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Seminars in Immunopathology Jan 2016Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed... (Review)
Review
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.
Topics: Animals; Antibodies, Monoclonal; Autoantibodies; Autoantigens; Desmogleins; Disease Progression; Epitopes; Genetic Predisposition to Disease; Humans; Immune Sera; Immunoglobulin Idiotypes; Mutation; Organ Specificity; Pemphigus; Signal Transduction; T-Lymphocyte Subsets; Translational Research, Biomedical
PubMed: 26597100
DOI: 10.1007/s00281-015-0541-1 -
Journal of Oral and Maxillofacial... 2017Pemphigus vulgaris is an autoimmune bullous disease involving both the skin and mucosal areas, which is characterized by intraepithelial flaccid blisters and erosions.... (Review)
Review
Pemphigus vulgaris is an autoimmune bullous disease involving both the skin and mucosal areas, which is characterized by intraepithelial flaccid blisters and erosions. The pathogenesis of this disease is not yet completely established, but novel intuitions into its pathogenesis have recently been published. An unanswered question in its pathophysiology is the mechanism of acantholysis or loss of keratinocyte cell adhesion. Acantholysis seems to result from a communal action of autoantibodies against numerous keratinocyte self-antigens, of which desmogleins 1 and 3, desmocollins and nondesmosome components, such as the mitochondrion, might take part in the disease initiation. Lately, apoptosis was described as a possible underlying mechanism of acantholysis. Likewise, apoptolysis is assumed to be the association between suprabasal acantholytic and cell death pathways. Hence, the present review focuses on the current concepts in the pathogenesis of the pemphigus in a nutshell.
PubMed: 28932036
DOI: 10.4103/jomfp.JOMFP_143_17 -
International Journal of Molecular... Jun 2022Pemphigus is a life-threatening autoimmune disease. Several phenotypic variants are part of this family of bullous disorders. The disease is mainly mediated by... (Review)
Review
Pemphigus is a life-threatening autoimmune disease. Several phenotypic variants are part of this family of bullous disorders. The disease is mainly mediated by pathogenic autoantibodies, but is also directed against two desmosomal adhesion proteins, desmoglein 1 (DSG1) and 3 (DSG3), which are expressed in the skin and mucosae. By binding to their antigens, autoantibodies induce the separation of keratinocytes, in a process known as acantholysis. The two main Pemphigus variants are Pemphigus vulgaris and foliaceus. Several models of Pemphigus have been described: in vitro, ex vivo and in vivo, passive or active mouse models. Although no model is ideal, different models display specific characteristics that are useful for testing different hypotheses regarding the initiation of Pemphigus, or to evaluate the efficacy of experimental therapies. Different disease models also allow us to evaluate the pathogenicity of specific Pemphigus autoantibodies, or to investigate the role of previously not described autoantigens. The aim of this review is to provide an overview of Pemphigus disease models, with the main focus being on active models and their potential to reproduce different disease subgroups, based on the involvement of different autoantigens.
Topics: Acantholysis; Animals; Autoantibodies; Autoantigens; Desmoglein 1; Desmoglein 3; Mice; Pemphigus
PubMed: 35806044
DOI: 10.3390/ijms23137044 -
Minerva Stomatologica Apr 2007Pemphigus, a group of bullous diseases affecting the oral mucosa and the skin, is caused by antibody-mediated autoimmune reaction to desmogleins (Dsg), desmosomal... (Review)
Review
Pemphigus, a group of bullous diseases affecting the oral mucosa and the skin, is caused by antibody-mediated autoimmune reaction to desmogleins (Dsg), desmosomal transmembrane glycoproteins, leading to acantholysis. Pemphigus is classified into pemphigus vulgaris (PV), with suprabasal acantholysis, and pemphigus foliaceus (PF), with acantholysis in the more superficial epidermis. Pemphigus vulgaris is characterized by IgG autoantibodies against desmoglein 3 (Dsg 3), whereas the target of PF is Dsg1, although about 50% of PV patients also have Dsg1 autoantibodies. The clinical phenotype appears to be determined by the distribution of Dsg1 and Dsg3. PV patients with oral mucosal lesions have predominantly Dsg3 autoantibodies. Lesion distribution is related to the location of the antigen (Dgs 3 and/or Dgs 1) in the epithelium and specific autoantibody production. Coexpression of Dsg 1 and Dsg 3 in keratinocytes protects against blister formations in the presence of antibodies against only one of the two desmogleins. Recent molecular studies have shown that acantholysis can occur also in the presence of antibodies against 9 alpha nicotinic acetylcholine receptor (AChR). Cholinergic agonists can protect keratinocyte monolayers against anti-Dsg antibody-induced acantholysis and reverse acantholysis produced by PV IgGs.
Topics: Acantholysis; Adult; Antibody Specificity; Autoantibodies; Autoantigens; Cholinergic Agents; Desmoglein 1; Desmoglein 3; Desmosomes; Female; Genetic Predisposition to Disease; Humans; Immunoglobulin G; Keratinocytes; Male; Middle Aged; Pemphigus; Receptors, Nicotinic
PubMed: 17452959
DOI: No ID Found -
Actas Dermo-sifiliograficas Sep 2017Darier disease is an autosomal-dominant inherited condition caused by mutation of a gene, which produces a protein involved in calcium channel regulation. The disease...
Darier disease is an autosomal-dominant inherited condition caused by mutation of a gene, which produces a protein involved in calcium channel regulation. The disease has a variety of manifestations and lacks consistent genotype-phenotype correlations. Acral hemorrhagic Darier disease causes macules, papules, vesicles and/or hemorrhagic blisters on the extremities. Other classic signs of the disease may be present in the same patient or relatives. Histopathology reveals dyskeratosis and suprabasal acantholysis with hemorrhagic lacunae. We report 3 new cases of this type of Darier disease triggered by injuries. Response to retinoid therapy was good.
Topics: Acitretin; Adult; Darier Disease; Dermatologic Agents; Female; Hand Injuries; Humans; Isotretinoin; Male; Middle Aged; Nails, Malformed; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Seasons; Tretinoin
PubMed: 28407871
DOI: 10.1016/j.ad.2017.02.012 -
SAGE Open Medical Case Reports 2023Segmental Darier's disease is an uncommon subtype of Darier's genodermatosis, resulting from a mutation in the ATPase type 2 during early embryogenesis. It typically...
Segmental Darier's disease is an uncommon subtype of Darier's genodermatosis, resulting from a mutation in the ATPase type 2 during early embryogenesis. It typically presents as a persistent, pruritic papular eruption following the lines of Blaschko. Histopathology of Darier's disease demonstrates acantholysis, dyskeratosis, and corps ronds. First-line treatment includes topical retinoids, calcineurin inhibitors, and synthetic vitamin D analogues. Severe disease may require systemic therapy with oral retinoids, immunomodulators, magnesium, and low-dose naltrexone. Segmental Darier's disease is important to recognize both clinically and histologically as it may resemble other acantholytic Blaschkolinear dermatoses and should be considered in individuals presenting with a chronic localized papular eruption in a Blaschkoid distribution. Herein, we present a case of a 48-year-old male with segmental Darier's disease who improved significantly following acitretin treatment.
PubMed: 37032996
DOI: 10.1177/2050313X231160938 -
Dermatologic Clinics Jul 2011Pemphigus foliaceus is an acquired autoimmune blistering disease in which the body's immune system produces IgG autoantibodies that target the intercellular adhesion... (Review)
Review
Pemphigus foliaceus is an acquired autoimmune blistering disease in which the body's immune system produces IgG autoantibodies that target the intercellular adhesion glycoprotein desmoglein-1, which is principally expressed in the granular layer of the epidermis, resulting in the loss of intercellular connections between keratinocytes (acantholysis) and the formation of subcorneal blisters within the epidermis. This article summarizes the epidemiology, clinical features, techniques for diagnosis, and drugs associated with treatment of this rare disease.
Topics: Diagnosis, Differential; Humans; Incidence; Pemphigus; Prevalence; Skin
PubMed: 21605805
DOI: 10.1016/j.det.2011.03.012 -
The Ocular Surface Jan 2020A review of the published literature on the history, pathogenesis, and treatment of pemphigus vulgaris (PV) and its ocular involvement. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
A review of the published literature on the history, pathogenesis, and treatment of pemphigus vulgaris (PV) and its ocular involvement.
METHODS
Literature searches were conducted in MEDLINE (Ovid), and google scholar for pemphigus vulgaris and ocular PV. Inclusion criteria were given to meta-analysis, case-controlled studies, and documented case reports. The data were examined and independently analyzed by more than two of the authors.
RESULTS
PV is a humoral autoimmune disease with a preponderance of IgG4 anti-desmoglein 3 antibodies. Upon antibody binding, there is an intracellular signaling mechanism that leads to blister formation. Ocular findings are seen in up to 16% of PV patients with conjunctivitis being the most common clinical presentation. New steroid-sparing agents have helped with the control of this deadly disease, and with better understanding of the pathogenesis of PV, other cytokine blockers currently available are promising steroid-sparing agents.
CONCLUSIONS
Ocular pemphigus can occasionally present prior to mucocutaneous findings. Recalcitrant conjunctivitis with conjunctival blisters should warrant a workup for systemic PV.
Topics: Autoantibodies; Case-Control Studies; Eye; Eye Diseases; Humans; Immunoglobulin G; Pemphigus
PubMed: 31614200
DOI: 10.1016/j.jtos.2019.09.008 -
Case Reports in Dermatology 2021Darier's disease is a rare genodermatosis characterized clinically by dyskeratotic papules in the seborrheic and intertriginous areas and nail abnormalities....
Darier's disease is a rare genodermatosis characterized clinically by dyskeratotic papules in the seborrheic and intertriginous areas and nail abnormalities. Dyskeratosis and acantholysis are typical histological findings. Darier's disease is not known to be inflammatory by nature as inflammation occurs primarily due to local infections, and it may therefore differ from inflammatory dermatoses such as psoriasis and cutaneous lupus in response to antigen stimulation. Known triggers of Darier's disease primarily include exogenous factors such as sun exposure, friction, or infection. We present a case of a 47-year-old white female with a flare of Darier's disease 2 days following her first vaccination with COVID-19 vaccine (ChAdOx1-s [recombinant]) (Vaxzevria [previously known as COVID-19 vaccine AstraZeneca]). In this case report, we discuss possible mechanisms linking the vaccination and the flare of Darier's disease. We consider inflammatory mechanisms as well as a random co-occurrence. Due to the close time-related association between the disease flare and the COVID-19 vaccination, we find an urge to make other clinicians aware of a possible association.
PubMed: 34594203
DOI: 10.1159/000517256 -
Biology Feb 2022Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell-cell detachment (acantholysis) resulting in mucocutaneous blistering. The... (Review)
Review
BACKGROUND
Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell-cell detachment (acantholysis) resulting in mucocutaneous blistering. The exact pathogenesis of blister formation is unknown and this has hampered the development of non-steroidal, mechanism-based treatments for this autoimmune disease. This systematic review aims to investigate the role of caspases in the pathogenesis of PV to inform the choice of more targeted therapeutic agents.
METHODS
A systematic search of MEDLINE/PubMed and Scopus databases was conducted to identify eligible studies. Multiple phases of inclusion and exclusion of the primary articles were conducted in pairs, and studies were recorded and analysed according to the latest version of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Risk of bias assessment was conducted for extracted in vivo animal intervention studies using SYRCLE's risk of bias tool.
RESULTS
Eight articles from a total of 2338 in vitro, in vivo, and human studies met the inclusion criteria, with a high degree of inter-rater reliability. By and large, the results show that caspase activation was pathogenic in experimental PV because pan-caspase inhibitors could block or reduce PV acantholysis and blistering in vitro and in vivo, respectively. The pathogenic pathways identified involved caspase-1 and caspase-3. One study failed to show any improvement in the PV model with a caspase inhibitor. The majority of animal studies had high or unclear risk of bias.
CONCLUSION
There are consistent data pointing towards a pathogenic role of caspase activation in PV acantholysis. However, high-quality evidence to confirm that caspase inhibition can prevent PV-induced blistering in vivo is limited. Therefore, further research is required to test the preclinical efficacy of caspase inhibitors in PV.
PubMed: 35205180
DOI: 10.3390/biology11020314