglein 1, and desmoglein 3 as a valuable method for establishing the diagnosis and differentiating the 2 subtypes of IgA pemphigus. Isotretinoin was an effective drug in the treatment of subcorneal pustular dermatosis type of IgA pemphigus in this patient.

  • Pemphigus Vulgaris Antigen (Desmoglein 3) Is Localized in the Lower Epidermis, the Site of Blister Formation in Patients
    The Journal of investigative dermatology, 1996
    Co-Authors: Masayuki Amagai, Peter J Koch, Takeji Nishikawa, John R Stanley
    Abstract:

    In patients with pemphigus vulgaris, autoantlbodies against the desmosomal glycoprotein desmoglein 3 (Dsg3) cause blisters due to loss of keratinocyte cell-cell adhesion in the basal and immediate suprabasal layer of the deeper epidermis, leaving the superficial intact. Autoantibodies from these patients, usually bind to the cell surface of keratinocytes throughout the entire epidermis, as determined by indirect immunofluorescence. To explain this apparent paradox, we immunoadsorbed pemphigus vulgares sera with the extracellular domains of Dsg3 and desmoglein 1 (Dsgl) produced by insect cells infected with recombinant baculovirus. When adsorbed with extracellular domains of both Dsg3 and Dsg1, these sera no longer stained epidermis, demonstrating that most. if not all, of their cell surface reactivity can be attributed to antibodies against the extracellular domains of these desmogleins. Adsorption with only the Dsg1 extracellular domain left antibodies that stained only the basal and immediate suprabasal layers of the epidermis and immunoprecipitated only Dsg3, not Dsg1, from extracts of cultured cells synthesizing these molecules. In contrast, adsorption with only the Dsg3 extracellular domain Left antibodies that stained only the more superficial epidermis and immunoprecipitated only Dsg1. These data localize Dsg3 exactly to the area in the epidermis where Blisters occur in pemphigus vulgaris.

  • assignment of the human genes for desmocollin 3 dsc3 and desmocollin 4 dsc4 to chromosome 18q12
    Genomics, 1995
    Co-Authors: Masayuki Amagai, Kathleen J Green, Yimin Wang, Shinsei Minoshima, Kazuo Kawamura, Nobuyoshi Shimizu
    Abstract:

    Desmosomes are adhesive intercellular junctions that contain two transmembrane components, desmoglein and desmocollin. cDNA cloning has revealed that both components are members of the cadherin supergene family and consist of multiple isotypes. Desmogleins (Dsg) have three isotypes, Dsg1, Dsg2, and Dsg3. Dsg1 and Dsg3 are also the target antigens of autoimmune blistering diseases, pemphigus foliaceus and pemphigus vulgaris, respectively. Previously, we have demonstrated that the human genes for Dsg1 and Dsg3 are located on chromosome 18q12 by fluorescence in situ hybridization (FISH). Furthermore, both genes were localized on a 320-kb genomic fragment separated by pulsed-field gel electrophoresis. For desmocollins (Dsc for protein, DSC for gene), human cDNAs for Dsc1 and Dsc3 have been isolated from three currently known isotypes. In this study, we report that human genes for Dsc3 and a novel desmocollin, Dsc4, are located on chromosome 18q12 as determined by FISH, suggesting a cluster for desmosomal cadherins on chromosome 18. 14 refs., 1 fig.