The Experts below are selected from a list of 1572 Experts worldwide ranked by ideXlab platform
Luis A Diaz - One of the best experts on this subject based on the ideXlab platform.
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biphasic activation of p38mapk suggests that apoptosis is a downstream event in pemphigus Acantholysis
Journal of Biological Chemistry, 2009Co-Authors: Hua En Lee, Luis A Diaz, Paula Berkowitz, Michael P Chua, Puneet S Jolly, David S RubensteinAbstract:In pemphigus vulgaris and pemphigus foliaceus (PF), autoantibodies against desmoglein-3 and desmoglein-1 induce epidermal cell detachment (Acantholysis) and blistering. Activation of keratinocyte intracellular signaling pathways is emerging as an important component of pemphigus IgG-mediated Acantholysis. We previously reported activation of p38 mitogen-activated protein kinase (MAPK) in response to pathogenic pemphigus vulgaris and PF IgG. Inhibition of p38MAPK blocked pemphigus IgG-induced cytoskeletal reorganization in tissue culture and blistering in pemphigus mouse models. We now extend these observations by demonstrating two peaks of p38MAPK activation in pemphigus tissue culture and mouse models. Administration of the p38MAPK inhibitor SB202190 before PF IgG injection blocked both peaks of p38MAPK phosphorylation and blister formation, consistent with our previous findings; however, administration of the inhibitor 4 h after PF IgG injection blocked only the later peak of p38MAPK activation but failed to block blistering. Examination of the temporal relationship of p38MAPK phosphorylation and apoptosis showed that apoptosis occurs at or after the second peak of p38MAPK activation. The time course of p38MAPK activation and apoptotic markers, as well as the ability of inhibitors of p38MAPK to block activation of the proapoptotic proteinase caspase-3, suggest that activation of apoptosis is downstream to, and a consequence of, p38MAPK activation in pemphigus Acantholysis. Furthermore, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to Acantholysis, whereas the later peak of p38MAPK and apoptosis may not be essential for Acantholysis.
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desmosome signaling inhibition of p38mapk prevents pemphigus vulgaris igg induced cytoskeleton reorganization
Journal of Biological Chemistry, 2005Co-Authors: Paula Berkowitz, Luis A Diaz, Zhi Liu, Jan J Enghild, Michael P Chua, David S RubensteinAbstract:In the human autoimmune blistering disease pemphigus vulgaris (PV) pathogenic antibodies bind the desmosomal cadherin desmoglein-3 (dsg3), causing epidermal cell-cell detachment (Acantholysis). Pathogenic PV dsg3 autoantibodies were used to initiate desmosome signaling in human keratinocyte cell cultures. Heat shock protein 27 (HSP27) and p38MAPK were identified as proteins rapidly phosphorylated in response to PV IgG. Inhibition of p38MAPK activity prevented PV IgG-induced HSP27 phosphorylation, keratin filament retraction, and actin reorganization. These observations suggest that PV IgG binding to dsg3 activates desmosomal signal transduction cascades leading to (i) p38MAPK and HSP27 phosphorylation and (ii) cytoskeletal reorganization, supporting a mechanistic role for signaling in PV IgG-induced Acantholysis. Targeting desmosome signaling via inhibition of p38MAPK and HSP27 phosphorylation may provide novel treatments for PV and other desmosome-associated blistering diseases.
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pemphigus foliaceus with neutrophilic spongiosis evolving to an atypical pemphigus phenotype
Journal of The American Academy of Dermatology, 2004Co-Authors: Tatiana Villas Boas Gabbi, Luis A Diaz, Evandro A. Rivitti, Celina Wakisaka Maruta, Isabela Miranda Bernardelli, Claudia Giuli Santi, Vanessa Kodani, Mirian Nacagami Sotto, Julio Hilariovargas, Valeria AokiAbstract:A 46-year-old Brazilian man, with initial pustular lesions, neutrophilic spongiosis and subcorneal cleavage evolved to an atypical pemphigus phenotype, with suprabasal Acantholysis. Interestingly, his autoantibody profile, tested by immunofluorescence, immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation revealed exclusive IgG anti-desmoglein 1 antibodies in all phases of the disease.
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in vivo blockade of pemphigus vulgaris Acantholysis by inhibition of intracellular signal transduction cascades
British Journal of Dermatology, 2004Co-Authors: Ignacio Sanchezcarpintero, Luis A Diaz, David S Rubenstein, A Espana, Beatriz Pelacho, Lopez N Moratalla, Maria J LopezzabalzaAbstract:Summary Background Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however, in vitro data suggest a role for activation of intracellular signalling cascades. Objectives To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced Acantholysis in vivo. Methods We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades. Results Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced Acantholysis in vivo. Conclusions These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced Acantholysis.
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UVB-induced Acantholysis in endemic Pemphigus foliaceus (Fogo selvagem) and Pemphigus vulgaris.
Journal of the American Academy of Dermatology, 2000Co-Authors: Vitor Manoel Silva Dos Reis, Luis A Diaz, Roseli Peres Toledo, Argelia Lopez, José Eduardo Costa MartinsAbstract:Abstract Background: The autoantibody-mediated disease in fogo selvagem (FS) is aggravated by sunlight exposure. Objective: The aim of this study was to test whether UVB exposure of uninvolved skin of patients with FS (n = 21) enhances epidermal Acantholysis and in vivo binding of FS autoantibodies as compared with a control group (n = 4). Another control group included 8 patients with pemphigus vulgaris (PV). Results: Exposure of uninvolved skin of FS to UVB induces Acantholysis (15/21 patients) with in vivo binding of IgG and C3 to the epidermal intercellular spaces (17/21 patients). Similar results were found in PV (6/8 patients). The test was negative in the control group. Conclusion: Sunlight exposure is harmful in the clinical course of patients with FS and those with PV. Protection from sunlight should be part of the treatment of these patients. (J Am Acad Dermatol 2000;42:571-6.)
Sergei A Grando - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of synergy of autoantibodies to m3 muscarinic acetylcholine receptor and secretory pathway ca2 mn2 atpase isoform 1 in patients with non desmoglein pemphigus vulgaris
International Immunopharmacology, 2020Co-Authors: Alex I Chernyavsky, Krupa G Patel, Sergei A GrandoAbstract:Pemphigus vulgaris (PV) is a potentially lethal mucocutaneous blistering disease characterized by IgG autoantibodies (AuAbs) binding to epidermal keratinocytes and inducing a devastating blistering disease affecting oral and/or esophageal surfaces and, sometimes, also the skin. Anti-keratinocyte AuAbs developed by the desmoglein (Dsg) 1/3 AuAb-negative acute PV patients are pathogenic, as they induced Acantholysis and epidermal split in the experimental models of PV in vitro and in vivo. These PV patients have various combinations of AuAbs to keratinocyte muscarinic acetylcholine receptor subtype M3 (M3AR), the secretory pathway Ca2+/Mn2+-ATPase isoform 1 (SPCA1), and desmocollin 3 whose relative concentrations correlate with the disease activity. In this study, we identified new molecular mechanisms of the synergistic cooperation of AuAbs to M3AR and SPCA1 in inducing Acantholysis in the anti-Dsg 1/3 AuAb-negative PV patients. Anti-M3AR AuAb was found to play an important role in determining the level of intraepidermal split just above the basal cells, caspase to mediate early pro-apoptotic events triggered by anti-SPCA1 AuAb, and the neonatal Fc receptor (FcRn) to contribute to the pathobiological actions of both anti-M3AR and anti-SPCA1 AuAbs. Altogether, these novel results support our original hypothesis that pemphigus Acantholysis is a complex disease process (also known as apoptolysis) initiated by AuAbs directed against different keratinocyte proteins that play important roles in supporting cell viability and regulating vital cell functions.
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differential coupling of m1 muscarinic and α7 nicotinic receptors to inhibition of pemphigus Acantholysis
Journal of Biological Chemistry, 2008Co-Authors: Alex I Chernyavsky, Juan Arredondo, Timothy Piser, Evert Karlsson, Sergei A GrandoAbstract:The mechanisms mediating and regulating assembly and disassembly of intercellular junctions is a subject of intensive research. The IgG autoantibodies produced in patients with the immunoblistering skin disease pemphigus vulgaris (PV) can induce keratinocyte (KC) dyshesion (Acantholysis) via mechanisms that involve signaling kinases targeting intercellular adhesion molecules, thus providing a useful model to study the physiologic regulation of KC cohesion. Previous studies showed that activation of Src and protein kinase C are the earliest events in the PV IgG-induced intracellular phosphorylation cascades and that cholinergic agonists are effective for treating patients with pemphigus. In this study, we sought to elucidate the molecular mechanisms allowing cholinergic agonists to inhibit PV IgG-induced Acantholysis and phosphorylation of KC adhesion molecules. The extent of Acantholysis in KC monolayers correlated closely with the degree of PV IgG-induced phosphorylation of p120- and β-catenins, with classic isoforms of protein kinase C mediating serine phosphorylation of β-catenin and Src-tyrosine phosphorylation of p120-catenin. The M1 muscarinic agonist pilocarpine blocked phosphorylation of both catenins, which could be abolised by the M1 antagonist MT7. The α7 nicotinic agonist AR-R17779 inhibited phosphorylation of P120-cateinin. The α7 antagonist methyllycaconitine abolished the effect of AR-R17779. Okadaic acid abrogated protective effects of agonists on phosphorylation of β-catenin, and pervanadate, on that of p120-catenin. Stimulation of KCs with pilocarpine significantly (p
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activation of keratinocyte muscarinic acetylcholine receptors reverses pemphigus Acantholysis
Journal of The European Academy of Dermatology and Venereology, 1993Co-Authors: Sergei A Grando, Mark V. DahlAbstract:We studied neuroendocrine mediator regulation of adhesion and motility of human epidermal keratinocytes (EK) and found that cholinergic compounds control EK cell-matrix and cell-cell attachment. In this study, we tested the anti-acantholytic activity of muscarinic agonists in pemphigus and non-pemphigus Acantholysis, and investigated the effects of pemphigus antibody (Pab) on the the keratinocyte muscarinic acetylcholine receptors (mAChR). Acantholysis produced by Pab from two patients with pemphigus vulgaris was compared with Acantholysis induced by the serine protease trypsin. the calcium chelator EOT A or the muscarinic antagonist atropine. Trypsinized EK first lost contact with microplate surface and then retracted their intercellular filaments. EDTA-treated cells first detached from each other and then from the dish. EK cultures treated with Pab or atropine rounded up and retracted their intercellular filaments simultaneously, although it took hours to obtain Acantholysis with Pab treatment compared to several seconds with atropine treatment. Addition of acetylcholine or other muscarinic agonists (bethanechol. carbachol or methacholine) to acantholytic cultures reversed both pemphigus and non-pemphigus Acantholysis. Acantholysis induced by atropine reversed spontaneously. Short-term preexposure of EK to Pab significantly increased, and long-term preexposure significantly decreased, the [3H]atropine binding to keratinocyte mAChR. We conclude that muscarinic agonists reverse various types of Acantholysis. including Acantholysis induced by Pab, and that binding of Pab to EK may affect the ability of keratinocyte mAChR to bind its ligands.
Shigaku Ikeda - One of the best experts on this subject based on the ideXlab platform.
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Effects of Steroid, Retinoid, and Protease Inhibitors on the Formation of Acantholysis Induced in Organ Culture of Skins from Patients with Benign Familial Chronic Pemphigus
The Journal of investigative dermatology, 1991Co-Authors: Shigaku Ikeda, Hideoki OgawaAbstract:Abstract Skin explants from two lesional areas and four normal-appearing areas of four patients with benign familial chronic pemphigus (BFCP) were organ cultured with and without various reagents. After 24-h culturing of involved skin with medium only, dissociation of keratinocytes, which was also observed prior to culturing, was exacerbated, and the epidermis became edematous, with a large section detaching from the dermis. These phenomena were not suppressed even when betamethasone, retinol acetate, or camostat mesilate (serine protease inhibitor) was added to the medium. On the other hand, in the cultures of uninvolved skin explants with medium only, widened intercellular spaces were observed 24–48 h after initiation of culture, and dissociation of keratinocytes and acantholytic clefts became apparent after 72 h. Such culture-induced Acantholysis was almost completely suppressed by the addition of betamethasone, but not suppressed by the addition of retinol acetate, EDTA, N-ethylmaleimaide, or pepstatin A. Camostat and SBTI incompletely suppressed the Acantholysis. These findings suggest the possibility that steroid may reduce blistering and that an organ culture of non-lesional benign familial chronic pemphigus (BFCP) skin may be useful for clarifying the pathogenesis, as well as for discovering new drugs for the treatment of BFCP. Further experiments are required to clarify the role of serine proteases in the Acantholysis in this disease.
Beno Michel - One of the best experts on this subject based on the ideXlab platform.
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apoptotic mechanism in pemphigus autoimmunoglobulins induced Acantholysis possible involvement of the egf receptor
Autoimmunity, 2006Co-Authors: Marina Frusiczlotkin, Beno Michel, Dorin Raichenberg, Xin Wang, Michael David, Yoram MilnerAbstract:Pemphigus is an autoimmune cutaneous disease characterized by circulating autoantibodies that cause blistering and erosions on skin and mucous membranes. Circulating autoantibodies bind to epidermal cell membrane and cause cell-cell detachment (Acantholysis), leading to epidermal tissue damage and cell death. The principal target of pemphigus vulgaris autoantibodies (PV-IgG) is desmosomal cadherin desmoglein 3 (Dsg3), a constituent of desmosomes, mediating cell-cell adhesion. Several hypotheses for the mechanisms of Acantholysis induction by PV-IgG exist, but the actual mechanism is not clear as yet. We have previously reported on apoptosis induction in PV-IgG-mediated epidermal tissue and cell damage as a possible mechanism of Acantholysis and cell death (Wang et al. 2004, Apoptosis, 9:131-143). In this study we investigated the involvement of the EGFR and intracellular signal transduction pathways in the PV-IgG-induced apoptosis. We show here that PV-IgG induced activation/autophosphorylation of EGFR in cultured keratinocytes in vitro. The specific tyrosine kinase inhibitor AG1478 abrogated EGFR autophosphorylation, cell death, FasL appearance and Acantholysis, all induced by PV-IgG, in parallel, confirming the involvement of EGFR in this Fas apoptotic cascade. Activation of EGFR was followed by phosphorylation of its downstream substrates, MAP kinase ERK and transcription factor c-Jun, and internalization of EGFR. Pharmacological inactivation of the EGFR and ERK kinase activities, by use of specific inhibitors AG1478 and PD98059 respectively, blocked PV-IgG-induced phosphorylation of EGFR, ERK and c-Jun and cellular apoptosis, measured by flow cytometry and caspase 3 activity. Prolonged activation of EGFR by PV-IgG led to dramatic internalization of this receptor, possibly reducing the ability of the cell to perform survival signals. This suggests that activation of EGFR, followed by its internalization, is pivotal for intracellular apoptotic signal transduction via ERK/c-Jun pathways, leading to Acantholysis. Our experimental data indicate that the EGFR is instrumental in transducing apoptotic/acantholytic signals in keratinocytes cultures in response to PV-IgG treatment. The acantholytic effect caused by PV-IgG binding to cell surface receptors begins with and depends on cell surface receptor (EGFR) activation of intracellular signaling pathways (ERK pathway) and apoptosis induction (FasR pathway), which later lead to major cell-cell separation (Acantholysis) and cell death.
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Corticosteroids, aurothioglucose and soybean trypsin inhibitor do not prevent pemphigus antibody-induced Acantholysis in vitro
British Journal of Dermatology, 2006Co-Authors: John R. Schiltz, Chung-hong Hu, Beno MichelAbstract:SUMMARY Hydrocortisone, triamcinolone acetonide, aurothioglucose and soybean trypsin inhibitor were added to normal human skin explants cultured with IgG from pemphigus serum to determine if Acantholysis could be prevented. At the therapeutic concentrations used none of these compounds prevented binding of the autoantibody to the epidermal target cells, and none prevented Acantholysis. These experiments support the concepts that the pemphigus antibody alone is responsible for producing the acantholytic lesions of pemphigus, that the therapeutic effectiveness of steroids and gold salts is probably due to their ability to reduce serum autoantibody titres and that pemphigus Acantholysis is probably not caused by a serine proteinase.
David S Rubenstein - One of the best experts on this subject based on the ideXlab platform.
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Apoptotic Pathways in Pemphigus
2020Co-Authors: Meryem Bektas, Puneet Jolly, David S RubensteinAbstract:Pemphigus is a group of human autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins induce loss of cell-cell adhesion (Acantholysis). In addition to steric hindrance and activation of intracellular signaling, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces Acantholysis. We review the current literature examining the role of apoptosis in pemphigus. Current data suggest that apoptosis is not required for blister induction, but that activation of proapoptotic proteins, including caspase cysteine proteinases, may sensitize cells to the acantholytic effects of pemphigus IgG
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perp and pemphigus a disease of desmosome destabilization
Journal of Investigative Dermatology, 2009Co-Authors: Meryem Bektas, David S RubensteinAbstract:In this issue, Nguyen et al. demonstrate a role for Perp in desmosome assembly and trafficking and pemphigus IgG–mediated Acantholysis, providing further insights into the complexity of desmosome structure and regulation.
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biphasic activation of p38mapk suggests that apoptosis is a downstream event in pemphigus Acantholysis
Journal of Biological Chemistry, 2009Co-Authors: Hua En Lee, Luis A Diaz, Paula Berkowitz, Michael P Chua, Puneet S Jolly, David S RubensteinAbstract:In pemphigus vulgaris and pemphigus foliaceus (PF), autoantibodies against desmoglein-3 and desmoglein-1 induce epidermal cell detachment (Acantholysis) and blistering. Activation of keratinocyte intracellular signaling pathways is emerging as an important component of pemphigus IgG-mediated Acantholysis. We previously reported activation of p38 mitogen-activated protein kinase (MAPK) in response to pathogenic pemphigus vulgaris and PF IgG. Inhibition of p38MAPK blocked pemphigus IgG-induced cytoskeletal reorganization in tissue culture and blistering in pemphigus mouse models. We now extend these observations by demonstrating two peaks of p38MAPK activation in pemphigus tissue culture and mouse models. Administration of the p38MAPK inhibitor SB202190 before PF IgG injection blocked both peaks of p38MAPK phosphorylation and blister formation, consistent with our previous findings; however, administration of the inhibitor 4 h after PF IgG injection blocked only the later peak of p38MAPK activation but failed to block blistering. Examination of the temporal relationship of p38MAPK phosphorylation and apoptosis showed that apoptosis occurs at or after the second peak of p38MAPK activation. The time course of p38MAPK activation and apoptotic markers, as well as the ability of inhibitors of p38MAPK to block activation of the proapoptotic proteinase caspase-3, suggest that activation of apoptosis is downstream to, and a consequence of, p38MAPK activation in pemphigus Acantholysis. Furthermore, these observations suggest that the earlier peak of p38MAPK activation is part of the mechanism leading to Acantholysis, whereas the later peak of p38MAPK and apoptosis may not be essential for Acantholysis.
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desmosome signaling inhibition of p38mapk prevents pemphigus vulgaris igg induced cytoskeleton reorganization
Journal of Biological Chemistry, 2005Co-Authors: Paula Berkowitz, Luis A Diaz, Zhi Liu, Jan J Enghild, Michael P Chua, David S RubensteinAbstract:In the human autoimmune blistering disease pemphigus vulgaris (PV) pathogenic antibodies bind the desmosomal cadherin desmoglein-3 (dsg3), causing epidermal cell-cell detachment (Acantholysis). Pathogenic PV dsg3 autoantibodies were used to initiate desmosome signaling in human keratinocyte cell cultures. Heat shock protein 27 (HSP27) and p38MAPK were identified as proteins rapidly phosphorylated in response to PV IgG. Inhibition of p38MAPK activity prevented PV IgG-induced HSP27 phosphorylation, keratin filament retraction, and actin reorganization. These observations suggest that PV IgG binding to dsg3 activates desmosomal signal transduction cascades leading to (i) p38MAPK and HSP27 phosphorylation and (ii) cytoskeletal reorganization, supporting a mechanistic role for signaling in PV IgG-induced Acantholysis. Targeting desmosome signaling via inhibition of p38MAPK and HSP27 phosphorylation may provide novel treatments for PV and other desmosome-associated blistering diseases.
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in vivo blockade of pemphigus vulgaris Acantholysis by inhibition of intracellular signal transduction cascades
British Journal of Dermatology, 2004Co-Authors: Ignacio Sanchezcarpintero, Luis A Diaz, David S Rubenstein, A Espana, Beatriz Pelacho, Lopez N Moratalla, Maria J LopezzabalzaAbstract:Summary Background Pemphigus vulgaris (PV) is an autoimmune disease characterized by mucocutaneous intraepithelial blisters and pathogenic autoantibodies against desmoglein 3. The mechanism of blister formation in pemphigus has not been defined; however, in vitro data suggest a role for activation of intracellular signalling cascades. Objectives To investigate the contribution of these signalling pathways to the mechanism of PV IgG-induced Acantholysis in vivo. Methods We used the passive transfer mouse model. Mice were injected with IgG fractions of sera from a patient with PV, with or without pretreatment with inhibitors of proteins that mediate intracellular signalling cascades. Results Inhibitors of tyrosine kinases, phospholipase C, calmodulin and the serine/threonine kinase protein kinase C prevented PV IgG-induced Acantholysis in vivo. Conclusions These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced Acantholysis.