Materiały źródłowe

• #1 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. […] DSG3 is a pivotal player in mediating outside-in signaling involved in cell junction remodeling, cell proliferation, differentiation, migration or apoptosis, thus validating its biological function in tissue integrity and homeostasis beyond desmosome adhesion. […] 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.

• #2 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.

• #3 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. […] The different forms of pemphigus are distinguished by their clinical features, associated autoantigens, and laboratory findings.

• #4 P/P Clinical Information – IPPF

  https://www.pemphigus.org/p-p-clinical-information/

  Pemphigus is defined as a group of life-threatening blistering disorders characterized by acantholysis resulting in the formation of intraepithelial blisters in mucous membranes and skin. […] The intraepidermal blistering observed in pemphigus occurs due to an immune response that results in the deposition of autoantibodies against epidermal cell surface antigens within the epithelium of mucous membranes or skin. The mechanism through which acantholysis occurs is not fully understood. […] The molecular mechanisms where the binding of autoantibodies to epithelial cells leads to acantholysis are still intensively debated. Several mechanisms for antibody-mediated acantholysis have been proposed, including the induction of signal transduction events that trigger cell separation and the inhibition of adhesive molecule function through steric hindrance. In particular, the theory of apoptolysis suggests that acantholysis results from autoantibody-mediated induction of cellular signals that trigger enzymatic cascades that lead to structural collapse of cells and cellular shrinkage.

• #5 Pemphigus Vulgaris – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560860/

  Pemphigus vulgaris is a rare autoimmune disease that causes blistering on cutaneous and mucosal surfaces. […] This activity explores the historical context and etiology of PV, tracing back to its initial description in 1788, shedding light on its pathogenesis involving acantholysis, which leads to blister formation. […] The precise etiology of pemphigus vulgaris is unknown; however, multiple studies have linked pemphigus vulgaris with autoantibodies targeting cadherins, ultimately leading to acantholysis and dissociation of keratinocytes. […] PV is caused by autoantibodies that target cadherins, specifically desmogleins, though there may be some role for desmocollin; thus, this is a type 2 hypersensitivity reaction. […] Acantholysis, or the loss of keratinocyte-keratinocyte adhesion, is interrupted by circulating IgG autoantibodies to intercellular adhesion molecules.

• #6 Pemphigus Vulgaris – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560860/

  A super-compensation hypothesis recently submitted by Sinha et al. proposes that additional factors may also play a role in PV. […] The pathogenesis of PV has been described in more detail by Hammers et al. […] In patients with PV, autoantibodies against desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) is the purported cause. […] The most common targets of desmoglein for IgG antibodies are the extracellular cadherin domains, which can result in the loss of desmosome-adhesive properties. […] It is generally believed that the amino portion of the cadherin proteins is most implicated in the pathogenesis of acantholysis leading to PV. […] Many animal models have shown that enzymatic inactivation of Dsg 1 and gene deletion of Dsg 3 results in pathology similar to PV. […] The binding of antibodies to desmogleins has been confirmed by epitope mapping and is presumed to disrupt desmoglein binding by affecting steric hindrance. […] Another theory for the pathophysiology of PV is the desmoglein nonassembly depletion hypothesis.

• #7 SciELO Brazil – Pemphigus vulgaris Pemphigus vulgaris

  https://www.scielo.br/j/abd/a/nV5V8fJtZw7kQhhDbzffyVL/

  Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. […] The formation of autoantibodies against components of desmosomes has long been considered the main process in pemphigus pathogenesis. […] The basic pathophysiology of pemphigus is the inhibition of the adhesive function of desmogleins by autoantibodies, which leads to the formation of blisters. […] PV is caused by the presence of IgG autoantibodies directed against Dsg1 and/or Dsg3, part of the desmosomes present on the surface of keratinocytes, which play a primary pathogenic role in the induction of loss of intercellular adhesion, resulting in the formation of blisters. […] However, the mechanism by which the binding of autoantibodies to desmogleins leads to acantholysis remains uncertain. Possible hypotheses for this phenomenon include: alterations in intracellular transduction signaling and rupture of the cytoskeleton, resulting in keratinocyte shrinkage; spatial impediment for desmoglein adhesion; and formation of desmoglein-deficient desmosomes, among others. […] It is known that there is a genetic predisposition determined by human leukocyte antigen (HLA); HLA-DRB1*04 and HLA-A*10 are more frequent in Ashkenazi Jews with pemphigus.

• #8 Pemphigus Vulgaris (PV) | Causes, Pathophysiology, Mechanism

  https://medically.roche.com/global/en/microsites/about-pv/pathophysiology-and-mechanisms-of-disease.html

  Patients with PV have autoantibodies to desmoglein proteins that cause a loss of cell-cell adhesion in the skin and mucosal membranes resulting in blisters and erosions. […] PV is an autoimmune disease and caused by the development of immunoglobulin G (IgG) antibodies against the extracellular domains of desmogleins, specifically desmoglein 1 (DSG1) and desmoglein 3 (DSG3). […] The autoantibodies to DSG1 and DSG3 disrupt the DSG-mediated binding between epithelial cells driving the loss of cell-cell adhesions between keratinocytes, a process known as acantholysis. It is as a result of acantholysis that severe blisters develop on the skin and/or mucosal membranes. […] Anti-DSG antibodies are hypothesized to result in acantholysis through two mechanisms: (1) auto-antibody-mediated steric hindrance of desmosomal adhesion and/or interference with desmosome assembly, and (2) intracellular cell signaling pathways that augment the autoimmune response.

• #9 Pemphigus vulgaris – Wikipedia

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

  Pemphigus vulgaris is a rare chronic blistering skin disease and the most common form of pemphigus. […] It is classified as a type II hypersensitivity reaction in which antibodies are formed against desmosomes, components of the skin that function to keep certain layers of skin bound to each other. As desmosomes are attacked, the layers of skin separate and the clinical picture resembles a blister. These blisters are due to acantholysis, or breaking apart of intercellular connections through an autoantibody-mediated response. […] Pemphigus is an autoimmune disease caused by antibodies directed against both desmoglein 1 and desmoglein 3 present in desmosomes. Loss of desmosomes results in loss of cohesion between keratinocytes in the epidermis, and a disruption of the barrier function served by intact skin. The process is classified as a type II hypersensitivity reaction (in which antibodies bind to antigens on the body’s own tissues).

• #10

  https://step2.medbullets.com/dermatology/120089/pemphigus-vulgaris

  autoantibodies (IgG) against desmoglein, a component of the desmosome […] type II hypersensitivity reaction […] this disrupts keratinocyte adhesion and separation of the epidermis.

• #11 Pemphigus Vulgaris – Dermatology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.856.3.

  Pemphigus refers to a group of rare autoimmune blistering diseases characterized by acantholysis (loss of cell-cell adhesion) and formation of intraepidermal blisters in the mucous membranes, skin, or both. Pemphigus vulgaris (PV) is the most common type, occurring in ~1 per 1,000,000 people per year. The hallmark of PV is the presence of circulating and tissue-bound autoantibodies against desmosomal proteins, desmoglein 1 (Dsg1), and desmoglein 3 (Dsg3), resulting in the loss of keratinocyte cell-cell adhesion within the epidermis. […] Histopathology of the affected skin demonstrates suprabasal epidermal acantholysis and intraepidermal clefting with superficial mixed dermal inflammatory infiltrates including eosinophils. The base of the blister may have intact keratinocytes separated from one another, giving the tombstone appearance. Direct immunofluorescence of the perilesional skin is the gold standard to detect tissue-bound autoantibodies. It typically shows intercellular deposition of IgG, C3, or both, within the epidermis, giving the chicken wire appearance.

• #12 SciELO Brazil – Pemphigus vulgaris Pemphigus vulgaris

  https://www.scielo.br/j/abd/a/nV5V8fJtZw7kQhhDbzffyVL/

  Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. […] The formation of autoantibodies against components of desmosomes has long been considered the main process in pemphigus pathogenesis. […] The basic pathophysiology of pemphigus is the inhibition of the adhesive function of desmogleins by autoantibodies, which leads to the formation of blisters. […] PV is caused by the presence of IgG autoantibodies directed against Dsg1 and/or Dsg3, part of the desmosomes present on the surface of keratinocytes, which play a primary pathogenic role in the induction of loss of intercellular adhesion, resulting in the formation of blisters. […] However, the mechanism by which the binding of autoantibodies to desmogleins leads to acantholysis remains uncertain. Possible hypotheses for this phenomenon include: alterations in intracellular transduction signaling and rupture of the cytoskeleton, resulting in keratinocyte shrinkage; spatial impediment for desmoglein adhesion; and formation of desmoglein-deficient desmosomes, among others. […] It is known that there is a genetic predisposition determined by human leukocyte antigen (HLA); HLA-DRB1*04 and HLA-A*10 are more frequent in Ashkenazi Jews with pemphigus.

• #13 Pemphigus vulgaris* | Anais Brasileiros de Dermatologia

  http://www.anaisdedermatologia.org.br/en-pemphigus-vulgaris-articulo-S0365059620306048

  Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. […] The formation of autoantibodies against components of desmosomes has long been considered the main process in pemphigus pathogenesis. […] The basic pathophysiology of pemphigus is the inhibition of the adhesive function of desmogleins by autoantibodies, which leads to the formation of blisters. […] The mechanism by which the binding of autoantibodies to desmogleins leads to acantholysis remains uncertain. Possible hypotheses for this phenomenon include: alterations in intracellular transduction signaling and rupture of the cytoskeleton, resulting in keratinocyte shrinkage; spatial impediment for desmoglein adhesion; and formation of desmoglein-deficient desmosomes, among others.

• #14 Pemphigus Vulgaris (PV) | Causes, Pathophysiology, Mechanism

  https://medically.roche.com/global/en/microsites/about-pv/pathophysiology-and-mechanisms-of-disease.html

  Patients with PV have autoantibodies to desmoglein proteins that cause a loss of cell-cell adhesion in the skin and mucosal membranes resulting in blisters and erosions. […] PV is an autoimmune disease and caused by the development of immunoglobulin G (IgG) antibodies against the extracellular domains of desmogleins, specifically desmoglein 1 (DSG1) and desmoglein 3 (DSG3). […] The autoantibodies to DSG1 and DSG3 disrupt the DSG-mediated binding between epithelial cells driving the loss of cell-cell adhesions between keratinocytes, a process known as acantholysis. It is as a result of acantholysis that severe blisters develop on the skin and/or mucosal membranes. […] Anti-DSG antibodies are hypothesized to result in acantholysis through two mechanisms: (1) auto-antibody-mediated steric hindrance of desmosomal adhesion and/or interference with desmosome assembly, and (2) intracellular cell signaling pathways that augment the autoimmune response.

• #15 Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050696

  Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). […] Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. […] Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. […] Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. […] A major unresolved question is whether the loss of cell-cell adhesion triggered by pemphigus IgG is caused by direct inhibition of desmoglein cis or trans interactions (steric hindrance), by endocytosis of cell surface Dsg3, by the activation of cellular signaling pathways, or by some combination of these events.

• #16 Pemphigus vulgaris* | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-pemphigus-vulgaris-articulo-S0365059620306048

  Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. […] The formation of autoantibodies against components of desmosomes has long been considered the main process in pemphigus pathogenesis. […] The basic pathophysiology of pemphigus is the inhibition of the adhesive function of desmogleins by autoantibodies, which leads to the formation of blisters. […] The mechanism by which the binding of autoantibodies to desmogleins leads to acantholysis remains uncertain. Possible hypotheses for this phenomenon include: alterations in intracellular transduction signaling and rupture of the cytoskeleton, resulting in keratinocyte shrinkage; spatial impediment for desmoglein adhesion; and formation of desmoglein-deficient desmosomes, among others. […] It is known that there is a genetic predisposition determined by human leukocyte antigen (HLA); HLA–DRB1*04 and HLA-A*10 are more frequent in Ashkenazi Jews with pemphigus.

• #17 Pemphigus vulgaris* | Anais Brasileiros de Dermatologia

  https://www.anaisdedermatologia.org.br/en-pemphigus-vulgaris-articulo-S0365059620306048

  Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. […] The formation of autoantibodies against components of desmosomes has long been considered the main process in pemphigus pathogenesis. […] The basic pathophysiology of pemphigus is the inhibition of the adhesive function of desmogleins by autoantibodies, which leads to the formation of blisters. […] The mechanism by which the binding of autoantibodies to desmogleins leads to acantholysis remains uncertain. Possible hypotheses for this phenomenon include: alterations in intracellular transduction signaling and rupture of the cytoskeleton, resulting in keratinocyte shrinkage; spatial impediment for desmoglein adhesion; and formation of desmoglein-deficient desmosomes, among others. […] It is known that there is a genetic predisposition determined by human leukocyte antigen (HLA); HLA–DRB1*04 and HLA-A*10 are more frequent in Ashkenazi Jews with pemphigus.

• #18 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

  This theory explores new mechanisms with the findings obtained by independent groups. […] 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. […] 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. […] The findings suggest that oxidative stress-mediated YAP dysregulation likely plays a key role in pemphigus blistering, indicating the potential therapeutic role of antioxidants in the treatment of PV.

• #19

  https://link.springer.com/article/10.1007/s10495-022-01726-z

  Pemphigus Vulgaris (PV) is a severe autoimmune disease characterized by supra-basal blisters in the skin and mucous membranes of a wide range of mammals, including humans. […] It has been stated that auto-antibodies are produced, for unknown reasons, which are directed against desmogleins present on the epithelium and thus leads to acantholysis and intraepithelial blistering. […] But the exact mechanism is still not completely understood. […] Here we would like to shed light on a new pathologic mechanism i.e., apoptolysis, which emphasizes that apoptotic enzymes contribute to acantholysis development both in terms of molecular events and chronologic sequence. […] A possible role of apoptolysis has been discussed in purview of PV.

• #20 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 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. […] 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.

• #21 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.

• #22 Pemphigus vulgaris* | Anais Brasileiros de Dermatologia

  http://www.anaisdedermatologia.org.br/en-pemphigus-vulgaris-articulo-S0365059620306048

  Desmogleins have four isoforms: Dsg1 (160 kDa) and Dsg3 (130 kDa) are only expressed in the squamous stratified epithelium, where pemphigus bullous lesions occur; Dsg2 is expressed in all tissues with desmosomes, including the simple epithelium and the myocardium; Dsg4 is expressed in the hair follicles, and is possibly implicated in scalp lesions, which are common in pemphigus. […] In mucosal PV, the main antigen involved is Dsg3. In the skin, isolated Dsg3 dysfunction is unable to produce blisters, as it is entirely compensated by Dsg1. However, in the mucosa, the low concentration of Dsg1 is not sufficient to compensate for the Dsg3 dysfunction, which leads to the predominance of mucosal lesions without cutaneous involvement. […] PV is caused by the presence of IgG autoantibodies directed against Dsg1 and/or Dsg3, part of the desmosomes present on the surface of keratinocytes, which play a primary pathogenic role in the induction of loss of intercellular adhesion, resulting in the formation of blisters.

• #23 Types and Pathogenesis of Pemphigus Vulgaris

  https://www.longdom.org/open-access/types-and-pathogenesis-of-pemphigus-vulgaris-97871.html

  This theory is explained by distribution of DSG in skin and mucosa. According to this theory the DSG3 and DSG1 gets distributed solely or both. When the autoantibodies attack these desmoglein, if both DSG3 and DSG1 are present one loss would be compensated by the other. If only one desmoglein is present it leads to pemphigus vulgaris.

• #24 Pemphigus vulgaris* | Anais Brasileiros de Dermatologia

  http://www.anaisdedermatologia.org.br/en-pemphigus-vulgaris-articulo-S0365059620306048

  Desmogleins have four isoforms: Dsg1 (160 kDa) and Dsg3 (130 kDa) are only expressed in the squamous stratified epithelium, where pemphigus bullous lesions occur; Dsg2 is expressed in all tissues with desmosomes, including the simple epithelium and the myocardium; Dsg4 is expressed in the hair follicles, and is possibly implicated in scalp lesions, which are common in pemphigus. […] In mucosal PV, the main antigen involved is Dsg3. In the skin, isolated Dsg3 dysfunction is unable to produce blisters, as it is entirely compensated by Dsg1. However, in the mucosa, the low concentration of Dsg1 is not sufficient to compensate for the Dsg3 dysfunction, which leads to the predominance of mucosal lesions without cutaneous involvement. […] PV is caused by the presence of IgG autoantibodies directed against Dsg1 and/or Dsg3, part of the desmosomes present on the surface of keratinocytes, which play a primary pathogenic role in the induction of loss of intercellular adhesion, resulting in the formation of blisters.

• #25

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

  Pemphigus vulgaris pathogenesis had been considered well understood and was in danger of being finished, as was physics at the end of the 19th century. […] With the publication in this issue of a paper by Nguyen and colleagues, the understanding of pemphigus pathogenesis must undergo a major revision. […] The mechanism by which PV IgG induces acantholysis has been subject to dispute. […] However, it has become dogma that the autoantigen responsible for PV is desmoglein 3 (Dsg3), a 130-kDa desmosomal adhesion molecule. […] The different locations of epidermal separation seen in PV and in PF can be explained by the distribution of Dsg3 and Dsg1, further supporting the role of these autoantigens in pemphigus. […] Because the two desmogleins apparently compensate for each others absence to prevent acantholysis, PF sera (containing antibodies to Dsg1 but not Dsg3) can disrupt the epidermis only at sites where Dsg1 is expressed exclusively; conversely, PV sera that contain antibodies to Dsg3 but not Dsg1 can disrupt the epidermis only at sites where Dsg3 is expressed exclusively.

• #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://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  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. […] 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.

• #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://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.

• #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://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  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. […] 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. […] This finding uncovers a previously unidentified biological function of this desmosomal cadherin in keratinocytes and suggests that blisters are partly due to the altered stress response that acts in the orchestra with p53 resulting in the damage of normal tissue homeostasis. […] Hence, disruption of this pathway may play an important part in PV pathology.

• #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://www.mdpi.com/2075-1729/11/7/621

  This theory explores new mechanisms with the findings obtained by independent groups. […] 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. […] 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. […] The findings suggest that oxidative stress-mediated YAP dysregulation likely plays a key role in pemphigus blistering, indicating the potential therapeutic role of antioxidants in the treatment of PV.

• #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://pmc.ncbi.nlm.nih.gov/articles/PMC8303937/

  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. […] 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. […] This finding uncovers a previously unidentified biological function of this desmosomal cadherin in keratinocytes and suggests that blisters are partly due to the altered stress response that acts in the orchestra with p53 resulting in the damage of normal tissue homeostasis. […] Hence, disruption of this pathway may play an important part in PV pathology.

• #31 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.

• #32 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 then ascertained the impact of DSG3 downregulation on p53 activity using a luciferase reporter under the regulation of a p53 binding motif. […] Given the facts that (1) p53 expression increases following DSG3 down-regulation and (2) p53 regulates ST18 expression, we hypothesized that down-regulation of DSG3 may result in a p53-dependent increase in ST18 expression, which in turn may explain the association between ST18 expression in the epidermis and increased risk for PV.

• #33 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

  Taken collectively, the present and previous observations suggest that ST18 overexpression in PV skin, which is genetically determined, boosts pro-inflammatory cytokine secretion and autoantibody-mediated DSG3 down-regulation, which result in impaired cell-cell adhesion within the epidermis. […] 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.

• #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://www.mdpi.com/2075-1729/11/7/621

  This theory explores new mechanisms with the findings obtained by independent groups. […] 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. […] 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. […] The findings suggest that oxidative stress-mediated YAP dysregulation likely plays a key role in pemphigus blistering, indicating the potential therapeutic role of antioxidants in the treatment of PV.

• #35 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

  This theory explores new mechanisms with the findings obtained by independent groups. […] 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. […] 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. […] The findings suggest that oxidative stress-mediated YAP dysregulation likely plays a key role in pemphigus blistering, indicating the potential therapeutic role of antioxidants in the treatment of PV.

• #36

  https://link.springer.com/article/10.1007/s10495-022-01726-z

  Pemphigus Vulgaris (PV) is a severe autoimmune disease characterized by supra-basal blisters in the skin and mucous membranes of a wide range of mammals, including humans. […] It has been stated that auto-antibodies are produced, for unknown reasons, which are directed against desmogleins present on the epithelium and thus leads to acantholysis and intraepithelial blistering. […] But the exact mechanism is still not completely understood. […] Here we would like to shed light on a new pathologic mechanism i.e., apoptolysis, which emphasizes that apoptotic enzymes contribute to acantholysis development both in terms of molecular events and chronologic sequence. […] A possible role of apoptolysis has been discussed in purview of PV.

• #37

  https://esmed.org/MRA/mra/article/view/773

  Pemphigus vulgaris (PV) is an organ-specific autoimmune blistering disease, affecting the skin and the mucous membranes. […] Cloning of cDNAs encoding pemphigus antigens has provided ample evidence that IgG autoantibodies recognize the desmogleins (DSGs) that are found in the adhering junctions, the desmosomes. Binding of such IgGs in the DSGs results in the weakening of intercellular adhesion of keratinocytes in the upper part of the epidermis and eventually to acantholysis. […] Mechanistically, the production of IgG autoantibodies against DSG1 and DSG3 is linked to disease pathogenesis. Recently, endoplasmic reticulum (ER) stress, a highly conserved cellular stress response, has been proposed to play a role in the development and progression of PV. […] The discovery that ER stress occurs during PV development implies that deregulated UPR may contribute to the pathogenesis of the disease. Future studies should be directed toward understanding how modulation of the ER can provide new therapeutic possibilities for the treatment of PV patients.

• #38 The role of T cells in the immunopathogenesis of pemphigus vulgaris | Medicina Cutánea ILA

  https://www.medicinacutaneaila.com/frame_eng.php?id=85

  Pemphigus vulgaris is an antibody mediated autoimmune blistering disease with the formation of blisters and erosions on skin and/or mucous membranes. […] In the past years, there is mounting evidence of the important role of T cell in the pathogenesis of this disease. T helper (Th) type 1 and T follicular helper cells are relevant in the production of autoantibodies. Th1 cell promote a proinflammatory milieu. Th17 cells seem to amplify the inflammatory response and contribute to tissue damage. […] On the other hand, T regulatory cells fail to suppress efficiently the above mentioned pathogenic immune responses. The understanding of the different roles these cellular subtypes and cytokines play in the immunopathogenesis of pemphigus vulgaris may lead to the use of novel therapeutic targets in the future.

• #39 The role of T cells in the immunopathogenesis of pemphigus vulgaris | Medicina Cutánea ILA

  https://www.medicinacutaneaila.com/frame_eng.php?id=85

  Pemphigus vulgaris is an antibody mediated autoimmune blistering disease with the formation of blisters and erosions on skin and/or mucous membranes. […] In the past years, there is mounting evidence of the important role of T cell in the pathogenesis of this disease. T helper (Th) type 1 and T follicular helper cells are relevant in the production of autoantibodies. Th1 cell promote a proinflammatory milieu. Th17 cells seem to amplify the inflammatory response and contribute to tissue damage. […] On the other hand, T regulatory cells fail to suppress efficiently the above mentioned pathogenic immune responses. The understanding of the different roles these cellular subtypes and cytokines play in the immunopathogenesis of pemphigus vulgaris may lead to the use of novel therapeutic targets in the future.

• #40 The role of T cells in the immunopathogenesis of pemphigus vulgaris | Medicina Cutánea ILA

  https://www.medicinacutaneaila.com/frame_eng.php?id=85

  Pemphigus vulgaris is an antibody mediated autoimmune blistering disease with the formation of blisters and erosions on skin and/or mucous membranes. […] In the past years, there is mounting evidence of the important role of T cell in the pathogenesis of this disease. T helper (Th) type 1 and T follicular helper cells are relevant in the production of autoantibodies. Th1 cell promote a proinflammatory milieu. Th17 cells seem to amplify the inflammatory response and contribute to tissue damage. […] On the other hand, T regulatory cells fail to suppress efficiently the above mentioned pathogenic immune responses. The understanding of the different roles these cellular subtypes and cytokines play in the immunopathogenesis of pemphigus vulgaris may lead to the use of novel therapeutic targets in the future.

• #41 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.

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

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

  The two antigens targeted by autoantibodies in PV are the 130-kDa glycoprotein Dsg3 and 160-kDa glycoprotein Dsg1. […] There is a genetic predisposition for developing PV; certain major histocompatibility complex (MHC) class II molecules, such as DR4 (DRB1*0402) and DRw6 (DQB1*0503) occurring more frequently among those affected. […] The loss of intraepidermal adhesion between keratinocytes is attributable to the binding of autoantibodies directed against desmosomal structural proteins, primarily desmogleins (Dsg1 and Dsg3) and, in rare cases, also desmocollin 1-3 or plakins. […] In patients with PV, most types of antibodies are oriented against desmosomal cadherins, Dsg1 and Dsg3, but other autoantibodies have been identified targeting other metabolic and structural proteins, such as Dsc1 and Dsc3 desmocolins, mitochondrial antigens, hSPCA1, thyroid peroxidase, muscarinic and nicotinic acetylcholine receptors, plakoglobin, E-cadherin and plakophilin 3.

• #43 Pemphigus | Choose the Right Test

  https://arupconsult.com/content/pemphigus

  Pemphigus refers to a group of uncommon and severe autoimmune blistering skin diseases that affect the epithelium, including skin and mucous membranes. The pemphigus diseases are caused by pathogenic autoantibodies against desmoglein 1 and desmoglein 3, two adhesion proteins found in keratinocytes. When the autoantibodies bind to the desmoglein 1 and 3 proteins, keratinocyte separation (acantholysis) occurs, which leads to blistering in the skin and mucous membranes. […] Pemphigus vulgaris and pemphigus foliaceus are the two primary subtypes of pemphigus. Of these, pemphigus vulgaris is the more common. […] A predisposing factor for pemphigus diseases is the presence of HLA gene variants such as HLA-DRB1*04:02 and HLA-DQB1*05:03, alleles that are reportedly detected in most patients with pemphigus vulgaris.

• #44 SciELO Brazil – Pemphigus vulgaris Pemphigus vulgaris

  https://www.scielo.br/j/abd/a/nV5V8fJtZw7kQhhDbzffyVL/

  Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. […] The formation of autoantibodies against components of desmosomes has long been considered the main process in pemphigus pathogenesis. […] The basic pathophysiology of pemphigus is the inhibition of the adhesive function of desmogleins by autoantibodies, which leads to the formation of blisters. […] PV is caused by the presence of IgG autoantibodies directed against Dsg1 and/or Dsg3, part of the desmosomes present on the surface of keratinocytes, which play a primary pathogenic role in the induction of loss of intercellular adhesion, resulting in the formation of blisters. […] However, the mechanism by which the binding of autoantibodies to desmogleins leads to acantholysis remains uncertain. Possible hypotheses for this phenomenon include: alterations in intracellular transduction signaling and rupture of the cytoskeleton, resulting in keratinocyte shrinkage; spatial impediment for desmoglein adhesion; and formation of desmoglein-deficient desmosomes, among others. […] It is known that there is a genetic predisposition determined by human leukocyte antigen (HLA); HLA-DRB1*04 and HLA-A*10 are more frequent in Ashkenazi Jews with pemphigus.

• #45 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  Pemphigus are intraepidermal autoimmune bullous dermatoses that occur with lesions on the skin and / or mucous membranes. […] They result from the production of pathogenic autoantibodies (usually IgG) that are directed against various desmosomal proteins (the desmogleins Dsg3 and Dsg1). The binding of these autoantibodies to desmosomal components compromises intraepidermal adhesion, leading to acantholysis and the formation of vesicles, blisters, and erosions on the skin and mucous membranes. […] Regardless of subtype, the formation of autoantibodies against desmosomal components has long been considered the chief event in the pathogenesis of pemphigus. In addition to the involvement of humoral immunity, the function of cellular immunity in it has been highlighted. […] The etiology of PV is unknown. Possible triggering factors include environmental agents, infections, drugs, and tumors. It is linked to specific HLAs, such as HLA-DRB1*04:02 (Jewish) and HLADQB1*05:03.

• #46 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.

• #47 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.

• #48 P/P Clinical Information – IPPF

  https://www.pemphigus.org/p-p-clinical-information/

  Autoantibodies against a variety of epithelial cell surface antigens have been identified in patients with pemphigus. […] Desmogleins are the antigens that have been most extensively studied in pemphigus vulgaris and pemphigus foliaceus. Desmogleins are components of desmosomes, integral structures for cell-to-cell adhesion. […] As with many other autoimmune diseases, the precipitating factors of pemphigus diseases are poorly understood. Both genetic and environmental factors may influence the development of pemphigus. […] Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris, and pemphigus has been reported to develop following burns or cutaneous electrical injury. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease.

• #49 Pemphigus Vulgaris | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688850/all/Pemphigus_Vulgaris?q=Hoarseness

  Autoantibodies (IgG) are directed against desmoglein (Dsg) 1 and 3 adhesion molecules. Dsgs interact with desmosomes, which hold epidermal cells together. The antibodies against Dsg molecules cause intraepidermal blister formation and acantholysis. […] Additionally, autoantibodies against Dsg 4, the acetylcholine receptor, and pemphaxin have been identified in patients with PV. The exact pathogenesis of pemphigus has yet to be fully explained and is likely a multiple hit process. Autoimmune; stimulus is unknown. […] Inducing factors include physical trauma, such as thermal burns, UV light, and ionizing radiation; neoplasm; emotional stress; drugs; and infections. Most patients lack a recognized inducing factor.

• #50 P/P Clinical Information – IPPF

  https://www.pemphigus.org/p-p-clinical-information/

  Autoantibodies against a variety of epithelial cell surface antigens have been identified in patients with pemphigus. […] Desmogleins are the antigens that have been most extensively studied in pemphigus vulgaris and pemphigus foliaceus. Desmogleins are components of desmosomes, integral structures for cell-to-cell adhesion. […] As with many other autoimmune diseases, the precipitating factors of pemphigus diseases are poorly understood. Both genetic and environmental factors may influence the development of pemphigus. […] Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris, and pemphigus has been reported to develop following burns or cutaneous electrical injury. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease.

• #51 P/P Clinical Information – IPPF

  https://www.pemphigus.org/p-p-clinical-information/

  Autoantibodies against a variety of epithelial cell surface antigens have been identified in patients with pemphigus. […] Desmogleins are the antigens that have been most extensively studied in pemphigus vulgaris and pemphigus foliaceus. Desmogleins are components of desmosomes, integral structures for cell-to-cell adhesion. […] As with many other autoimmune diseases, the precipitating factors of pemphigus diseases are poorly understood. Both genetic and environmental factors may influence the development of pemphigus. […] Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris, and pemphigus has been reported to develop following burns or cutaneous electrical injury. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease.

• #52 Pemphigus Vulgaris: A Complete Overview — DermNet

  https://dermnetnz.org/topics/pemphigus-vulgaris

  Pemphigus vulgaris is an autoimmune blistering disease. […] In pemphigus vulgaris, immunoglobulin type G (IgG) autoantibodies bind to a protein called desmoglein 3 (DSG3), which is found in desmosomes in the keratinocytes near the bottom of the epidermis. […] The result is the keratinocytes separate from each other, and are replaced by fluid (the blister). […] About 50% of patients with pemphigus vulgaris also have anti-DSG1 antibodies. […] Large epidemiological studies have suggested a rare link between herpes virus infection and pemphigus.

• #53 Phemphigus Vulgaris

  https://www.pediatriconcall.com/articles/pediatric-dermatology/phemphigus-vulgaris/phemphigus-vulgaris-introduction

  It is caused due to the auto-antibodies to the desmogleins (desmoglein 3), which are intracellular adhesion proteins. This results in the damaged cell to cell adhesions and hence, the formation of blisters and ulcers. […] Even though it is thought to be genetically transmitted, some of the etiological agents considered are garlic in diet, drugs with sulfhydryl radical, cosmetics, Human herpesvirus -8 (HHV-8) and is often associated with myasthenia gravis.

• #54 Drug-Induced Pemphigus: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1063684-overview

  Pemphigus is an autoimmune bullous disease characterized by blisters and erosions of the skin and mucous membranes. Several variants of the disease exist, including pemphigus vulgaris, pemphigus foliaceous, and drug-induced pemphigus. Patients with drug-induced pemphigus have autoantibodies that are either circulating or tissue bound. […] A variety of drugs have been implicated in the onset of drug-induced pemphigus. Some of these drugs induce antibody formation, which results in acantholysis via a mechanism identical to that found in idiopathic pemphigus. Other drugs are postulated to induce acantholysis directly in the absence of antibody formation. […] Drugs that induce pemphigus may be categorized into 2 groups: thiol drugs and nonthiol drugs. Thiol drugs are reported most frequently as the culprits of drug-induced pemphigus.

• #55 Phemphigus Vulgaris

  https://www.pediatriconcall.com/articles/pediatric-dermatology/phemphigus-vulgaris/phemphigus-vulgaris-introduction

  It is caused due to the auto-antibodies to the desmogleins (desmoglein 3), which are intracellular adhesion proteins. This results in the damaged cell to cell adhesions and hence, the formation of blisters and ulcers. […] Even though it is thought to be genetically transmitted, some of the etiological agents considered are garlic in diet, drugs with sulfhydryl radical, cosmetics, Human herpesvirus -8 (HHV-8) and is often associated with myasthenia gravis.

• #56 P/P Clinical Information – IPPF

  https://www.pemphigus.org/p-p-clinical-information/

  Autoantibodies against a variety of epithelial cell surface antigens have been identified in patients with pemphigus. […] Desmogleins are the antigens that have been most extensively studied in pemphigus vulgaris and pemphigus foliaceus. Desmogleins are components of desmosomes, integral structures for cell-to-cell adhesion. […] As with many other autoimmune diseases, the precipitating factors of pemphigus diseases are poorly understood. Both genetic and environmental factors may influence the development of pemphigus. […] Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus and pemphigus vulgaris, and pemphigus has been reported to develop following burns or cutaneous electrical injury. Viral infections, certain food compounds, ionizing radiation, and pesticides have been suggested as additional stimuli for this disease.

• #57 Pemphigus Vulgaris | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688850/all/Pemphigus_Vulgaris?q=Hoarseness

  Autoantibodies (IgG) are directed against desmoglein (Dsg) 1 and 3 adhesion molecules. Dsgs interact with desmosomes, which hold epidermal cells together. The antibodies against Dsg molecules cause intraepidermal blister formation and acantholysis. […] Additionally, autoantibodies against Dsg 4, the acetylcholine receptor, and pemphaxin have been identified in patients with PV. The exact pathogenesis of pemphigus has yet to be fully explained and is likely a multiple hit process. Autoimmune; stimulus is unknown. […] Inducing factors include physical trauma, such as thermal burns, UV light, and ionizing radiation; neoplasm; emotional stress; drugs; and infections. Most patients lack a recognized inducing factor.

• #58 Drug-Induced Pemphigus: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1063684-overview

  Pemphigus is an autoimmune bullous disease characterized by blisters and erosions of the skin and mucous membranes. Several variants of the disease exist, including pemphigus vulgaris, pemphigus foliaceous, and drug-induced pemphigus. Patients with drug-induced pemphigus have autoantibodies that are either circulating or tissue bound. […] A variety of drugs have been implicated in the onset of drug-induced pemphigus. Some of these drugs induce antibody formation, which results in acantholysis via a mechanism identical to that found in idiopathic pemphigus. Other drugs are postulated to induce acantholysis directly in the absence of antibody formation. […] Drugs that induce pemphigus may be categorized into 2 groups: thiol drugs and nonthiol drugs. Thiol drugs are reported most frequently as the culprits of drug-induced pemphigus.

• #59 Drug-Induced Pemphigus: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1063684-overview

  Thiol drugs are postulated to induce acantholysis through biochemical mechanisms without antibody formation. Experiments with skin explants have demonstrated that thiol drugs can induce acantholysis directly. […] Nonthiol drugs are more likely to induce acantholysis via immune mechanisms. Studies of cases of non-thiolinduced pemphigus reveal the presence of autoantibodies that recognize pemphigus antigens, in particular desmoglein 3, which is the pemphigus vulgaris antigen. In fact, this group of patients tends to have clinical, histologic, immunologic, and prognostic features similar to idiopathic pemphigus vulgaris. […] One case report describes localized pemphigus foliaceus induced by topical imiquimod treatment. Imiquimod does not contain thiol, sulfur, or amide groups in its structure. The exact mechanism of acantholysis induction from this medication is unknown. Because imiquimod is known to cause a localized immune response at the site of application, the generation of antibodies to desmoglein 1 has been postulated as a mechanism of action.

• #60 Cytokine profiles in the sera of Egyptian patients with oral pemphigus vulgaris

  http://revodonto.bvsalud.org/scielo.php?script=sci_arttext&pid=S1677-32252011000200002

  Cytokines have been suggested to play an important role in the pathogenesis of various inflammatory and autoimmune diseases, including the potentially fatal blistering disease, oral pemphigus vulgaris (PV). […] These data showed that TNF- and IL-6 levels were significantly increased in the sera of Egyptian patients with oral PV and this might suggest its role in the pathogenesis of this disease. […] Recently, there has been increasing interest in the role of cytokines in the pathogenesis of various inflammatory and autoimmune diseases, including the potentially fatal blistering disease, PV. […] Moreover, experimental studies revealed that synergistic cooperation of pemphigus antibodies with IL-6 and TNF- in the pathogenesis of PV. […] The present findings showed that TNF- and IL-6 levels were significantly increased in the sera of Egyptian patients with oral PV, probably suggesting its role in the pathogenesis of this disease.

• #61 Cytokine profiles in the sera of Egyptian patients with oral pemphigus vulgaris

  http://revodonto.bvsalud.org/scielo.php?script=sci_arttext&pid=S1677-32252011000200002

  Cytokines have been suggested to play an important role in the pathogenesis of various inflammatory and autoimmune diseases, including the potentially fatal blistering disease, oral pemphigus vulgaris (PV). […] These data showed that TNF- and IL-6 levels were significantly increased in the sera of Egyptian patients with oral PV and this might suggest its role in the pathogenesis of this disease. […] Recently, there has been increasing interest in the role of cytokines in the pathogenesis of various inflammatory and autoimmune diseases, including the potentially fatal blistering disease, PV. […] Moreover, experimental studies revealed that synergistic cooperation of pemphigus antibodies with IL-6 and TNF- in the pathogenesis of PV. […] The present findings showed that TNF- and IL-6 levels were significantly increased in the sera of Egyptian patients with oral PV, probably suggesting its role in the pathogenesis of this disease.

• #62 Pemphigus Vulgaris: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1064187-overview

  Pemphigus antibody fixes components of complement to the surface of epidermal cells. Antibody binding may activate complement with the release of inflammatory mediators and recruitment of activated T cells. T cells are clearly required for the production of the autoantibodies, but their role in the pathogenesis of pemphigus vulgaris remains poorly understood. Interleukin (IL)-2 is the main activator of T lymphocytes, and increased soluble receptors have been detected in patients with active pemphigus vulgaris.

• #63 Pemphigus Vulgaris: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1064187-overview

  Pemphigus antibody fixes components of complement to the surface of epidermal cells. Antibody binding may activate complement with the release of inflammatory mediators and recruitment of activated T cells. T cells are clearly required for the production of the autoantibodies, but their role in the pathogenesis of pemphigus vulgaris remains poorly understood. Interleukin (IL)-2 is the main activator of T lymphocytes, and increased soluble receptors have been detected in patients with active pemphigus vulgaris.

• #64 Pemphigus Vulgaris – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560860/

  A super-compensation hypothesis recently submitted by Sinha et al. proposes that additional factors may also play a role in PV. […] The pathogenesis of PV has been described in more detail by Hammers et al. […] In patients with PV, autoantibodies against desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) is the purported cause. […] The most common targets of desmoglein for IgG antibodies are the extracellular cadherin domains, which can result in the loss of desmosome-adhesive properties. […] It is generally believed that the amino portion of the cadherin proteins is most implicated in the pathogenesis of acantholysis leading to PV. […] Many animal models have shown that enzymatic inactivation of Dsg 1 and gene deletion of Dsg 3 results in pathology similar to PV. […] The binding of antibodies to desmogleins has been confirmed by epitope mapping and is presumed to disrupt desmoglein binding by affecting steric hindrance. […] Another theory for the pathophysiology of PV is the desmoglein nonassembly depletion hypothesis.

• #65 Revisiting pemphigus vulgaris: A case report and review of literature – International Journal of Case Reports and Images (IJCRI)

  https://www.ijcasereportsandimages.com/archive/article-full-text/101417Z01PD2023

  Different theories are established to understand the pathogenesis of pemphigus vulgaris. They are the desmoglein compensation theory, multiple hits hypothesis, the antibody induced apoptosis theory, basal cell shrinkage hypothesis, and the apoptolysis theory. […] Pemphigus vulgaris is generally seen in patients with certain HLA genotypes that generate B-cells which are responsible for the specific autoantibodies. These B-cells are activated by a complex interaction with CD4+ T helper 2 (Th2) cells and the over-activation of these Th2 cells leads to the autoantibody production that is essential for pemphigus vulgaris. […] The production of IgG autoantibodies against the cell membrane proteins, the desmogleins of the keratinocytes results in acantholysis. […] Acantholysis is described as the loss of coherence among epidermal cells due to the breakdown of intercellular bridges. […] The criteria for the diagnosis of pemphigus are the presence of appropriate clinical lesion, histopathological picture of acantholysis in biopsy specimens, and identification of autoantibodies in the tissue or serum, or both.

• #66 Revisiting pemphigus vulgaris: A case report and review of literature – International Journal of Case Reports and Images (IJCRI)

  https://www.ijcasereportsandimages.com/archive/article-full-text/101417Z01PD2023

  Different theories are established to understand the pathogenesis of pemphigus vulgaris. They are the desmoglein compensation theory, multiple hits hypothesis, the antibody induced apoptosis theory, basal cell shrinkage hypothesis, and the apoptolysis theory. […] Pemphigus vulgaris is generally seen in patients with certain HLA genotypes that generate B-cells which are responsible for the specific autoantibodies. These B-cells are activated by a complex interaction with CD4+ T helper 2 (Th2) cells and the over-activation of these Th2 cells leads to the autoantibody production that is essential for pemphigus vulgaris. […] The production of IgG autoantibodies against the cell membrane proteins, the desmogleins of the keratinocytes results in acantholysis. […] Acantholysis is described as the loss of coherence among epidermal cells due to the breakdown of intercellular bridges. […] The criteria for the diagnosis of pemphigus are the presence of appropriate clinical lesion, histopathological picture of acantholysis in biopsy specimens, and identification of autoantibodies in the tissue or serum, or both.

• #67 Revisiting pemphigus vulgaris: A case report and review of literature – International Journal of Case Reports and Images (IJCRI)

  https://www.ijcasereportsandimages.com/archive/article-full-text/101417Z01PD2023

  Different theories are established to understand the pathogenesis of pemphigus vulgaris. They are the desmoglein compensation theory, multiple hits hypothesis, the antibody induced apoptosis theory, basal cell shrinkage hypothesis, and the apoptolysis theory. […] Pemphigus vulgaris is generally seen in patients with certain HLA genotypes that generate B-cells which are responsible for the specific autoantibodies. These B-cells are activated by a complex interaction with CD4+ T helper 2 (Th2) cells and the over-activation of these Th2 cells leads to the autoantibody production that is essential for pemphigus vulgaris. […] The production of IgG autoantibodies against the cell membrane proteins, the desmogleins of the keratinocytes results in acantholysis. […] Acantholysis is described as the loss of coherence among epidermal cells due to the breakdown of intercellular bridges. […] The criteria for the diagnosis of pemphigus are the presence of appropriate clinical lesion, histopathological picture of acantholysis in biopsy specimens, and identification of autoantibodies in the tissue or serum, or both.

• #68 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.

• #69 The Role Of Antibody Subclass In The Pathogenesis Of Pemphigus Vulgaris

  https://repository.upenn.edu/items/7960902d-7de1-4a89-bdac-824f0436b606

  A marvel of evolution, the adaptive immune system has the capacity to respond to almost any foreign antigen in a highly specific manner. […] The focus of this thesis is to characterize the role of class-switching (the changing of antibody constant regions) in the pathogenesis of autoimmune disease, and in particular to trace the lineage of antigen-specific autoreactive B cells by analyzing clonal relationships between antibodies of different constant regions. […] The work presented in this thesis focuses on pemphigus vulgaris, or PV, a model antibody-mediated autoimmune disease characterized by a response to the cell adhesion protein desmoglein (Dsg) 3, which holds keratinocytes together in the epidermis. […] An enigmatic feature of this disease is the predominance of antibodies from the IgG4 subclass during active disease, which ordinarily appears to have few effector functions and may serve as a “brake” on the immune system in the setting of continuous stimulation by antigen.

• #70 The Role Of Antibody Subclass In The Pathogenesis Of Pemphigus Vulgaris

  https://repository.upenn.edu/items/7960902d-7de1-4a89-bdac-824f0436b606

  Finding that the subclass has very little effect on antibody affinity, pathogenicity, or epitope preference, we then sought to determine whether B cells expressing autoantibodies of different subclasses share lineages, indicating common pathways of development. […] In particular, we found that anti-Dsg IgG4 B cells, which are believed to be central to disease pathogenesis, tended to not share lineages with other subclasses, and in general do not appear to share a precursor-product relationship with anti-Dsg IgG1 B cells. […] These findings are key to understanding the role of class-switching in the pathogenesis of PV, and may shed light on the class-switch mechanisms driving other autoimmune diseases and states of chronic antigen stimulation.

• #71 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  PV is characterized by acantholysis and the formation of intraepidermal blisters, resulting from the presence of IgG autoantibodies against the transmembrane desmosomal glycoprotein Dsg3 (130 kD) and, in certain cases, Dsg1 (160 kD). […] The treatment of autoimmune bullous dermatoses, including PV is usually based on systemic medications, because they comprise a severe group of mucosal and cutaneous diseases with significant morbidity and mortality. […] Systemic corticosteroids are the basis of the treatment for PV. They have potent anti-inflammatory and immunosuppressive activities. […] The introduction of these drugs in the 1950s was followed by a reduction in mortality from 75% to 30%. […] Azathioprine is a cytotoxic drug that is used in most autoimmune diseases. It is an imidazole derivative of mercaptopurine, which antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins.

• #72 Pemphigus Vulgaris – Dermatologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/pemphigus-vulgaris

  Pemphigus vulgaris is characterized by IgG autoantibodies directed against the calcium-dependent cadherins desmoglein 3 and sometimes desmoglein 1. […] Acantholysis (loss of intercellular adhesion with consequent epidermal blister formation) results from either direct inhibition of desmoglein function by autoantibody binding or from autoantibody-induced cell signaling that results in down-regulation of cell-cell adhesion. […] The autoantibodies are present in both serum and skin during active disease. […] Treatment of pemphigus vulgaris is aimed at decreasing production of pathogenic autoantibodies. One mainstay of treatment is systemic corticosteroids. […] The immunosuppressants rituximab, azathioprine, and mycophenolate mofetil help reduce the need for corticosteroids and thus minimize the undesirable effects of long-term corticosteroid use.

• #73 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  PV is characterized by acantholysis and the formation of intraepidermal blisters, resulting from the presence of IgG autoantibodies against the transmembrane desmosomal glycoprotein Dsg3 (130 kD) and, in certain cases, Dsg1 (160 kD). […] The treatment of autoimmune bullous dermatoses, including PV is usually based on systemic medications, because they comprise a severe group of mucosal and cutaneous diseases with significant morbidity and mortality. […] Systemic corticosteroids are the basis of the treatment for PV. They have potent anti-inflammatory and immunosuppressive activities. […] The introduction of these drugs in the 1950s was followed by a reduction in mortality from 75% to 30%. […] Azathioprine is a cytotoxic drug that is used in most autoimmune diseases. It is an imidazole derivative of mercaptopurine, which antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins.

• #74 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  PV is characterized by acantholysis and the formation of intraepidermal blisters, resulting from the presence of IgG autoantibodies against the transmembrane desmosomal glycoprotein Dsg3 (130 kD) and, in certain cases, Dsg1 (160 kD). […] The treatment of autoimmune bullous dermatoses, including PV is usually based on systemic medications, because they comprise a severe group of mucosal and cutaneous diseases with significant morbidity and mortality. […] Systemic corticosteroids are the basis of the treatment for PV. They have potent anti-inflammatory and immunosuppressive activities. […] The introduction of these drugs in the 1950s was followed by a reduction in mortality from 75% to 30%. […] Azathioprine is a cytotoxic drug that is used in most autoimmune diseases. It is an imidazole derivative of mercaptopurine, which antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins.

• #75 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  The efficacy of AZA as a corticosteroid-sparing agent in autoimmune bullous diseases, particularly in PV, is well documented and is the oldest and most prescribed immunosuppressive medication in this context. […] Chimeric anti-CD20 monoclonal antibody (which depletes normal and pathogenic B lymphocytes) has been used for cases of severe and refractory PV since 2006. […] Following the administration of rituximab, there is a rapid and sustained depletion of circulating and tissue B lymphocytes that persists for at least 6 to 12 months. […] Rituximab is generally well tolerated, and serious adverse effects are rare. […] Cyclophosphamide is an alkylating agent that selectively affects B lymphocytes and antibody production. […] Its main toxic effects are infertility, predisposition to neoplasia, lymphopenia, and sepsis. […] The evidence indicates that the major benefit of adjuvant use is the corticoid-sparing effect-not in modifying the course of the disease.

• #76 Treatment of pemphigus vulgaris. An overview in Mexico | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-treatment-of-pemphigus-vulgaris-an-overview-in-13084220

  Pemphigus is an autoimmune skin disease that can present in a variety of forms and can prove challenging to manage and treat. […] Pemphigus vulgaris (PV) is one of the more serious presentations that very often leads to serious patient conditions that are difficult to manage on an outpatient basis, and frequently requires intensive care. […] A close association has been observed between the disease and Major Histocompatibility Complex (MHC) class II antigens in certain ethnic groups such as those of Mediterranean origin that are susceptible to PV. […] The physiopathology of PV is characterized by the production of circulating antibodies targeted to desmoglein-3, and in some patients to desmoglein-1. […] The mechanism of action of the glucocorticoid pulses comprises the inhibition of acantholysis induced by IgG in PV, as a result of which the spread of keratinocyte deterioration is reduced.

• #77 Treatment of pemphigus vulgaris. An overview in Mexico | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-treatment-of-pemphigus-vulgaris-an-overview-in-13084220

  The utilization of these megadoses has revolutionized the treatment of PV, for although such therapy is not the first choice management option, it almost always improves patient prognosis when prescribed on an opportune basis. […] The treatment options for PV include substances known as adjuvant drugs, which are agents that support the effect of steroids administered fundamentally via the oral route. […] Azathioprine is one of the most common adjuvants to PV therapy, and has been shown to be effective in application to many diseases apart from PV. […] The administration of azathioprine as adjuvant therapy in PV increases percentage disease remission up to 45 %. […] The use of oral cyclophosphamide as steroid-sparing adjuvant therapy in PV has been documented in many reviews published in the literature.

• #78 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  The efficacy of AZA as a corticosteroid-sparing agent in autoimmune bullous diseases, particularly in PV, is well documented and is the oldest and most prescribed immunosuppressive medication in this context. […] Chimeric anti-CD20 monoclonal antibody (which depletes normal and pathogenic B lymphocytes) has been used for cases of severe and refractory PV since 2006. […] Following the administration of rituximab, there is a rapid and sustained depletion of circulating and tissue B lymphocytes that persists for at least 6 to 12 months. […] Rituximab is generally well tolerated, and serious adverse effects are rare. […] Cyclophosphamide is an alkylating agent that selectively affects B lymphocytes and antibody production. […] Its main toxic effects are infertility, predisposition to neoplasia, lymphopenia, and sepsis. […] The evidence indicates that the major benefit of adjuvant use is the corticoid-sparing effect-not in modifying the course of the disease.

• #79 Treatment of pemphigus vulgaris. An overview in Mexico | Allergologia et Immunopathologia

  https://www.elsevier.es/en-revista-allergologia-et-immunopathologia-105-articulo-treatment-of-pemphigus-vulgaris-an-overview-in-13084220

  The utilization of these megadoses has revolutionized the treatment of PV, for although such therapy is not the first choice management option, it almost always improves patient prognosis when prescribed on an opportune basis. […] The treatment options for PV include substances known as adjuvant drugs, which are agents that support the effect of steroids administered fundamentally via the oral route. […] Azathioprine is one of the most common adjuvants to PV therapy, and has been shown to be effective in application to many diseases apart from PV. […] The administration of azathioprine as adjuvant therapy in PV increases percentage disease remission up to 45 %. […] The use of oral cyclophosphamide as steroid-sparing adjuvant therapy in PV has been documented in many reviews published in the literature.

• #80 Refractory pemphigus vulgaris: Treatment options – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/refractory-pemphigus-vulgaris-treatment-options/

  Pemphigus vulgaris is an autoimmune mucocutaneous blistering disorder characterized by the presence of pathogenic autoantibodies against adhesion proteins on epidermal keratinocytes called desmogleins (DSG1 and DSG 3). […] Pemphigus that fails to respond sufficiently to optimal administration of these immunosuppressives is referred to as refractory pemphigus. […] Interventions that directly target the antibody-mediated pathogenesis of pemphigus such as rituximab, intravenous immunoglobulins (Ig), immunoadsorption, plasmapheresis, and intralesional immunomodulators are made use of, in the management of refractory pemphigus. […] Rituximab is a monoclonal antibody directed against CD20 antigen on B lymphocytes. This attains long-lasting B cell depletion. […] Intravenous immunoglobulin is effective for refractory pemphigus, it is used as adjuvant therapy to systemic corticosteroids and immunosuppressive adjuvants. However, the mechanism through which IVIG improves pemphigus is not clearly understood. Proposed mechanism includes a reduction in circulating pemphigus autoantibodies by stimulating an increase in the catabolism of immunoglobulins.

• #81 SciELO Brazil – Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus foliaceus – Brazilian Society of Dermatology Consensus on the treatment of autoimmune bullous dermatoses: pemphigus vulgaris and pemphigus folia

  https://www.scielo.br/j/abd/a/k7TDXkwSmCqWRYgGnZTKfwM/

  The efficacy of AZA as a corticosteroid-sparing agent in autoimmune bullous diseases, particularly in PV, is well documented and is the oldest and most prescribed immunosuppressive medication in this context. […] Chimeric anti-CD20 monoclonal antibody (which depletes normal and pathogenic B lymphocytes) has been used for cases of severe and refractory PV since 2006. […] Following the administration of rituximab, there is a rapid and sustained depletion of circulating and tissue B lymphocytes that persists for at least 6 to 12 months. […] Rituximab is generally well tolerated, and serious adverse effects are rare. […] Cyclophosphamide is an alkylating agent that selectively affects B lymphocytes and antibody production. […] Its main toxic effects are infertility, predisposition to neoplasia, lymphopenia, and sepsis. […] The evidence indicates that the major benefit of adjuvant use is the corticoid-sparing effect-not in modifying the course of the disease.

• #82 Rituximab in pemphigus – Indian Journal of Dermatology, Venereology and Leprology

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

  Pemphigus is a chronic, muco-cutaneous autoimmune blistering disorder; two main variants being pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV is the most common subtype, varying between 75 to 92% of total pemphigus patients. […] Rituximab is a chimeric monoclonal antibody directed against CD20 and acts by causing death of CD 20 positive cells by complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. […] Apoptosis of CD 20 positive cells is also believed to play a role. […] Thus rituximab leads to depletion of mature B lymphocytes which would transform into antibody producing short lived plasma cells. […] Rituximab is indicated in pemphigus patients who fail to respond adequately to conventional treatment modality, or in whom systemic corticosteroids and/or other immunosuppressants are contraindicated or cause severe adverse effects requiring its discontinuation.

• #83 Rituximab in pemphigus – Indian Journal of Dermatology, Venereology and Leprology

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

  Rituximab is also indicated in patients who relapse following treatment with conventional drugs. […] Currently no randomized control studies are available comparing the efficacy of rituximab to conventional treatment modalities. […] Review of patients with pemphigus treated with rituximab showed that 98% of PV patient responded to therapy with 40% having complete remission. […] Success rates were even better with PF with 100% responding to therapy and 40% having complete response. […] The serious infections reported in pemphigus patients include bacterial sepsis, bacterial pneumonia, pyelonephritis, Pneumocystis carinii pneumonia, bacterial arthritis, cytomegalovirus gastritis, Listeria monocytogenes sepsis, varicella zoster infection and cutaneous Mycobacterium chelonae infection.

• #84 Emerging treatment options for the management of pemphigus vulgaris | TCRM

  https://www.dovepress.com/emerging-treatment-options-for-the-management-of-pemphigus-vulgaris-peer-reviewed-fulltext-article-TCRM

  The benefit of removing plasma is the elimination of pathogenic autoantibodies from the circulation. The rationale behind plasmapheresis is based on the correlation observed between the titers of circulating anti-Dsg3 autoantibodies and disease activity. […] Immunoadsorption is another extracorporeal blood purification procedure that leads to the rapid removal of circulating autoantibodies against Dsg1 and Dsg3. […] The beneficial effect of IVIg may be achieved by one of the following pathways that are proposed to act synergistically to affect the disease pathogenesis: reduction of the titers of pathogenic autoantibodies; modulation of complement activation; saturation and blockade of Fc receptors.

• #85 Refractory pemphigus vulgaris: Treatment options – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/refractory-pemphigus-vulgaris-treatment-options/

  Immunoadsorption is a therapeutic option for pemphigus. It exerts effect through the removal of circulating autoantibodies (IgG) with very high specificity. […] Plasmapheresis is an effective adjuvant therapy in severe pemphigus vulgaris patients for disease activity control by reducing serum levels of autoantibodies.

• #86 Emerging treatment options for the management of pemphigus vulgaris | TCRM

  https://www.dovepress.com/emerging-treatment-options-for-the-management-of-pemphigus-vulgaris-peer-reviewed-fulltext-article-TCRM

  The benefit of removing plasma is the elimination of pathogenic autoantibodies from the circulation. The rationale behind plasmapheresis is based on the correlation observed between the titers of circulating anti-Dsg3 autoantibodies and disease activity. […] Immunoadsorption is another extracorporeal blood purification procedure that leads to the rapid removal of circulating autoantibodies against Dsg1 and Dsg3. […] The beneficial effect of IVIg may be achieved by one of the following pathways that are proposed to act synergistically to affect the disease pathogenesis: reduction of the titers of pathogenic autoantibodies; modulation of complement activation; saturation and blockade of Fc receptors.

• #87 Refractory pemphigus vulgaris: Treatment options – Journal of Skin and Sexually Transmitted Diseases

  https://jsstd.org/refractory-pemphigus-vulgaris-treatment-options/

  Immunoadsorption is a therapeutic option for pemphigus. It exerts effect through the removal of circulating autoantibodies (IgG) with very high specificity. […] Plasmapheresis is an effective adjuvant therapy in severe pemphigus vulgaris patients for disease activity control by reducing serum levels of autoantibodies.

• #88 Emerging treatment options for the management of pemphigus vulgaris | TCRM

  https://www.dovepress.com/emerging-treatment-options-for-the-management-of-pemphigus-vulgaris-peer-reviewed-fulltext-article-TCRM

  The benefit of removing plasma is the elimination of pathogenic autoantibodies from the circulation. The rationale behind plasmapheresis is based on the correlation observed between the titers of circulating anti-Dsg3 autoantibodies and disease activity. […] Immunoadsorption is another extracorporeal blood purification procedure that leads to the rapid removal of circulating autoantibodies against Dsg1 and Dsg3. […] The beneficial effect of IVIg may be achieved by one of the following pathways that are proposed to act synergistically to affect the disease pathogenesis: reduction of the titers of pathogenic autoantibodies; modulation of complement activation; saturation and blockade of Fc receptors.

• #89 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

  This theory explores new mechanisms with the findings obtained by independent groups. […] 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. […] 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. […] The findings suggest that oxidative stress-mediated YAP dysregulation likely plays a key role in pemphigus blistering, indicating the potential therapeutic role of antioxidants in the treatment of PV.

• #90 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://qmro.qmul.ac.uk/jspui/handle/123456789/72904

  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 purpose of this review is to summarize the earlier and recent advances highlighting our recent findings related to PV pathogenesis that may pave the way for future research to develop novel specific therapies in curing this disease.

• #91 Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050696

  These findings have important implications for designing model systems to study pemphigus pathomechanisms and for developing therapies to treat this devastating disease. […] The results of this study demonstrate that polyclonal PV patient IgG cause clustering of cell surface Dsg3, resulting in Dsg3 endocytosis and alterations in desmosome morphology. […] In contrast, pathogenic monoclonal antibodies, including AK23 and PV mAbs isolated from patients, failed to cause alterations in desmosomal protein organization. […] These results reveal signaling dependent and independent mechanisms for loss of adhesion in response to pathogenic Dsg3 antibodies. […] These findings clarify for the first time that Dsg3 depletion involving p38 MAPK and steric hindrance are two separate events caused by PV IgG. […] In contrast, monoclonal pathogenic antibodies cause loss of adhesion primarily through steric hindrance. […] These findings underscore the importance of using both patient derived IgG and monoclonal Dsg3 reagents to evaluate pemphigus pathomechanisms and possible therapeutic interventions.

• #92 MD TP63 – Investigating pemphigus vulgaris pathogenesis using a human skin organ culture model: Institut

  https://www.grk1727.uni-luebeck.de/projects/md-projects/md-tp63-investigating-pemphigus-vulgaris-pathogenesis-using-a-human-skin-organ-culture-model

  Pemphigus vulgaris (PV) is an autoimmune, intraepithelial, blistering disease affecting the skin and mucous membranes. Autoantibodies (IgG) form against Desmoglein (Dsg) 1 and Dsg 3 causing the keratinocytes to separate, which is also called acantholysis. The loss of cell adhesion leads to intraepithelial blistering of the skin and/ or mucous membranes presenting symptoms such as burning pain, bleeding and dysphagia in humans. […] New insides into the pathogenesis of PV are essential in order to develop and test possible new treatment options for this disease. […] In my project I am investigating the pathogenesis of PV in a human skin organ culture (HSOC) model previously established in our lab (Imke Burmester et al., 2019) to mimic the intraepidermal split formation of PV by injecting a single chain variable fragment (scFv). […] My aim is to determine at what time, after injection of the scFv, the split formation occurs within the HSOC and to investigate the proteome of skin samples from the HSOC over a time course of 24 hours.

• #93 The Role Of Antibody Subclass In The Pathogenesis Of Pemphigus Vulgaris

  https://repository.upenn.edu/items/7960902d-7de1-4a89-bdac-824f0436b606

  Finding that the subclass has very little effect on antibody affinity, pathogenicity, or epitope preference, we then sought to determine whether B cells expressing autoantibodies of different subclasses share lineages, indicating common pathways of development. […] In particular, we found that anti-Dsg IgG4 B cells, which are believed to be central to disease pathogenesis, tended to not share lineages with other subclasses, and in general do not appear to share a precursor-product relationship with anti-Dsg IgG1 B cells. […] These findings are key to understanding the role of class-switching in the pathogenesis of PV, and may shed light on the class-switch mechanisms driving other autoimmune diseases and states of chronic antigen stimulation.

• #94 The role of T cells in the immunopathogenesis of pemphigus vulgaris | Medicina Cutánea ILA

  https://www.medicinacutaneaila.com/frame_eng.php?id=85

  Pemphigus vulgaris is an antibody mediated autoimmune blistering disease with the formation of blisters and erosions on skin and/or mucous membranes. […] In the past years, there is mounting evidence of the important role of T cell in the pathogenesis of this disease. T helper (Th) type 1 and T follicular helper cells are relevant in the production of autoantibodies. Th1 cell promote a proinflammatory milieu. Th17 cells seem to amplify the inflammatory response and contribute to tissue damage. […] On the other hand, T regulatory cells fail to suppress efficiently the above mentioned pathogenic immune responses. The understanding of the different roles these cellular subtypes and cytokines play in the immunopathogenesis of pemphigus vulgaris may lead to the use of novel therapeutic targets in the future.

• #95

  https://journals.lww.com/ijdd/fulltext/2019/06010/evaluation_of_the_relation_between_t_lymphocytes.4.aspx

  Pemphigus vulgaris (PV) is an autoimmune bullous disease involving both the skin and mucus membranes. Infiltrating CD4+ and CD8+ T-lymphocytes may have a vital role in its pathogenesis. […] This work aimed to assess the role of CD4+ and CD8+ T-lymphocytes in the pathogenesis of PV and the correlation between number of T-lymphocytes infiltrate and clinical severity of the disease evaluated by ABSIS. […] CD4+ and CD8+ T-lymphocytes share in the pathogenesis of PV and CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions. […] The current study newly reported positive correlation between total lymphocytic count and ABSIS score which was not detected in previous reports. This correlation may help to predict the clinical state of the patient from histopathological evaluation of skin biopsy specimens and also add another advantage to ABSIS score that it can predict the lymphocytic infiltration in PV cases.

• #96 MD TP63 – Investigating pemphigus vulgaris pathogenesis using a human skin organ culture model: Institut

  https://www.grk1727.uni-luebeck.de/projects/md-projects/md-tp63-investigating-pemphigus-vulgaris-pathogenesis-using-a-human-skin-organ-culture-model

  Pemphigus vulgaris (PV) is an autoimmune, intraepithelial, blistering disease affecting the skin and mucous membranes. Autoantibodies (IgG) form against Desmoglein (Dsg) 1 and Dsg 3 causing the keratinocytes to separate, which is also called acantholysis. The loss of cell adhesion leads to intraepithelial blistering of the skin and/ or mucous membranes presenting symptoms such as burning pain, bleeding and dysphagia in humans. […] New insides into the pathogenesis of PV are essential in order to develop and test possible new treatment options for this disease. […] In my project I am investigating the pathogenesis of PV in a human skin organ culture (HSOC) model previously established in our lab (Imke Burmester et al., 2019) to mimic the intraepidermal split formation of PV by injecting a single chain variable fragment (scFv). […] My aim is to determine at what time, after injection of the scFv, the split formation occurs within the HSOC and to investigate the proteome of skin samples from the HSOC over a time course of 24 hours.

• #97

  https://esmed.org/MRA/mra/article/view/773

  Pemphigus vulgaris (PV) is an organ-specific autoimmune blistering disease, affecting the skin and the mucous membranes. […] Cloning of cDNAs encoding pemphigus antigens has provided ample evidence that IgG autoantibodies recognize the desmogleins (DSGs) that are found in the adhering junctions, the desmosomes. Binding of such IgGs in the DSGs results in the weakening of intercellular adhesion of keratinocytes in the upper part of the epidermis and eventually to acantholysis. […] Mechanistically, the production of IgG autoantibodies against DSG1 and DSG3 is linked to disease pathogenesis. Recently, endoplasmic reticulum (ER) stress, a highly conserved cellular stress response, has been proposed to play a role in the development and progression of PV. […] The discovery that ER stress occurs during PV development implies that deregulated UPR may contribute to the pathogenesis of the disease. Future studies should be directed toward understanding how modulation of the ER can provide new therapeutic possibilities for the treatment of PV patients.

• #98 The role of T cells in the immunopathogenesis of pemphigus vulgaris | Medicina Cutánea ILA

  https://www.medicinacutaneaila.com/frame_eng.php?id=85

  Pemphigus vulgaris is an antibody mediated autoimmune blistering disease with the formation of blisters and erosions on skin and/or mucous membranes. […] In the past years, there is mounting evidence of the important role of T cell in the pathogenesis of this disease. T helper (Th) type 1 and T follicular helper cells are relevant in the production of autoantibodies. Th1 cell promote a proinflammatory milieu. Th17 cells seem to amplify the inflammatory response and contribute to tissue damage. […] On the other hand, T regulatory cells fail to suppress efficiently the above mentioned pathogenic immune responses. The understanding of the different roles these cellular subtypes and cytokines play in the immunopathogenesis of pemphigus vulgaris may lead to the use of novel therapeutic targets in the future.

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