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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.

  • 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...

  • The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic.
    The Journal of investigative dermatology, 1999
    Co-Authors: Xiang Ding, Luis A Diaz, Janet A. Fairley, George J. Giudice, Zhi Liu
    Abstract:

    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.

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.

  • modern diagnosis of autoimmune blistering skin diseases
    Autoimmunity Reviews, 2010
    Co-Authors: Enno Schmidt, Detlef Zillikens
    Abstract:

    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.

  • pemphigus igg causes skin splitting in the presence of both desmoglein 1 and desmoglein 3
    American Journal of Pathology, 2007
    Co-Authors: Volker Spindler, Detlef Zillikens, Detlev Drenckhahn, Jens Waschke
    Abstract:

    According to the desmoglein (Dsg) compensation concept, different epidermal cleavage planes observed in pemphigus vulgaris and pemphigus foliaceus have been proposed to be caused by different autoantibody profiles against the desmosomal proteins Dsg 1 and Dsg 3. According to this model, Dsg 1 autoantibodies would only lead to epidermal splitting in those epidermal layers in which no Dsg 3 is present to compensate for the functional loss of Dsg 1. We provide evidence that both pemphigus foliaceus-IgG containing Dsg 1- but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were equally effective in causing epidermal splitting in human skin and keratinocyte dissociation in vitro. These effects were present where keratinocytes expressed both Dsg 1 and Dsg 3, demonstrating that Dsg 3 does not compensate for Dsg 1 inactivation. Rather, the cleavage plane in intact human skin caused by pemphigus autoantibodies was similar to the plane of keratinocyte dissociation in response to toxin B-mediated inactivation of Rho GTPases. Because we recently demonstrated that pemphigus-IgG causes epidermal splitting by inhibition of Rho A, we propose that Rho GTPase inactivation contributes to the mechanisms accounting for the cleavage plane in pemphigus skin splitting.

  • 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.

Hendri H. Pas - One of the best experts on this subject based on the ideXlab platform.

  • HLA class II alleles of susceptibility and protection in Brazilian and Dutch pemphigus foliaceus
    The British journal of dermatology, 2018
    Co-Authors: L De Sena Nogueira Maehara, Marcel F. Jonkman, Hendri H. Pas, F C De-souza-santana, Adriana Maria Porro, E V C Marcos, S. Ura, Ilja M. Nolte, Jane Tomimori
    Abstract:

    Pemphigus foliaceus (PF) is a worldwide chronic autoimmune bullous disease targeting desmoglein 1 (Dsg 1) on epithelial cell surface of skin and mucous membranes, causing lesions in skin but sparing mucosa, since the latter contain compensating desmoglein 3(1) . Several environmental triggers for the autoimmune reaction have been imputed, such as drugs, ultraviolet radiation and mercurium. Human leucocyte antigens class II (HLA-DR4) alleles were linked to the disease in Ashkenazi Jews and other populations(2) . For endemic pemphigus foliaceus in Brazil, named fogo selvagem (FS), HLA-DRB1*04 was shown to have a relative risk >14 for the disease(3) . This article is protected by copyright. All rights reserved.

  • The IgG "Lupus-Band" Deposition Pattern of Pemphigus Erythematosus Association With the Desmoglein 1 Ectodomain as Revealed by 3 Cases
    Archives of dermatology, 2012
    Co-Authors: Dyah A. M. Oktarina, Gilles F. H. Diercks, Marcel F. Jonkman, Angelique Poot, Duco Kramer, Hendri H. Pas
    Abstract:

    Background Pemphigus foliaceus is an autoimmune skin disease characterized by subcorneal blistering and IgG antibodies directed against desmoglein 1. In the skin, these antibodies deposit intraepidermally. On rare occasions, an additional “lupus band” of granular depositions of IgG and complement is seen along the epidermal basement membrane zone. This combined pattern has been connected with a variant of pemphigus foliaceus named pemphigus erythematosus. Observations We describe 3 pemphigus foliaceus cases in which phototherapy was administered after a misdiagnosis of psoriasis. This treatment resulted in a flare of skin lesions. Direct immunofluorescence of skin biopsy specimens that were obtained several weeks later demonstrated intraepidermal and granular basement membrane zone depositions. The basement membrane zone depositions consisted of IgG, complement, and the ectodomain of desmoglein 1 and were located below the lamina densa. Conclusions High doses of UV light are likely to induce the cleaving of the desmoglein 1 ectodomain. In patients with pemphigus foliaceus, the circulating anti–desmoglein 1 antibodies precipitate this cleaved-off ectodomain along the basement membrane zone, resulting in a lupus band–like appearance. In pemphigus erythematosus, a similar mechanism may be active, which might explain the lupus-band phenomenon.

  • igg induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis
    British Journal of Dermatology, 2011
    Co-Authors: Dyah A. M. Oktarina, Gilles F. H. Diercks, Marcel F. Jonkman, G Van Der Wier, Hendri H. Pas
    Abstract:

    Background In pemphigus circulating IgG is present with the desmosomal cadherins desmoglein (Dsg) 1 and 3. In the epidermis of patients, this IgG deposits in a pattern that is often partly granular and does not reflect the normal Dsg distribution. Objective To understand why the IgG deposits in a granular pattern in the skin of patients with pemphigus. Patients/Methods We analysed the distribution of IgG and desmosomal adhesion molecules in skin biopsies of 18 patients with pemphigus vulgaris (PV) and 10 with pemphigus foliaceus (PF) by double staining immunofluorescence. The effect of IgG on desmosomal proteins was studied in an in vitro skin model. Results In PF skin Dsg1, but not Dsg3, was aberrantly distributed in the same partly granular pattern as the IgG. Vice versa, in skin of PV patients with antiDsg3 antibodies, Dsg3, but not Dsg1, colocalized with the granular IgG. Plakoglobin also coclustered with IgG and Dsg, but this was far more prominent with Dsg1 than with Dsg3. In areas of heavy Dsg1 clustering, but not in areas of heavy Dsg3 clustering, intercellular widening between keratinocytes was present. Patient IgG, but not Fab fragments, induced the same Dsg clustering in vitro. Conclusions The IgG-induced clustering of the Dsg autoantigens underlies the granular IgG deposition in patient skin. In PF and in mucocutaneous PV, Dsg1 clustering, but not Dsg3 clustering, correlates with nonacantholytic intercellular widening between desmosomes. In the patient the Dsg becomes sequestered from desmosomal components which fits in with the desmoglein nonassembly depletion hypothesis, indicating that targeted nonjunctional Dsg is no longer available to be incorporated into desmosomes and this leads to disturbed assembly, and Dsg-depleted desmosomes.

  • Staphylococcal scalded skin syndrome: loss of desmoglein 1 in patient skin
    European journal of dermatology : EJD, 2010
    Co-Authors: A. Susanne Aalfs, D. A. Mira Oktarina, Gilles F. H. Diercks, Marcel F. Jonkman, Hendri H. Pas
    Abstract:

    Staphylococcal scalded skin syndrome (SSSS) is a blistering disease of the skin caused by an infection with certain strains of Staphylococcus aureus. In vitro studies have suggested that exfoliative toxins secreted by these bacteria cleave the desmosomal adhesion molecule desmoglein 1 leading to loss of cell-cell contact in the superficial epidermis. In this study we investigated the fate of desmoglein 1 in biopsies of patients with SSSS to see whether the ectodomain of desmoglein 1 is cleaved. Our data largely confirm previous in vitro data. The different biopsies demonstrated the loss of the ectodomain of desmoglein 1 to different degrees. The endodomain of desmoglein 1 meanwhile remained present. Most remarkably, in one of our patients, the immunofluorescent analysis demonstrated that not desmoglein1 but desmocollin 1, another desmosomal cadherin, became affected. This raises the question if other toxins and/or other bacteria than Staphylococcus aureus might also induce SSSS.

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.

Dyah A. M. Oktarina - One of the best experts on this subject based on the ideXlab platform.

  • The IgG "Lupus-Band" Deposition Pattern of Pemphigus Erythematosus Association With the Desmoglein 1 Ectodomain as Revealed by 3 Cases
    Archives of dermatology, 2012
    Co-Authors: Dyah A. M. Oktarina, Gilles F. H. Diercks, Marcel F. Jonkman, Angelique Poot, Duco Kramer, Hendri H. Pas
    Abstract:

    Background Pemphigus foliaceus is an autoimmune skin disease characterized by subcorneal blistering and IgG antibodies directed against desmoglein 1. In the skin, these antibodies deposit intraepidermally. On rare occasions, an additional “lupus band” of granular depositions of IgG and complement is seen along the epidermal basement membrane zone. This combined pattern has been connected with a variant of pemphigus foliaceus named pemphigus erythematosus. Observations We describe 3 pemphigus foliaceus cases in which phototherapy was administered after a misdiagnosis of psoriasis. This treatment resulted in a flare of skin lesions. Direct immunofluorescence of skin biopsy specimens that were obtained several weeks later demonstrated intraepidermal and granular basement membrane zone depositions. The basement membrane zone depositions consisted of IgG, complement, and the ectodomain of desmoglein 1 and were located below the lamina densa. Conclusions High doses of UV light are likely to induce the cleaving of the desmoglein 1 ectodomain. In patients with pemphigus foliaceus, the circulating anti–desmoglein 1 antibodies precipitate this cleaved-off ectodomain along the basement membrane zone, resulting in a lupus band–like appearance. In pemphigus erythematosus, a similar mechanism may be active, which might explain the lupus-band phenomenon.

  • ONLINE FIRST OBSERVATION The IgG “Lupus-Band ” Deposition Pattern
    2012
    Co-Authors: Of Pemphigus Erythematosus, Gilles F. H. Diercks, Dyah A. M. Oktarina, Phd Angelique, M. Poot, Md Duco Kramer, Arch Dermatol
    Abstract:

    Background: Pemphigus foliaceus is an autoimmune skin disease characterized by subcorneal blistering and IgG antibodies directed against desmoglein 1. In the skin, these antibodies deposit intraepidermally. On rare occasions, an additional “lupus band ” of granular depositions of IgG and complement is seen along the epidermal basement membrane zone. This combined pattern has been connected with a variant of pemphigus foliaceus named pemphigus erythematosus. Observations: We describe 3 pemphigus foliaceus cases in which phototherapy was administered after a misdiagnosis of psoriasis. This treatment resulted in a flare of skin lesions. Direct immunofluorescence of skin biopsy specimens that were obtained several weeks later demonstrated intraepidermal and granular basement membrane zone depositions. The basement membrane zone depositions consisted of IgG, complement, and the ectodomain of desmoglein 1 and were located below the lamina densa. Conclusions: High doses of UV light are likely to induce the cleaving of the desmoglein 1 ectodomain. In patients with pemphigus foliaceus, the circulating anti– desmoglein 1 antibodies precipitate this cleaved-off ectodomain along the basement membrane zone, resulting in a lupus band–like appearance. In pemphigus erythematosus, a similar mechanism may be active, which might explain the lupus-band phenomenon

  • Association With the Desmoglein 1 Ectodomain as Revealed by 3 Cases
    2012
    Co-Authors: Of Pemphigus Erythematosus, Gilles F. H. Diercks, Dyah A. M. Oktarina, Phd Angelique, M. Poot, Md Duco Kramer, Phd Marcel, F. Jonkman, Phd Hendri, H. Pas
    Abstract:

    Background: Pemphigus foliaceus is an autoimmune skin disease characterized by subcorneal blistering and IgG antibodies directed against desmoglein 1. In the skin, these antibodies deposit intraepidermally. On rare occasions, an additional “lupus band ” of granular depositions of IgG and complement is seen along the epidermal basement membrane zone. This combined pattern has been connected with a variant of pemphigus foliaceus named pemphigus erythematosus. Observations: We describe 3 pemphigus foliaceus cases in which phototherapy was administered after a misdiagnosis of psoriasis. This treatment resulted in a flare of skin lesions. Direct immunofluorescence of skin biopsy specimens that were obtained several weeks later demonstrated intraepidermal and granular basement membrane zone depositions. The basement membrane zone depositions consisted of IgG, complement, and the ectodomain of desmoglein 1 and were located below the lamina densa. Conclusions: High doses of UV light are likely to induce the cleaving of the desmoglein 1 ectodomain. In patients with pemphigus foliaceus, the circulating anti– desmoglein 1 antibodies precipitate this cleaved-off ectodomain along the basement membrane zone, resulting in a lupus band–like appearance. In pemphigus erythematosus, a similar mechanism may be active, which might explain the lupus-band phenomenon

  • igg induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis
    British Journal of Dermatology, 2011
    Co-Authors: Dyah A. M. Oktarina, Gilles F. H. Diercks, Marcel F. Jonkman, G Van Der Wier, Hendri H. Pas
    Abstract:

    Background In pemphigus circulating IgG is present with the desmosomal cadherins desmoglein (Dsg) 1 and 3. In the epidermis of patients, this IgG deposits in a pattern that is often partly granular and does not reflect the normal Dsg distribution. Objective To understand why the IgG deposits in a granular pattern in the skin of patients with pemphigus. Patients/Methods We analysed the distribution of IgG and desmosomal adhesion molecules in skin biopsies of 18 patients with pemphigus vulgaris (PV) and 10 with pemphigus foliaceus (PF) by double staining immunofluorescence. The effect of IgG on desmosomal proteins was studied in an in vitro skin model. Results In PF skin Dsg1, but not Dsg3, was aberrantly distributed in the same partly granular pattern as the IgG. Vice versa, in skin of PV patients with antiDsg3 antibodies, Dsg3, but not Dsg1, colocalized with the granular IgG. Plakoglobin also coclustered with IgG and Dsg, but this was far more prominent with Dsg1 than with Dsg3. In areas of heavy Dsg1 clustering, but not in areas of heavy Dsg3 clustering, intercellular widening between keratinocytes was present. Patient IgG, but not Fab fragments, induced the same Dsg clustering in vitro. Conclusions The IgG-induced clustering of the Dsg autoantigens underlies the granular IgG deposition in patient skin. In PF and in mucocutaneous PV, Dsg1 clustering, but not Dsg3 clustering, correlates with nonacantholytic intercellular widening between desmosomes. In the patient the Dsg becomes sequestered from desmosomal components which fits in with the desmoglein nonassembly depletion hypothesis, indicating that targeted nonjunctional Dsg is no longer available to be incorporated into desmosomes and this leads to disturbed assembly, and Dsg-depleted desmosomes.