Materiały źródłowe

• #1 Pathogenesis, clinical manifestations, and diagnosis of pemphigus – UpToDate

  https://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-pemphigus

  Pemphigus is defined as a group of life-threatening blistering disorders characterized by acantholysis (loss of keratinocyte to keratinocyte adhesion) that results in the formation of intraepithelial blisters in mucous membranes and skin. The process of acantholysis is induced by the binding of circulating immunoglobulin G (IgG) autoantibodies to intercellular adhesion molecules. […] The pathogenesis, clinical features, and diagnosis of pemphigus will be discussed here. […] The different forms of pemphigus are distinguished by their clinical features, associated autoantigens, and laboratory findings.

• #2 Pathogenesis, clinical manifestations, and diagnosis of pemphigus – UpToDate

  https://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-pemphigus/print

  Pemphigus is defined as a group of life-threatening blistering disorders characterized by acantholysis (loss of keratinocyte to keratinocyte adhesion) that results in the formation of intraepithelial blisters in mucous membranes and skin. The process of acantholysis is induced by the binding of circulating immunoglobulin G (IgG) autoantibodies to intercellular adhesion molecules. […] The pathogenesis, clinical features, and diagnosis of pemphigus will be discussed here.

• #3 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. […] Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. […] Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. […] Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. […] The pathological mechanisms of PV are controversial and remain a hot topic under debate in the field. […] Various signaling pathways are at play in the development of pemphigus acantholysis.

• #4 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. […] Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. […] Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. […] Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. […] The pathological mechanisms of PV are controversial and remain a hot topic under debate in the field. […] Ample studies support the concept that PV is caused by the pathogenic IgG autoantibodies directed against DSG3 as well as DSG1.

• #5 Pemphigus – Wikipedia

  https://en.wikipedia.org/wiki/Pemphigus

  Pemphigus, from 1886 medical book Microscopic image of direct immunofluorescence using an anti-IgG antibody. The tissue is skin from a patient with Pemphigus vulgaris. Note the intercellular IgG deposits in the epidermis and the early intraepidermal vesicle caused by acantholysis. Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes. In pemphigus, autoantibodies form against desmoglein, which forms the „glue” that attaches adjacent epidermal cells via attachment points called desmosomes. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes detached, a phenomenon called acantholysis. This causes blisters that slough off and turn into sores. […] Pemphigus defines a group of autoimmune intraepithelial blistering diseases that are characterized by loss of normal cell-cell adhesion (acantholysis), and by the presence of pathogenic (predominantly IgG) autoantibodies reacting against epithelial adhesion molecules. […] Definitive diagnosis also requires the demonstration of antidesmoglein autoantibodies by direct immunofluorescence on the skin biopsy. These antibodies appear as IgG deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire.

• #6 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. […] Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. […] Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. […] Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. […] The pathological mechanisms of PV are controversial and remain a hot topic under debate in the field. […] Ample studies support the concept that PV is caused by the pathogenic IgG autoantibodies directed against DSG3 as well as DSG1.

• #7 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. […] Understanding these mechanisms of disease has led to rational targeted therapeutic strategies. […] Immunochemical and molecular cloning techniques have shown that the antigens in pemphigus are desmogleins (Dsgs), transmembrane glycoproteins of desmosomes that confer cell-cell adhesion within the epidermis. […] The pivotal role of the pemphigus antigens for keratinocyte adhesion has been shown by genetic deletion of the PV antigen, Dsg3, in mice and enzymatic inactivation of the PF antigen, Dsg1, by exfoliative toxin A (produced by Staphylococcus aureus) in mice and humans.

• #8 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. […] Understanding these mechanisms of disease has led to rational targeted therapeutic strategies. […] Immunochemical and molecular cloning techniques have shown that the antigens in pemphigus are desmogleins (Dsgs), transmembrane glycoproteins of desmosomes that confer cell-cell adhesion within the epidermis. […] The pivotal role of the pemphigus antigens for keratinocyte adhesion has been shown by genetic deletion of the PV antigen, Dsg3, in mice and enzymatic inactivation of the PF antigen, Dsg1, by exfoliative toxin A (produced by Staphylococcus aureus) in mice and humans.

• #9 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Passive transfer experiments in mice have confirmed the pathogenicity of circulating IgG antibodies from pemphigus patients, which result in dose-dependent disease and point to a predominance of the IgG4 subclass in PF patients’ sera and in disease induction among mice. […] The observation of neonatal PV in babies born to mothers with PV corresponds to a passive transfer experiment in humans. […] Dissection of the serum autoantibody profiles in pemphigus patients led to the observation that PV patients show a dual status of serum antibodies. […] These autoantibody profiles, combined with the determination of the normal tissue distributions of Dsg3 and Dsg1, led to the desmoglein compensation model to explain the distinct histological sites of blister formation in mucosal PV, mucocutaneous PV, and PF.

• #10 Pemphigus in India – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/pemphigus-in-india/

  Pemphigus being an autoimmune disease driven by autoantibody against epidermal antigen, it is expected from immunological point of view that Th2 predominance would be observed. […] The predominant subclass involved in pathogenesis of pemphigus is IgG 4 irrespective of type of pemphigus, as was assessed by direct immunofluorescence (DIF) as well as indirect immunofluorescence (IIF) study using normal human abdominal skin as substrate.

• #11 Pathogenesis of Endemic Pemphigus Foliaceus | Plastic Surgery Key

  https://plasticsurgerykey.com/pathogenesis-of-endemic-pemphigus-foliaceus/

  The autoantibody response in FS is based on IgG, and is predominantly of the IgG4 subclass. […] Total IgG4, F(ab)2, and Fab fragments of FS IgG are all pathogenic in the FS mouse model. […] Anti-Dsg1 antibodies are detected not only in the sera of FS patients, but also in normal controls that live in endemic areas. […] At the molecular level, FS immunopathogenesis presents as an epitope-spreading model. […] When analyzing preclinical stages of FS, EC-5 remains the major domain involved in the autoimmune response; however, intramolecular spreading may occur at the disease onset, leading to an EC1-2 oriented IgG response.

• #12 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Abundant data suggest that some pemphigus antibodies directly interfere with cell adhesion. […] Mechanistically, some PV autoantibodies have been shown to interfere directly with homophilic trans-interaction of Dsg3 molecules, presumably through steric hindrance of Dsg adhesion. […] The model discussed here has been called the Dsg nonassembly depletion hypothesis. […] This model attributes loss of cell adhesion to the ability of multivalent pemphigus anti-Dsg antibodies to crosslink and cluster Dsgs. […] Early evidence implicating intracellular signaling mechanisms in induction of acantholysis came from the observation that polyclonal PV IgG causes retraction of keratin intermediate filaments in cultured keratinocytes from wild-type mice but not from PG-deficient mice. […] This signaling cascade was also shown to be active in PV and PF patients’ skin.

• #13 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Abundant data suggest that some pemphigus antibodies directly interfere with cell adhesion. […] Mechanistically, some PV autoantibodies have been shown to interfere directly with homophilic trans-interaction of Dsg3 molecules, presumably through steric hindrance of Dsg adhesion. […] The model discussed here has been called the Dsg nonassembly depletion hypothesis. […] This model attributes loss of cell adhesion to the ability of multivalent pemphigus anti-Dsg antibodies to crosslink and cluster Dsgs. […] Early evidence implicating intracellular signaling mechanisms in induction of acantholysis came from the observation that polyclonal PV IgG causes retraction of keratin intermediate filaments in cultured keratinocytes from wild-type mice but not from PG-deficient mice. […] This signaling cascade was also shown to be active in PV and PF patients’ skin.

• #14 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] This theory explores new mechanisms with the findings obtained by independent groups. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53. […] It indicates that the loss/disruption of DSG3 alone is sufficient to induce aberrant p53 response and thus the disruption of DSG3 mediated intercellular junctions does not result solely from steric hindrance but rather causes dysfunction of cellular anti-stress response.

• #15 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] Disruption of this remodeling process including the activation of the above-mentioned signaling pathways has been reported in PV. […] The apoptosis pathway in PV is proved by experimental studies that demonstrate that apoptotic signaling is activated by PV autoantibody and anti-Fas receptor (FasR) antibody. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53.

• #16 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] Disruption of this remodeling process including the activation of the above-mentioned signaling pathways has been reported in PV. […] The apoptosis pathway in PV is proved by experimental studies that demonstrate that apoptotic signaling is activated by PV autoantibody and anti-Fas receptor (FasR) antibody. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53.

• #17

  https://www.jci.org/articles/view/11828

  Desmogleins 1 and 3 are members of the cadherin family of adhesion molecules. They are transmembrane proteins that interact with plakoglobin, a component of the dense plaque of the desmosome. It is believed that antibodies to Dsg3 and Dsg1 directly induce acantholysis by interfering with the adhesive function of these target molecules. […] Induction of acantholysis is an active process that appears to be more complex than the simple interaction of antibodies with adhesion molecules. Signaling events associated with binding of PV sera to keratinocytes include activation of phospholipase C, resulting in increases in both inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). […] Grando and colleagues have proposed that blistering in PV is the result of synergy between anti-desmoglein antibodies and anticholinergic receptor antibodies. Antibodies to keratinocyte cholinergic receptors induce acantholysis, in this view, while antibodies to Dsg3 deplete Dsg3 from desmosomes. […] The work of Nguyen et al. raises a number of crucial questions about the pathogenesis of blistering in PV and PF.

• #18 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Pemphigus vulgaris is an autoimmune condition that is more likely to develop in patients with certain HLA types after triggers. Central to the pathogenesis of pemphigus is the presence of immunoglobulin (Ig) antibodies against proteins on the cell surface of keratinocytes. Immunochemical and molecular cloning studies have shown that antigenic targets in PV are desmogleins. Desmogleins (Dsg) are desmosome-associated transmembrane glycoproteins that provide cell-cell adhesion in the epidermis. The main antigen in PV is Dsg3 (130 kDa), but 50% of patients also have autoantibodies against Dsg1 (160 kDa). The ratio of Dsg1 and Dsg3 antibodies appear to correlate with the clinical severity of PV; those with only Dsg3 antibodies have predominantly oral lesions. IgG antibodies against Dsgs impair the adhesive function of desmosomes and inhibit cell-cell adhesion. This results in epidermal acantholysis and drooping blister formation, which is the characteristic clinical feature of pemphigus diseases.

• #19 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  The localization of blister formation and involvement of mucosal surfaces varies with the pemphigus disease subtype and can be explained by the Dsg compensation theory. This theory states that on cutaneous surfaces, Dsg 1 is expressed in all layers of the epidermis, while Dsg 3 is expressed in deeper layers. Dsg 1 expression in the mucosa is minimal, while Dsg 3 is dominant. The interpretation of the Dsg compensation theory, as it relates to the clinical manifestations in pemphigus, can be summarized as follows: Only patients with antibodies to Dsg 3 should have mucosal dominant PV because Dsg 1 compensates for the loss of Dsg 3 in the skin. Mucous membranes predominantly contain Dsg 3; low levels of Dsg 1 in the mucosa cannot replace the lost Dsg 3 and lead to epithelial acantholysis and mucosal erosions. When antibodies against both Dsg 1 and 3 develop, epidermal acantholysis occurs in both the skin and mucous membranes. It is still a matter of debate whether the Dsg compensation theory can adequately explain the complex pathogenic mechanism of pemphigus.

• #20 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  The localization of blister formation and involvement of mucosal surfaces varies with the pemphigus disease subtype and can be explained by the Dsg compensation theory. This theory states that on cutaneous surfaces, Dsg 1 is expressed in all layers of the epidermis, while Dsg 3 is expressed in deeper layers. Dsg 1 expression in the mucosa is minimal, while Dsg 3 is dominant. The interpretation of the Dsg compensation theory, as it relates to the clinical manifestations in pemphigus, can be summarized as follows: Only patients with antibodies to Dsg 3 should have mucosal dominant PV because Dsg 1 compensates for the loss of Dsg 3 in the skin. Mucous membranes predominantly contain Dsg 3; low levels of Dsg 1 in the mucosa cannot replace the lost Dsg 3 and lead to epithelial acantholysis and mucosal erosions. When antibodies against both Dsg 1 and 3 develop, epidermal acantholysis occurs in both the skin and mucous membranes. It is still a matter of debate whether the Dsg compensation theory can adequately explain the complex pathogenic mechanism of pemphigus.

• #21 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Abundant data suggest that some pemphigus antibodies directly interfere with cell adhesion. […] Mechanistically, some PV autoantibodies have been shown to interfere directly with homophilic trans-interaction of Dsg3 molecules, presumably through steric hindrance of Dsg adhesion. […] The model discussed here has been called the Dsg nonassembly depletion hypothesis. […] This model attributes loss of cell adhesion to the ability of multivalent pemphigus anti-Dsg antibodies to crosslink and cluster Dsgs. […] Early evidence implicating intracellular signaling mechanisms in induction of acantholysis came from the observation that polyclonal PV IgG causes retraction of keratin intermediate filaments in cultured keratinocytes from wild-type mice but not from PG-deficient mice. […] This signaling cascade was also shown to be active in PV and PF patients’ skin.

• #22 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  Abundant data suggest that some pemphigus antibodies directly interfere with cell adhesion. […] Mechanistically, some PV autoantibodies have been shown to interfere directly with homophilic trans-interaction of Dsg3 molecules, presumably through steric hindrance of Dsg adhesion. […] The model discussed here has been called the Dsg nonassembly depletion hypothesis. […] This model attributes loss of cell adhesion to the ability of multivalent pemphigus anti-Dsg antibodies to crosslink and cluster Dsgs. […] Early evidence implicating intracellular signaling mechanisms in induction of acantholysis came from the observation that polyclonal PV IgG causes retraction of keratin intermediate filaments in cultured keratinocytes from wild-type mice but not from PG-deficient mice. […] This signaling cascade was also shown to be active in PV and PF patients’ skin.

• #23

  https://www.jci.org/articles/view/11828

  Desmogleins 1 and 3 are members of the cadherin family of adhesion molecules. They are transmembrane proteins that interact with plakoglobin, a component of the dense plaque of the desmosome. It is believed that antibodies to Dsg3 and Dsg1 directly induce acantholysis by interfering with the adhesive function of these target molecules. […] Induction of acantholysis is an active process that appears to be more complex than the simple interaction of antibodies with adhesion molecules. Signaling events associated with binding of PV sera to keratinocytes include activation of phospholipase C, resulting in increases in both inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). […] Grando and colleagues have proposed that blistering in PV is the result of synergy between anti-desmoglein antibodies and anticholinergic receptor antibodies. Antibodies to keratinocyte cholinergic receptors induce acantholysis, in this view, while antibodies to Dsg3 deplete Dsg3 from desmosomes. […] The work of Nguyen et al. raises a number of crucial questions about the pathogenesis of blistering in PV and PF.

• #24 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  However, there is evidence also suggesting pemphigus blistering is not solely caused by autoantibody targeting to DSG3 but rather results from intracellular signaling mediated by non-DSGs targeting autoantibodies that leads to shrinkage of cell and apoptosis. […] The binding of PV IgG to DSG3 has been demonstrated to stimulate the phospholipase C signaling pathway which causes calcium release and PKC activation leading eventually to the desmosome and cell surface DSG3 depletion and the loss of intercellular cohesion and formation of blisters. […] DSG3 have been indicated as a key mediator involved in desmosome remodeling, epidermal proliferation and differentiation, cell migration and apoptosis, and thus validating that DSG3 acts as a signaling molecule that has a major impact on tissue integrity and homeostasis.

• #25 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. […] Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. […] Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. […] Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. […] The pathological mechanisms of PV are controversial and remain a hot topic under debate in the field. […] Various signaling pathways are at play in the development of pemphigus acantholysis.

• #26 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. […] Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. […] Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. […] Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. […] The pathological mechanisms of PV are controversial and remain a hot topic under debate in the field. […] Ample studies support the concept that PV is caused by the pathogenic IgG autoantibodies directed against DSG3 as well as DSG1.

• #27 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] This theory explores new mechanisms with the findings obtained by independent groups. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53. […] It indicates that the loss/disruption of DSG3 alone is sufficient to induce aberrant p53 response and thus the disruption of DSG3 mediated intercellular junctions does not result solely from steric hindrance but rather causes dysfunction of cellular anti-stress response.

• #28 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] Disruption of this remodeling process including the activation of the above-mentioned signaling pathways has been reported in PV. […] The apoptosis pathway in PV is proved by experimental studies that demonstrate that apoptotic signaling is activated by PV autoantibody and anti-Fas receptor (FasR) antibody. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53.

• #29 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] This theory explores new mechanisms with the findings obtained by independent groups. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53. […] It indicates that the loss/disruption of DSG3 alone is sufficient to induce aberrant p53 response and thus the disruption of DSG3 mediated intercellular junctions does not result solely from steric hindrance but rather causes dysfunction of cellular anti-stress response.

• #30 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] Disruption of this remodeling process including the activation of the above-mentioned signaling pathways has been reported in PV. […] The apoptosis pathway in PV is proved by experimental studies that demonstrate that apoptotic signaling is activated by PV autoantibody and anti-Fas receptor (FasR) antibody. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53.

• #31 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] This theory explores new mechanisms with the findings obtained by independent groups. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53. […] It indicates that the loss/disruption of DSG3 alone is sufficient to induce aberrant p53 response and thus the disruption of DSG3 mediated intercellular junctions does not result solely from steric hindrance but rather causes dysfunction of cellular anti-stress response.

• #32 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  Hence, disruption of this pathway may play an important part in PV pathology. […] Collectively, it is likely that PV autoantibodies targeting DSG3 affect its function in the anti-stress network that leads to oxidative/antioxidative imbalance in cells. […] As a consequence, oxidative stress can occur in PV cells resulting in DSBs and hence the activation of a chain of reactions including ATM, c-Myc and p38 MAPK, and subsequently evokes the p53 pathway leading to deregulation of the apoptotic machinery and PV blistering. […] The pathological mechanisms underlying the pemphigus acantholysis are complex and remain not completely clear. […] Our recent studies shed new light on the unprecedented roles of DSG3 and suggest its mediated signaling towards p53, YAP and ROS in cellular stress response with the evidence of dysregulation of these axes being demonstrated in PV.

• #33 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  Collectively, it is likely that PV autoantibodies targeting DSG3 affect its function in the anti-stress network that leads to oxidative/antioxidative imbalance in cells. […] Taken together, the above-discussed studies link together several unrelated pathways and open new avenues of research to investigate the pathogenesis and stress-induced tissue damage in PV.

• #34 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  Hence, disruption of this pathway may play an important part in PV pathology. […] Collectively, it is likely that PV autoantibodies targeting DSG3 affect its function in the anti-stress network that leads to oxidative/antioxidative imbalance in cells. […] As a consequence, oxidative stress can occur in PV cells resulting in DSBs and hence the activation of a chain of reactions including ATM, c-Myc and p38 MAPK, and subsequently evokes the p53 pathway leading to deregulation of the apoptotic machinery and PV blistering. […] The pathological mechanisms underlying the pemphigus acantholysis are complex and remain not completely clear. […] Our recent studies shed new light on the unprecedented roles of DSG3 and suggest its mediated signaling towards p53, YAP and ROS in cellular stress response with the evidence of dysregulation of these axes being demonstrated in PV.

• #35 Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression | Scientific Reports

  https://www.nature.com/articles/s41598-022-09951-x

  Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease which is to a large extent genetically determined, and results, at least in part, from the deleterious activity of autoantibodies directed against desmoglein (DSG)3, a prominent intra-epidermal adhesion molecule. […] We previously showed that rs17315309, a strong risk variant for PV within the promoter of the ST18 transcription factor gene, promotes epidermal ST18 up-regulation in a p53/p63-dependent manner. […] Increased ST18 expression was then shown to markedly augment PV autoantibodies-mediated loss of KCs cohesion. […] Here, we demonstrate that ST18 overexpression significantly increases autoantibody-mediated DSG3 down-regulation in keratinocytes. […] DSG3 decreased expression boosts p53 function through p38 mitogen-activated protein kinase (p38MAPK) activation and dramatically augments p53-dependent ST18 promoter activity.

• #36 Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression | Scientific Reports

  https://www.nature.com/articles/s41598-022-09951-x

  Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease which is to a large extent genetically determined, and results, at least in part, from the deleterious activity of autoantibodies directed against desmoglein (DSG)3, a prominent intra-epidermal adhesion molecule. […] We previously showed that rs17315309, a strong risk variant for PV within the promoter of the ST18 transcription factor gene, promotes epidermal ST18 up-regulation in a p53/p63-dependent manner. […] Increased ST18 expression was then shown to markedly augment PV autoantibodies-mediated loss of KCs cohesion. […] Here, we demonstrate that ST18 overexpression significantly increases autoantibody-mediated DSG3 down-regulation in keratinocytes. […] DSG3 decreased expression boosts p53 function through p38 mitogen-activated protein kinase (p38MAPK) activation and dramatically augments p53-dependent ST18 promoter activity.

• #37 Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression | Scientific Reports

  https://www.nature.com/articles/s41598-022-09951-x

  Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease which is to a large extent genetically determined, and results, at least in part, from the deleterious activity of autoantibodies directed against desmoglein (DSG)3, a prominent intra-epidermal adhesion molecule. […] We previously showed that rs17315309, a strong risk variant for PV within the promoter of the ST18 transcription factor gene, promotes epidermal ST18 up-regulation in a p53/p63-dependent manner. […] Increased ST18 expression was then shown to markedly augment PV autoantibodies-mediated loss of KCs cohesion. […] Here, we demonstrate that ST18 overexpression significantly increases autoantibody-mediated DSG3 down-regulation in keratinocytes. […] DSG3 decreased expression boosts p53 function through p38 mitogen-activated protein kinase (p38MAPK) activation and dramatically augments p53-dependent ST18 promoter activity.

• #38 Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression | Scientific Reports

  https://www.nature.com/articles/s41598-022-09951-x

  Finally, the PV risk variant rs17315309 is associated with increased p53 expression in PV skin. […] Here we demonstrate that ST18 overexpression steers a p53-dependent process resulting in enhanced autoantibody-mediated membranal DSG3 down-regulation in KCs, revealing a novel and pivotal self-perpetuating pathomechanism in PV. […] Given the fact that ST18 up-regulation increases anti-DSG3 antibodies-mediated DSG3 down-regulation and given the fact that ST18 expression is under p53 regulation, we next investigated the effect of autoantibody-mediated DSG3 down-regulation on p53 expression. […] We now show that ST18 induces DSG3 down-regulation, which in turn activates p53 which is required for ST18 up-regulation. […] The fact that DSG3 down-regulation stimulates p53 expression in a p38MAPK-dependent fashion sets the stage for a self-perpetuating mechanism which explains PV chronicity. Thus, ST18 plays a pivotal role in autoimmunity propagation in PV.

• #39 Up-regulation of ST18 in pemphigus vulgaris drives a self-amplifying p53-dependent pathomechanism resulting in decreased desmoglein 3 expression | Scientific Reports

  https://www.nature.com/articles/s41598-022-09951-x

  Finally, the PV risk variant rs17315309 is associated with increased p53 expression in PV skin. […] Here we demonstrate that ST18 overexpression steers a p53-dependent process resulting in enhanced autoantibody-mediated membranal DSG3 down-regulation in KCs, revealing a novel and pivotal self-perpetuating pathomechanism in PV. […] Given the fact that ST18 up-regulation increases anti-DSG3 antibodies-mediated DSG3 down-regulation and given the fact that ST18 expression is under p53 regulation, we next investigated the effect of autoantibody-mediated DSG3 down-regulation on p53 expression. […] We now show that ST18 induces DSG3 down-regulation, which in turn activates p53 which is required for ST18 up-regulation. […] The fact that DSG3 down-regulation stimulates p53 expression in a p38MAPK-dependent fashion sets the stage for a self-perpetuating mechanism which explains PV chronicity. Thus, ST18 plays a pivotal role in autoimmunity propagation in PV.

• #40 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Intracellular kinase signaling has been identified in the pathogenic process of PV. The binding of autoantibodies in PV promotes phosphorylation of kinases. In the study in which patients with a diagnosis of PV were examined, kinases (e.g., phosphokinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), cyclin-dependent kinase (Cdk2), sarcoma-associated kinase (Src), extracellular signal-regulated kinase (ERK), Bruton tyrosine kinase (BTK), apoptosis signal regulatory kinase (ASK1), epidermal growth factor receptor kinase (EFGRK)), tyrosine kinase (TK)) were found to be phosphorylated in PV-induced models. Inhibition of these pathways reduces acantholysis in vitro and in vivo. The role of p38MAPK has been highlighted in multiple studies. p38MAPK is activated after PVIgG-binding upstream of Rho kinase. In particular, p38MAPK inhibition prevents PV-IgG-induced redistribution of Dsg3 and results in PV-IgG and Dsg3 co-localizing at the cell membrane. As a result, p38MAPK inhibition has been shown to prevent both histologic and clinical blister formation in both in vivo and in vitro models. Therefore, p38MAPK plays an essential role in regulating Dsg3 internalization and must be considered as a key component in PV pathogenicity.

• #41 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Intracellular kinase signaling has been identified in the pathogenic process of PV. The binding of autoantibodies in PV promotes phosphorylation of kinases. In the study in which patients with a diagnosis of PV were examined, kinases (e.g., phosphokinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), cyclin-dependent kinase (Cdk2), sarcoma-associated kinase (Src), extracellular signal-regulated kinase (ERK), Bruton tyrosine kinase (BTK), apoptosis signal regulatory kinase (ASK1), epidermal growth factor receptor kinase (EFGRK)), tyrosine kinase (TK)) were found to be phosphorylated in PV-induced models. Inhibition of these pathways reduces acantholysis in vitro and in vivo. The role of p38MAPK has been highlighted in multiple studies. p38MAPK is activated after PVIgG-binding upstream of Rho kinase. In particular, p38MAPK inhibition prevents PV-IgG-induced redistribution of Dsg3 and results in PV-IgG and Dsg3 co-localizing at the cell membrane. As a result, p38MAPK inhibition has been shown to prevent both histologic and clinical blister formation in both in vivo and in vitro models. Therefore, p38MAPK plays an essential role in regulating Dsg3 internalization and must be considered as a key component in PV pathogenicity.

• #42 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Intracellular kinase signaling has been identified in the pathogenic process of PV. The binding of autoantibodies in PV promotes phosphorylation of kinases. In the study in which patients with a diagnosis of PV were examined, kinases (e.g., phosphokinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), cyclin-dependent kinase (Cdk2), sarcoma-associated kinase (Src), extracellular signal-regulated kinase (ERK), Bruton tyrosine kinase (BTK), apoptosis signal regulatory kinase (ASK1), epidermal growth factor receptor kinase (EFGRK)), tyrosine kinase (TK)) were found to be phosphorylated in PV-induced models. Inhibition of these pathways reduces acantholysis in vitro and in vivo. The role of p38MAPK has been highlighted in multiple studies. p38MAPK is activated after PVIgG-binding upstream of Rho kinase. In particular, p38MAPK inhibition prevents PV-IgG-induced redistribution of Dsg3 and results in PV-IgG and Dsg3 co-localizing at the cell membrane. As a result, p38MAPK inhibition has been shown to prevent both histologic and clinical blister formation in both in vivo and in vitro models. Therefore, p38MAPK plays an essential role in regulating Dsg3 internalization and must be considered as a key component in PV pathogenicity.

• #43 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Intracellular kinase signaling has been identified in the pathogenic process of PV. The binding of autoantibodies in PV promotes phosphorylation of kinases. In the study in which patients with a diagnosis of PV were examined, kinases (e.g., phosphokinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), cyclin-dependent kinase (Cdk2), sarcoma-associated kinase (Src), extracellular signal-regulated kinase (ERK), Bruton tyrosine kinase (BTK), apoptosis signal regulatory kinase (ASK1), epidermal growth factor receptor kinase (EFGRK)), tyrosine kinase (TK)) were found to be phosphorylated in PV-induced models. Inhibition of these pathways reduces acantholysis in vitro and in vivo. The role of p38MAPK has been highlighted in multiple studies. p38MAPK is activated after PVIgG-binding upstream of Rho kinase. In particular, p38MAPK inhibition prevents PV-IgG-induced redistribution of Dsg3 and results in PV-IgG and Dsg3 co-localizing at the cell membrane. As a result, p38MAPK inhibition has been shown to prevent both histologic and clinical blister formation in both in vivo and in vitro models. Therefore, p38MAPK plays an essential role in regulating Dsg3 internalization and must be considered as a key component in PV pathogenicity.

• #44 Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus | Scientific Reports

  https://www.nature.com/articles/s41598-017-03697-7

  Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1+aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.

• #45 Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus | Scientific Reports

  https://www.nature.com/articles/s41598-017-03697-7

  Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1+aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.

• #46 Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus | Scientific Reports

  https://www.nature.com/articles/s41598-017-03697-7

  Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1+aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus.

• #47 Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus | Scientific Reports

  https://www.nature.com/articles/s41598-017-03697-7

  The signaling patterns identified here appear to be complex. Activation of p38MAPK was found under all pathological conditions which is in line with all publications where a role of this pathway in pemphigus pathogenesis has been reported downstream of PV-IgG, PF-IgG and AK23. This indicates that antibodies against Dsg3 as well as autoantibody fractions containing aDsg1 but not aDsg3 can activate p38MAPK signaling. […] The identification of signaling pathways activated by specific desmosomal and non-desmosomal autoantibodies should be a primary focus for future studies.

• #48 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://www.mdpi.com/2075-1729/11/7/621

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] Disruption of this remodeling process including the activation of the above-mentioned signaling pathways has been reported in PV. […] The apoptosis pathway in PV is proved by experimental studies that demonstrate that apoptotic signaling is activated by PV autoantibody and anti-Fas receptor (FasR) antibody. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53.

• #49

  https://journals.lww.com/jpat/fulltext/2017/21020/current_concepts_of_pemphigus_with_a_deep_insight.15.aspx

  Pemphigus vulgaris is an autoimmune bullous disease involving both the skin and mucosal areas, which is characterized by intraepithelial flaccid blisters and erosions. The pathogenesis of this disease is not yet completely established, but novel intuitions into its pathogenesis have recently been published. An unanswered question in its pathophysiology is the mechanism of acantholysis or loss of keratinocyte cell adhesion. Acantholysis seems to result from a communal action of autoantibodies against numerous keratinocyte self-antigens, of which desmogleins 1 and 3, desmocollins and nondesmosome components, such as the mitochondrion, might take part in the disease initiation. […] Lately, apoptosis was described as a possible underlying mechanism of acantholysis. Likewise, apoptolysis is assumed to be the association between suprabasal acantholytic and cell death pathways.

• #50

  https://journals.lww.com/jpat/fulltext/2017/21020/current_concepts_of_pemphigus_with_a_deep_insight.15.aspx

  This lesion also exhibits morphologically characteristic acantholysis due to loss of cell-cell adhesion among the keratinocytes. […] However, novel insights into Dsg biology and pemphigus pathology have been recommended, and new questions are evolving as the conventional concepts of the pathogenesis of pemphigus are being confronted. […] In the year 1881, the term acantholysis was coined by Auspitz, and it is derived from the Greek words Akantha, meaning a thorn or prickle, and lysis, i.e., loosening. Acantholysis means loss of coherence among epidermal cells due to the breakdown of intercellular bridges. […] Primary acantholysis refers to the dissociation and disintegration of desmosomes leading to the separation of keratinocytes which may be either due to the direct injury to desmosomes or due to the hereditary defects in their assembly. It is of key pathogenetic relevance in diseases of the pemphigus group.

• #51 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Caspases are involved in the pathogenesis of PV through apoptosis and acantholysis. Caspases are activated through various cellular pathways to affect programmed cell death. While apoptosis via caspases is a normal process in the body, the presence of PV-IgG causes pathological activation of caspases in keratinocytes. In all studies, inhibition of caspases has been shown to reduce apoptosis and acantholysis and thus have a positive effect on cell-cell adhesion. […] The pathogenesis of pemphigus involves the production of activated B-cells and IgG with stimulation by IL-4 by T-helper 2 (Th2) cells. Excessive activation of Th2 cells causes the production of autoantibodies required for PV. Th2 cells secrete IL-4 and multiple interleukins (IL), which are known to play an important role in pemphigus. IL-4 promotes antibody production by primed B cells and an isotype switching from IgG1 to IgG4 antibodies which are important in the active form of PV. IL-4 also causes naive CD4+ T cells to differentiate into Th2 cells, thus maintaining the disease. Production of autoantibodies and epitope binding are sufficient for the loss of adhesions directly between desmosomes.

• #52 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  Pemphigus is an autoimmune blistering disease where autoantibodies target desmoglein (Dsg) antigens on keratinocytes, triggering the p38 MAPK pathway, Dsg internalization, desmosomal dissolution, and keratinocyte apoptosis, are essential for blister formation. […] Recent research indicates keratinocyte pyroptosis may exacerbate acantholysis and delay wound healing. […] The present findings highlight a significant upregulation of pyroptosis-related proteins, which play a crucial role in the inflammatory response and blister formation characteristic of pemphigus. […] Pyroptosis significantly contributes to the pathogenesis of pemphigus and presents a promising target for therapy. […] Understanding the clinical implications of pyroptosis in pemphigus is essential. […] Pyroptosis is caused by the activation of inflammasomes via two major pathways: classical and non-classical.

• #53 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  Pemphigus is an autoimmune blistering disease where autoantibodies target desmoglein (Dsg) antigens on keratinocytes, triggering the p38 MAPK pathway, Dsg internalization, desmosomal dissolution, and keratinocyte apoptosis, are essential for blister formation. […] Recent research indicates keratinocyte pyroptosis may exacerbate acantholysis and delay wound healing. […] The present findings highlight a significant upregulation of pyroptosis-related proteins, which play a crucial role in the inflammatory response and blister formation characteristic of pemphigus. […] Pyroptosis significantly contributes to the pathogenesis of pemphigus and presents a promising target for therapy. […] Understanding the clinical implications of pyroptosis in pemphigus is essential. […] Pyroptosis is caused by the activation of inflammasomes via two major pathways: classical and non-classical.

• #54 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  Pemphigus is an autoimmune blistering disease where autoantibodies target desmoglein (Dsg) antigens on keratinocytes, triggering the p38 MAPK pathway, Dsg internalization, desmosomal dissolution, and keratinocyte apoptosis, are essential for blister formation. […] Recent research indicates keratinocyte pyroptosis may exacerbate acantholysis and delay wound healing. […] The present findings highlight a significant upregulation of pyroptosis-related proteins, which play a crucial role in the inflammatory response and blister formation characteristic of pemphigus. […] Pyroptosis significantly contributes to the pathogenesis of pemphigus and presents a promising target for therapy. […] Understanding the clinical implications of pyroptosis in pemphigus is essential. […] Pyroptosis is caused by the activation of inflammasomes via two major pathways: classical and non-classical.

• #55 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  Pemphigus is an autoimmune blistering disease where autoantibodies target desmoglein (Dsg) antigens on keratinocytes, triggering the p38 MAPK pathway, Dsg internalization, desmosomal dissolution, and keratinocyte apoptosis, are essential for blister formation. […] Recent research indicates keratinocyte pyroptosis may exacerbate acantholysis and delay wound healing. […] The present findings highlight a significant upregulation of pyroptosis-related proteins, which play a crucial role in the inflammatory response and blister formation characteristic of pemphigus. […] Pyroptosis significantly contributes to the pathogenesis of pemphigus and presents a promising target for therapy. […] Understanding the clinical implications of pyroptosis in pemphigus is essential. […] Pyroptosis is caused by the activation of inflammasomes via two major pathways: classical and non-classical.

• #56 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  The relationship between pyroptosis and acantholysis may primarily revolve around the inflammatory response triggered by pyroptosis and its detrimental impact on skin tissue integrity. […] Pyroptosis is commonly activated in response to intracellular pathogens, resulting in skin inflammation. […] Elevated levels of inflammatory cytokines, including IL-18 and IL-1, have been documented in several skin disorders, suggesting their potential role in linking pyroptosis to acantholysis. […] Exploring the role of pyroptosis in pemphigus pathogenesis and its therapeutic implications requires digging deeper into Caspase activation and how Caspase inhibitors, particularly those targeting Caspase-1, can help treat the disease. […] Recent research has revealed that innate immunity, including the recruitment of innate immune cells, the release of inflammatory mediators, and the activation of the complement system, also plays a significant role in the pathological process of pemphigus.

• #57 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  The relationship between pyroptosis and acantholysis may primarily revolve around the inflammatory response triggered by pyroptosis and its detrimental impact on skin tissue integrity. […] Pyroptosis is commonly activated in response to intracellular pathogens, resulting in skin inflammation. […] Elevated levels of inflammatory cytokines, including IL-18 and IL-1, have been documented in several skin disorders, suggesting their potential role in linking pyroptosis to acantholysis. […] Exploring the role of pyroptosis in pemphigus pathogenesis and its therapeutic implications requires digging deeper into Caspase activation and how Caspase inhibitors, particularly those targeting Caspase-1, can help treat the disease. […] Recent research has revealed that innate immunity, including the recruitment of innate immune cells, the release of inflammatory mediators, and the activation of the complement system, also plays a significant role in the pathological process of pemphigus.

• #58 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  The relationship between pyroptosis and acantholysis may primarily revolve around the inflammatory response triggered by pyroptosis and its detrimental impact on skin tissue integrity. […] Pyroptosis is commonly activated in response to intracellular pathogens, resulting in skin inflammation. […] Elevated levels of inflammatory cytokines, including IL-18 and IL-1, have been documented in several skin disorders, suggesting their potential role in linking pyroptosis to acantholysis. […] Exploring the role of pyroptosis in pemphigus pathogenesis and its therapeutic implications requires digging deeper into Caspase activation and how Caspase inhibitors, particularly those targeting Caspase-1, can help treat the disease. […] Recent research has revealed that innate immunity, including the recruitment of innate immune cells, the release of inflammatory mediators, and the activation of the complement system, also plays a significant role in the pathological process of pemphigus.

• #59 New insights into pyroptosis in pemphigus: from cellular structure to therapeutic targeting | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-new-insights-into-pyroptosis-in-avance-S0365059625000273

  The relationship between pyroptosis and acantholysis may primarily revolve around the inflammatory response triggered by pyroptosis and its detrimental impact on skin tissue integrity. […] Pyroptosis is commonly activated in response to intracellular pathogens, resulting in skin inflammation. […] Elevated levels of inflammatory cytokines, including IL-18 and IL-1, have been documented in several skin disorders, suggesting their potential role in linking pyroptosis to acantholysis. […] Exploring the role of pyroptosis in pemphigus pathogenesis and its therapeutic implications requires digging deeper into Caspase activation and how Caspase inhibitors, particularly those targeting Caspase-1, can help treat the disease. […] Recent research has revealed that innate immunity, including the recruitment of innate immune cells, the release of inflammatory mediators, and the activation of the complement system, also plays a significant role in the pathological process of pemphigus.

• #60 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  There is a strong association between certain human leukocyte antigen (HLA) class II alleles and susceptibility to PV. […] These data suggest that patients who develop the disease must have HLA class II molecules capable of presenting Dsg3 peptides to T cells. […] To better understand the genetics and the precise function of human pemphigus antibodies, researchers have cloned anti-Dsg B cell repertoires from PV and PF patients to generate and analyze monoclonal antibodies. […] These studies suggest that there are specific clones of anti-Dsg B cells in pemphigus that may be eliminated with adequate treatment.

• #61 Mechanisms of Disease: Pemphigus and Bullous Pemphigoid

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5560122/

  There is a strong association between certain human leukocyte antigen (HLA) class II alleles and susceptibility to PV. […] These data suggest that patients who develop the disease must have HLA class II molecules capable of presenting Dsg3 peptides to T cells. […] To better understand the genetics and the precise function of human pemphigus antibodies, researchers have cloned anti-Dsg B cell repertoires from PV and PF patients to generate and analyze monoclonal antibodies. […] These studies suggest that there are specific clones of anti-Dsg B cells in pemphigus that may be eliminated with adequate treatment.

• #62 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Caspases are involved in the pathogenesis of PV through apoptosis and acantholysis. Caspases are activated through various cellular pathways to affect programmed cell death. While apoptosis via caspases is a normal process in the body, the presence of PV-IgG causes pathological activation of caspases in keratinocytes. In all studies, inhibition of caspases has been shown to reduce apoptosis and acantholysis and thus have a positive effect on cell-cell adhesion. […] The pathogenesis of pemphigus involves the production of activated B-cells and IgG with stimulation by IL-4 by T-helper 2 (Th2) cells. Excessive activation of Th2 cells causes the production of autoantibodies required for PV. Th2 cells secrete IL-4 and multiple interleukins (IL), which are known to play an important role in pemphigus. IL-4 promotes antibody production by primed B cells and an isotype switching from IgG1 to IgG4 antibodies which are important in the active form of PV. IL-4 also causes naive CD4+ T cells to differentiate into Th2 cells, thus maintaining the disease. Production of autoantibodies and epitope binding are sufficient for the loss of adhesions directly between desmosomes.

• #63 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Caspases are involved in the pathogenesis of PV through apoptosis and acantholysis. Caspases are activated through various cellular pathways to affect programmed cell death. While apoptosis via caspases is a normal process in the body, the presence of PV-IgG causes pathological activation of caspases in keratinocytes. In all studies, inhibition of caspases has been shown to reduce apoptosis and acantholysis and thus have a positive effect on cell-cell adhesion. […] The pathogenesis of pemphigus involves the production of activated B-cells and IgG with stimulation by IL-4 by T-helper 2 (Th2) cells. Excessive activation of Th2 cells causes the production of autoantibodies required for PV. Th2 cells secrete IL-4 and multiple interleukins (IL), which are known to play an important role in pemphigus. IL-4 promotes antibody production by primed B cells and an isotype switching from IgG1 to IgG4 antibodies which are important in the active form of PV. IL-4 also causes naive CD4+ T cells to differentiate into Th2 cells, thus maintaining the disease. Production of autoantibodies and epitope binding are sufficient for the loss of adhesions directly between desmosomes.

• #64 Pemphigus in India – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/pemphigus-in-india/

  Pemphigus being an autoimmune disease driven by autoantibody against epidermal antigen, it is expected from immunological point of view that Th2 predominance would be observed. […] The predominant subclass involved in pathogenesis of pemphigus is IgG 4 irrespective of type of pemphigus, as was assessed by direct immunofluorescence (DIF) as well as indirect immunofluorescence (IIF) study using normal human abdominal skin as substrate.

• #65 Comprehensive review on the pathophysiology, clinical variants and management of pemphigus (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.10770

  Pemphigus represents a group of chronic inflammatory disorders characterized by autoantibodies that target components of desmosomes, leading to the loss of intercellular adhesion between keratinocytes and causing intraepithelial blistering. […] Genetic factors are involved in the pathogenesis, with HLADR4 (DRB1*0402) and HLADRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris, HLA class II DRB1*0344 and HLA Cw*1445 correlated with paraneoplastic pemphigus, and HLADRB1*04:01, HLADRB1*04:06, HLADRB1*01:01, HLADRB1*14, associated with a higher risk of developing pemphigus foliaceus. […] Autoantibodies are conducted against structural desmosomal proteins in the skin and mucous membranes, mainly desmogleins, desmocollins and plakins. […] The pathogenic role of these non-Dsg autoantibodies is mentioned by some studies, which suggest that they synergistically complement the classic effects of anti-Dsg autoantibodies in the complex process of pemphigus pathogenesis.

• #66 Pemphigus in India – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/pemphigus-in-india/

  Pemphigus is a chronic autoimmune epidermal bullous disease caused by autoantibodies directed against desmogleins (Dsgs), that is, desmosomal glycoproteins expressed on the epithelial cells of the skin and mucosa, resulting in acantholysis. […] Apoptosis of keratinocytes may have a possible role in pathogenesis. […] Higher incidence of PV and earlier age at onset for pemphigus seen in Indian population have been attributed to higher frequency of DSG3FNx01TCCCC in Indian population. […] In an association analysis of intragenic single nucleotide polymorphism haplotypes to assess the contribution of Dsg 3 allele in susceptibility to PV, it was observed that two related haplotypes, DSG3FNx01TCCTC and DSG3FNx01TCCCC, were involved in the pathogenesis of PV in patients with British and North Indian descent, respectively.

• #67 Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03387-7

  Pemphigus is an autoimmune skin disease. Ectopic lymphoid-like structures (ELSs) were found to be commonly present in the pemphigus lesions, presumably supporting in situ desmoglein (Dsg)-specific antibody production. Yet functional phenotypes and the regulators of Lymphoid aggregates in pemphigus lesions remain largely unknown. […] Here, we provide the first transcriptomic characterization of lesion infiltrating immune cells which illustrates a distinct interplay network between adaptive and innate immune cells. It helps discover new regulators of local immune response, which potentially will provide a novel path forward to further uncover pemphigus pathological mechanisms and develop targeted therapy. […] Our findings corroborate the involvement of local immune dysregulation and altered Immune cell composition as potential drivers of pemphigus lesions. Moreover, we constructed a lncRNA-mediated competing endogenous RNA (ceRNA) network and identified epigenetic regulators, such as LINC01588 which might modulate Treg/Th17 balance via PPAR signaling pathway.

• #68 Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03387-7

  Pemphigus is an autoimmune skin disease. Ectopic lymphoid-like structures (ELSs) were found to be commonly present in the pemphigus lesions, presumably supporting in situ desmoglein (Dsg)-specific antibody production. Yet functional phenotypes and the regulators of Lymphoid aggregates in pemphigus lesions remain largely unknown. […] Here, we provide the first transcriptomic characterization of lesion infiltrating immune cells which illustrates a distinct interplay network between adaptive and innate immune cells. It helps discover new regulators of local immune response, which potentially will provide a novel path forward to further uncover pemphigus pathological mechanisms and develop targeted therapy. […] Our findings corroborate the involvement of local immune dysregulation and altered Immune cell composition as potential drivers of pemphigus lesions. Moreover, we constructed a lncRNA-mediated competing endogenous RNA (ceRNA) network and identified epigenetic regulators, such as LINC01588 which might modulate Treg/Th17 balance via PPAR signaling pathway.

• #69 Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03387-7

  We also compared the functional analysis results of SIMC with that of PBMC to better understand the unique roles of SIMC. The GO analysis results showed that PBMC had an over-representation of inflammatory cytokines and chemokines, while SIMC had a signature of neutrophil aggregations and other metabolism-related pathways. These results indicated that SIMC and PBMC had vastly different functional phenotypes. […] Interestingly, SIMC and PBMC shared similarity in the KEGG results. The IL-17 signaling pathway was over-represented in both SIMC and PBMC which is consistent with previous reports. […] Our study is also the first to demonstrate an increased infiltration of NK cell in pemphigus lesions. In addition, we found that LINC10588 was negatively correlated to PPAR signaling which may be related to the pathogenesis of pemphigus.

• #70 Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03387-7

  We also compared the functional analysis results of SIMC with that of PBMC to better understand the unique roles of SIMC. The GO analysis results showed that PBMC had an over-representation of inflammatory cytokines and chemokines, while SIMC had a signature of neutrophil aggregations and other metabolism-related pathways. These results indicated that SIMC and PBMC had vastly different functional phenotypes. […] Interestingly, SIMC and PBMC shared similarity in the KEGG results. The IL-17 signaling pathway was over-represented in both SIMC and PBMC which is consistent with previous reports. […] Our study is also the first to demonstrate an increased infiltration of NK cell in pemphigus lesions. In addition, we found that LINC10588 was negatively correlated to PPAR signaling which may be related to the pathogenesis of pemphigus.

• #71 Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03387-7

  We also compared the functional analysis results of SIMC with that of PBMC to better understand the unique roles of SIMC. The GO analysis results showed that PBMC had an over-representation of inflammatory cytokines and chemokines, while SIMC had a signature of neutrophil aggregations and other metabolism-related pathways. These results indicated that SIMC and PBMC had vastly different functional phenotypes. […] Interestingly, SIMC and PBMC shared similarity in the KEGG results. The IL-17 signaling pathway was over-represented in both SIMC and PBMC which is consistent with previous reports. […] Our study is also the first to demonstrate an increased infiltration of NK cell in pemphigus lesions. In addition, we found that LINC10588 was negatively correlated to PPAR signaling which may be related to the pathogenesis of pemphigus.

• #72 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  Hence, disruption of this pathway may play an important part in PV pathology. […] Collectively, it is likely that PV autoantibodies targeting DSG3 affect its function in the anti-stress network that leads to oxidative/antioxidative imbalance in cells. […] As a consequence, oxidative stress can occur in PV cells resulting in DSBs and hence the activation of a chain of reactions including ATM, c-Myc and p38 MAPK, and subsequently evokes the p53 pathway leading to deregulation of the apoptotic machinery and PV blistering. […] The pathological mechanisms underlying the pemphigus acantholysis are complex and remain not completely clear. […] Our recent studies shed new light on the unprecedented roles of DSG3 and suggest its mediated signaling towards p53, YAP and ROS in cellular stress response with the evidence of dysregulation of these axes being demonstrated in PV.

• #73 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  Hence, disruption of this pathway may play an important part in PV pathology. […] Collectively, it is likely that PV autoantibodies targeting DSG3 affect its function in the anti-stress network that leads to oxidative/antioxidative imbalance in cells. […] As a consequence, oxidative stress can occur in PV cells resulting in DSBs and hence the activation of a chain of reactions including ATM, c-Myc and p38 MAPK, and subsequently evokes the p53 pathway leading to deregulation of the apoptotic machinery and PV blistering. […] The pathological mechanisms underlying the pemphigus acantholysis are complex and remain not completely clear. […] Our recent studies shed new light on the unprecedented roles of DSG3 and suggest its mediated signaling towards p53, YAP and ROS in cellular stress response with the evidence of dysregulation of these axes being demonstrated in PV.

• #74 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. […] Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. […] Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. […] Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. […] The pathological mechanisms of PV are controversial and remain a hot topic under debate in the field. […] Various signaling pathways are at play in the development of pemphigus acantholysis.

• #75 Evolving Mechanisms in the Pathophysiology of Pemphigus Vulgaris: A Review Emphasizing the Role of Desmoglein 3 in Regulating p53 and the Yes-Associated Protein

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  The phosphorylation of DSG3 is caused by the binding of pathogenic PV IgGs to DSG3 followed by its dissociation from plakoglobin and then endocytosis-mediated degradation. […] This theory explores new mechanisms with the findings obtained by independent groups. […] Rehman et al. have identified DSG3 acting as an anti-stress protein by counterbalancing p53 in the maintenance of normal epithelial homeostasis and demonstrated disruption of this regulation in PV. […] The study addresses the long-term controversy in the field of pemphigus research and fills the gap for the link between DSG3 and p53. […] It indicates that the loss/disruption of DSG3 alone is sufficient to induce aberrant p53 response and thus the disruption of DSG3 mediated intercellular junctions does not result solely from steric hindrance but rather causes dysfunction of cellular anti-stress response.

• #76

  https://journals.lww.com/jpat/fulltext/2017/21020/current_concepts_of_pemphigus_with_a_deep_insight.15.aspx

  Current evidence states that a part from the anti-Dsg1 and anti-Dsg3 antibodies, additional desmosomal, and nondesmosomal proteins such as cell-membrane receptors (nicotinic acetylcholine receptor, pemphaxin, thyroperoxidase and some other annexins) can be a target for the pemphigus. […] The current pemphigus research is clarifying new mechanisms of keratinocyte detachment in Pemphigus. Researches have put forward that apoptosis may possibly be responsible for the causal mechanisms of acantholysis. […] This results in the separation and splitting of preexisting desmosomes from the cell membrane by shear forces, thus entirely separating the collapsing cells and stimulating the production of scavenging antibodies. […] In conclusion, Dsgs are the key target antigens, though other autoantigens are also being explored. It is important that these autoantigens cannot elicit pemphigus alone without the presence of anti-Dsg antibodies; nonetheless, they may worsen the disease. Hence, this review summarizes that the structural damage (acantholysis) and death (apoptosis) of keratinocytes in pemphigus are intervened by the same set of cell death enzymes.

• #77 Pemphigus Vulgaris | IntechOpen

  https://www.intechopen.com/chapters/81673

  Proteases are enzymes that hydrolyze peptide bonds within proteins. Proteases have been blamed because the use of various protease inhibitors was found to be effective in inhibiting PV-associated acantholysis in studies. Pemphigus antibodies (described as IgGp) may mediate acantholysis by the activation and release of non-lysosomal proteolytic enzymes from epidermal cells. Recent data indicate that the proteolytic enzyme is an activator of plasminogen. This has been demonstrated by the addition of a plasmin inhibitor such as aprotinin, which can inhibit the development of acantholysis when PV or PF IgG is added to the skin in organ cultures. Both plasminogen and IgG are required to cause acantholysis. […] There are many mechanisms in the pathogenesis of PV that are still not understood and more studies are needed.

• #78 Comprehensive review on the pathophysiology, clinical variants and management of pemphigus (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.10770

  Research on some of these non-Dsg autoantibodies implies that they complement the typical effects of anti-Dsg autoantibodies in pemphigus pathogenesis. […] The etiopathogenesis of PNP is not completely known, but it is plausible that both autoantibodies and cell-mediated immunity play a key role. […] The most common autoantibodies detected in PNP are directed against the plakin family, such as envoplakin (210-kDa), periplakin (190-kDa), bullous pemphigoid antigen I (230-kDa), desmoplakin I (250-kDa), desmoplakin II (210-kDa), plectin (500-kDa), and 2-macroglobulin-like-1 (170-kDa). […] The exact pathomechanism of IgA pemphigus is not well defined, but it is related to IgA autoantibodies that target desmosomal and non-desmosomal keratinocyte cell surface components. […] The pathophysiology and autoantigen profile of bullous autoimmune diseases, especially pemphigus and its subforms, are more complex than previously assumed.

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