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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

  • Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: a paradigm of human autoimmunity.
    Journal of autoimmunity, 2008
    Co-Authors: Donna A. Culton, Evandro A. Rivitti, Ye Qian, David S. Rubenstein, Gunter Hans Filhio, Luis A Diaz
    Abstract:

    Pemphigus encompasses a group of organ specific, antibody mediated autoimmune diseases of the skin characterized by keratinocyte detachment that leads to the development of blisters and erosions, which can become life-threatening. The pathogenic autoantibodies recognize Desmogleins, which are members of the desmosomal cadherin family of cell adhesion molecules. Desmoglein 3 is targeted in pemphigus vulgaris while Desmoglein 1 is targeted in pemphigus foliaceus and its endemic form, Fogo Selvagem. This review will briefly define the salient features of pemphigus and the proposed steps in pathogenesis. We will then summarize the most recent advances in three important areas of investigation: (i) epidemiologic, genetic, and immunologic features of Fogo Selvagem, (ii) molecular mechanisms of injury to the epidermis, and (iii) novel therapeutic strategies targeting specific steps in disease pathogenesis. The advances in each of these three seemingly separate areas contribute to the overall understanding of the pemphigus disease model. These recent advancements also underscore the dynamic interplay between the treatment of patients in a clinical setting and basic science research and have led to an integrative understanding of disease pathogenesis and treatment, allowing pemphigus to serve as a paradigm of human autoimmunity.

  • 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

  • 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...

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: 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, 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.

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 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.

  • 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.

  • 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, Detlef Zillikens, T. Hashimoto, 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, Detlef Zillikens, T. Hashimoto, 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.

Wasim Ahmad - One of the best experts on this subject based on the ideXlab platform.

  • a homozygous nonsense mutation in the human desmocollin 3 dsc3 gene underlies hereditary hypotrichosis and recurrent skin vesicles
    American Journal of Human Genetics, 2009
    Co-Authors: Muhammad Ayub, Sulman Basit, Musharraf Jelani, Fazalur Rehman, Muhammad Aamir Iqbal, Masoom Yasinzai, Wasim Ahmad
    Abstract:

    Desmosomes are the major players in epidermis and cardiac muscles and contribute to intercellular binding and maintenance of tissue integrity. Two important constituents of desmosomes are transmembrane cadherins named Desmogleins and desmocollins. The critical role of these desmosomal proteins in epithelial integrity has been illustrated by their disruption in mouse models and human diseases. In the present study, we have investigated a large family from Afghanistan in which four individuals are affected with hereditary hypotrichosis and the appearance of recurrent skin vesicle formation. All four affected individuals showed sparse and fragile hair on scalp, as well as absent eyebrows and eyelashes. Vesicles filled with thin, watery fluid were observed on the affected individuals' scalps and on most of the skin covering their bodies. A scalp-skin biopsy of an affected individual showed mild hair-follicle plugging. Candidate-gene-based homozygosity linkage mapping assigned the disease locus to 8.30 cM (8.51 Mbp) on chromosome 18q12.1. A maximum multipoint LOD score of 3.30 (θ = 0.00) was obtained at marker D18S877. Sequence analysis of four Desmoglein and three desmocollin genes, contained within the linkage interval, revealed a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in exon-14 of the desmocollin-3 (DSC3) gene.

  • Desmoglein 4 in hair follicle differentiation and epidermal adhesion evidence from inherited hypotrichosis and acquired pemphigus vulgaris
    Cell, 2003
    Co-Authors: Ana Kljuic, Wasim Ahmad, My G Mahoney, Amalia Martinezmir, Hisham Bazzi, John P Sundberg, Ryan F L Oshaughnessy, Moise L Levy, Xavier Montagutelli
    Abstract:

    Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as Desmogleins and desmocollins. We identified a cadherin family member, Desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of Desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that Desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.

  • characterization of the desmosomal cadherin gene family genomic organization of two Desmoglein genes on human chromosome 18q12
    Experimental Dermatology, 2001
    Co-Authors: Jorge Frank, Wasim Ahmad, P B Cserhalmifriedman, Andrey A Panteleyev, Vincent M Aita, Angela M. Christiano
    Abstract:

    : The human Desmoglein genes, Desmogleins 1–3, are members of the desmosomal cadherin superfamily, and encode critical components of the desmosome. These genes are tightly clustered within 150–200 kb of chromosome 18q12.1 and represent excellent candidate genes for genetic disorders of the epidermis linked to this region of the genome. Mutations in Desmoglein 1 have already been implicated in the genetic disorder striate palmoplantar keratoderma. Similarly, a mutation in Desmoglein 3 underlies the balding mouse phenotype, although no human mutations in Desmoglein 3 have been identified to date. In this study, we have characterized the genomic organization of two of the three Desmoglein genes mapped to chromosome 18q12. Comparison of their exon–intron structure reveals the high level of evolutionary conservation expected from these related genes. The identification of the genomic structure of the Desmoglein genes will facilitate mutation detection in genodermatoses with desmosomal abnormalities resulting from underlying defects in these genes.

Angela M. Christiano - One of the best experts on this subject based on the ideXlab platform.

  • Characterization of Desmoglein expression in the normal prostatic gland. Desmoglein 2 is an independent prognostic factor for aggressive prostate cancer.
    PLoS ONE, 2014
    Co-Authors: Alison G. Barber, Mireia Castillo-martin, Dennis M. Bonal, Benjamin A. Rybicki, Angela M. Christiano, Carlos Cordon-cardo
    Abstract:

    Purpose The expression of Desmogleins (DSGs), which are known to be crucial for establishing and maintaining the cell-cell adhesion required for tissue integrity, has been well characterized in the epidermis and hair follicle; however, their expression in other epithelial tissues such as prostate is poorly understood. Although downregulation of classical cadherins, such as E-cadherin, has been described in prostate cancer tissue samples, the expression of Desmogleins has only been previously reported in prostate cancer cell lines. In this study we characterized Desmoglein expression in normal prostate tissues, and further investigated whether Desmoglein 2 (DSG2) expression specifically can serve as a potential clinical prognostic factor for patients diagnosed with primary prostate cancer. Experimental Design We utilized immunofluorescence to examine DSG2 expression in normal prostate (n = 50) and in a clinically well-characterized cohort of prostate cancer patients (n = 414). Correlation of DSG2 expression with clinico-pathological characteristics and biochemical recurrence was analyzed to assess its clinical significance. Results These studies revealed that DSG2 and DSG4 were specifically expressed in prostatic luminal cells, whereas basal cells lack their expression. In contrast, DSG1 and DSG3 were not expressed in normal prostate epithelium. Further analyses of DSG2 expression in prostate cancer revealed that reduced levels of this biomarker were a significant independent marker of poor clinical outcome. Conclusion Here we report for the first time that a low DSG2 expression phenotype is a useful prognostic biomarker of tumor aggressiveness and may serve as an aid in identifying patients with clinically significant prostate cancer.

  • a recurrent intragenic deletion in the Desmoglein 4 gene underlies localized autosomal recessive hypotrichosis
    Journal of Investigative Dermatology, 2004
    Co-Authors: Celia Moss, Angela M. Christiano, Amalia Martinezmir, Hamut Lam, Marija Tadinstrapps, Ana Kljuic
    Abstract:

    Abbreviations: DSG4/DSG4, human Desmoglein 4 gene/protein mouse Desmoglein 4 gene/protein; LAH, localized autosomal recessive hypotrichosis

  • a novel mouse desmosomal cadherin family member Desmoglein 1γ
    Experimental Dermatology, 2003
    Co-Authors: Ana Kljuic, Angela M. Christiano
    Abstract:

    The mouse Desmogleins are members of the desmosomal cadherin superfamily, and are critical structural components of the desmosome. The genes encoding mouse Desmogleins are tightly clustered within 600 kb of chromosome 18, within a desmosomal cadherin gene family also containing the three desmocollin genes. In this study, we have characterized a novel mouse Desmoglein gene, highly homologous to both mouse and human Dsg1, designated Desmoglein 1 gamma (Dsg1c). Dsg1 gamma shares 83% amino acid identity to the previously described mouse Dsg1, now designated as Dsg1 alpha, and 32% and 40% identity to mouse Dsg2 and 3, respectively. The Dsg1 gamma gene maps within the desmosomal gene cluster, between Dsc1 and Dsg1 alpha. Comparison of its exon-intron structure revealed a high level of evolutionary conservation with related family members. In contrast to Dsg1 alpha and Dsg3 whose expression is largely restricted to the skin, Dsg1 gamma is also expressed in the brain, skeletal muscle, and liver, among other tissues, and is thus more similar to Dsg2 in its tissue distribution. Interestingly, an orthologous Dsg1 gamma was not found in the human genome, suggesting that the desmosomal cadherin gene cluster contracted during mammalian evolution.

  • characterization of the desmosomal cadherin gene family genomic organization of two Desmoglein genes on human chromosome 18q12
    Experimental Dermatology, 2001
    Co-Authors: Jorge Frank, Wasim Ahmad, P B Cserhalmifriedman, Andrey A Panteleyev, Vincent M Aita, Angela M. Christiano
    Abstract:

    : The human Desmoglein genes, Desmogleins 1–3, are members of the desmosomal cadherin superfamily, and encode critical components of the desmosome. These genes are tightly clustered within 150–200 kb of chromosome 18q12.1 and represent excellent candidate genes for genetic disorders of the epidermis linked to this region of the genome. Mutations in Desmoglein 1 have already been implicated in the genetic disorder striate palmoplantar keratoderma. Similarly, a mutation in Desmoglein 3 underlies the balding mouse phenotype, although no human mutations in Desmoglein 3 have been identified to date. In this study, we have characterized the genomic organization of two of the three Desmoglein genes mapped to chromosome 18q12. Comparison of their exon–intron structure reveals the high level of evolutionary conservation expected from these related genes. The identification of the genomic structure of the Desmoglein genes will facilitate mutation detection in genodermatoses with desmosomal abnormalities resulting from underlying defects in these genes.