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Life (Basel, Switzerland) Feb 2022Pemphigus is a group of blistering autoimmune diseases causing painful skin lesions, characterized by acantholysis and by the production of autoantibodies against,... (Review)
Review
Pemphigus is a group of blistering autoimmune diseases causing painful skin lesions, characterized by acantholysis and by the production of autoantibodies against, mainly, adhesion proteins. We reviewed the literature for molecules and/ or features involved in the 12 cell death pathways described by Nomenclature Committee on Cell Death, taking place in pemphigus patients, cell lines, or human skin organ cultures treated with sera or IgG from pemphigus patients or in pemphigus mouse models, and found 61 studies mentioning 97 molecules involved in cell death pathways. Among the molecules, most investigated were pleiotropic molecules such as TNF and CASP3, followed by FASL and CASP8, and then by FAS, BAX, BCL2, and TP53, all involved in more than one pathway but interpreted to function only within apoptosis. Most of these previous investigations focused only on apoptosis, but four recent studies, using TUNEL assays and/or electron microscopy, disqualified this pathway as a previous event of acantholysis. For PV, apoptolysis was suggested as a cell death mechanism based on pathogenic autoantibodies diversity, mitochondrial dysfunction, and p38 MAPK signaling. To answer those many questions that remain on cell death and pemphigus, we propose well-controlled, statistically relevant investigations on pemphigus and cell death pathways besides apoptosis, to overcome the challenges of understanding the etiopathology of pemphigus diseases.
PubMed: 35330080
DOI: 10.3390/life12030329 -
Clinics and Practice May 2020Ameloblastoma is the only odontogenic tumor that displays diversified histomorphological features with subtypes like follicular, plexiform, acanthomatous, granular cell,...
Ameloblastoma is the only odontogenic tumor that displays diversified histomorphological features with subtypes like follicular, plexiform, acanthomatous, granular cell, clear cell, desmoplastic etc. In this paper we presented an extremely unusual presentation of ameloblastoma, which is characterized by desmolysis or acantholysis of stellate reticulum-like cells caused due to keratinocyte dissociation. A 35-year-old male patient presented with a painless hard 3×3 cm swelling in the mandibular right posterior region in the past 4-5 months. Radiographic examination revealed a multilocular radiolucent lesion in the body of mandible with resorption of the roots. Histopathological examination revealed ameloblastic follicles with central cells showing keratinocyte dissociation leading to desmolysis/acantholysis. Desmolytic cells were seen as an isolated entity in the follicular space with round to polygonal shaped morphology. Future retrospective studies on archival samples of ameloblastoma are recommended to relook into identification of such rare phenomenon. This will help in better understanding of the incidence rate and biological behavior of this rare variant of ameloblastoma.
PubMed: 32549972
DOI: 10.4081/cp.2020.1255 -
Archives of Pathology & Laboratory... Sep 2009Grover disease, also known as transient acantholytic dermatosis, is a papulovesicular rash of the upper trunk, generally among older white males; it is usually pruritic... (Review)
Review
Grover disease, also known as transient acantholytic dermatosis, is a papulovesicular rash of the upper trunk, generally among older white males; it is usually pruritic but temporary. Grover disease is characterized by 4 different acantholytic histologic patterns, and it has been associated with numerous disorders, including hematologic malignancies. Follow-up and treatment are often difficult to evaluate secondary to the spontaneous remittance and occasional fluctuant course of the disease. Our objective will be to discuss the diagnostic considerations of Grover disease and focus on the postulated pathogenesis, including concurrent disorders and the role of the pathologist in examining skin biopsies of this nonhereditary vesicobullous disorder. Although recognized as a common condition, Grover disease's pathogenesis still remains unknown. Because Grover disease has been associated frequently with other dermatologic and nondermatologic skin conditions, inspection for other pathologic processes within the skin biopsy is essential to rule out other concomitant disorders, including hematopoietic malignancies.
Topics: Acantholysis; Humans; Keratinocytes; Male
PubMed: 19722762
DOI: 10.5858/133.9.1490 -
BioMed Research International 2018Scalp is a unique location for pemphigus because of the abundance of desmogleins localized in hair follicles. Scalp involvement is observed in up to 60% of patients in... (Review)
Review
Scalp is a unique location for pemphigus because of the abundance of desmogleins localized in hair follicles. Scalp involvement is observed in up to 60% of patients in the course of pemphigus. The lesions may occasionally lead to alopecia. Unforced removal of anagen hairs in a pull test is a sign of high disease activity. Direct immunofluorescence of plucked hair bulbs is considered a reliable diagnostic method in patients with pemphigus. Follicular acantholysis is a characteristic histopathological feature of pemphigus lesions localized on the scalp. Trichoscopy may serve as a supplementary method in the diagnosis of pemphigus. This review summarizes the most recent data concerning scalp involvement in pemphigus vulgaris and pemphigus foliaceus. A systematic literature search was conducted in three medical databases: PubMed, Embase, and Web of Science. The analysis included literature data about desmoglein distribution in hair follicles, as well as information about clinical manifestations, histopathology, immunopathology, and trichoscopy of scalp lesions in pemphigus and their response to treatment.
Topics: Alopecia; Desmogleins; Fluorescent Antibody Technique, Direct; Hair Follicle; Humans; Pemphigus; Scalp
PubMed: 29770335
DOI: 10.1155/2018/6154397 -
Anais Brasileiros de Dermatologia 2019Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by mucocutaneous lesions associated with benign and malignant neoplasms....
Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by mucocutaneous lesions associated with benign and malignant neoplasms. Diagnostic criteria include the presence of chronic mucositis and polymorphic cutaneous lesions with occult or confirmed neoplasia; histopathological analysis exhibiting intraepidermal acantholysis, necrotic keratinocytes, and vacuolar interface dermatitis; direct immunofluorescence with intercellular deposits (IgG and C3) and at the basement membrane zone (IgG); indirect immunofluorescence with intercellular deposition of IgG (substrates: monkey esophagus and simple, columnar, and transitional epithelium); and, autoreactivity to desmogleins 1 and 3, desmocollins 1, 2, and 3, desmoplakins I and II, envoplakin, periplakin, epiplakin, plectin, BP230, and α-2-macroglobulin-like protein 1. Neoplasias frequently related to paraneoplastic pemphigus include chronic lymphocytic leukemia, non-Hodgkin lymphoma, carcinomas, Castleman disease, thymoma, and others. Currently, there is no standardized treatment for paraneoplastic pemphigus. Systemic corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, rituximab, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin have been used, with variable outcomes. Reported survival rates in 1, 2, and 5 years are 49%, 41%, and 38%, respectively.
Topics: Autoantibodies; Erythema; Humans; Mouth Diseases; Paraneoplastic Syndromes; Pemphigus; Skin
PubMed: 31644609
DOI: 10.1590/abd1806-4841.20199165 -
Biomedicines May 2022Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported....
Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported. Among them, IgG/IgA pemphigus is less well defined and seldom reported. To characterize the clinical, histopathologic, and immunohistochemical presentation of IgG/IgA pemphigus, we retrospectively identified 22 patients with the disease at a referral center in Taiwan. These patients showed two types of skin lesion: annular or arciform erythemas with blisters or erosions (45.5%) and discrete erosions or blisters such as those in conventional pemphigus (54.5%). Mucosal involvement was found in 40.9%. Histopathologic analysis identified acantholysis (77.3%) and intra-epidermal aggregates of neutrophils (40.9%) and eosinophils (31.8%). Direct immunofluorescence studies showed IgG/IgA (100%) and C3 (81.8%) depositions in the intercellular space of the epidermis. In immunohistochemical staining, patients with IgG/IgA pemphigus demonstrated significantly higher levels of epidermal expression of interleukin-8 and matrix metalloproteinase-9 than those with conventional pemphigus (p < 0.05). In conclusion, although IgG/IgA pemphigus is heterogeneous in presentation, it shows characteristic features that are different from other forms of pemphigus and should be considered a distinct type of pemphigus.
PubMed: 35625932
DOI: 10.3390/biomedicines10051197 -
Cureus Jun 2023Grover's disease (GD) is a rare skin condition that presents as a pruritic, erythematous papular, or papulovesicular rash. We report a unique case of GD triggered by...
Grover's disease (GD) is a rare skin condition that presents as a pruritic, erythematous papular, or papulovesicular rash. We report a unique case of GD triggered by honeybee stings. An 80-year-old Caucasian male presented with a pruritic papulovesicular rash on his trunk and arms after being stung by honeybees. He had a history of honeybee venom allergy and developed immediate erythema at the sting sites, which progressed over two days. His laboratory tests were unremarkable, including a complete blood count and comprehensive metabolic profile. Despite using oral antihistamines, emollients, and topical steroids, his rash continued to progress onto his neck, face, scalp, and back. A skin biopsy of the rash revealed suprabasilar and intraspinous acantholysis with focal corps ronds and upper dermis lymphocytic infiltrate -- the histopathologic finding of GD. He had failed first-line treatment for GD. However, after five months and significant morbidity, he was successfully treated with systemic steroids, high-potency topical steroids, emollients, and antihistamines for extensive and prolonged GD. This case report highlights honeybee venom as a possible trigger of GD and discusses a potential immune-mediated etiopathogenesis, which can be used to guide further research and management of this rare disease.
PubMed: 37476136
DOI: 10.7759/cureus.40648 -
Drug Design, Development and Therapy 2023Thalidomide (Tha) can be used as a selective treatment for mild pemphigus vulgaris (PV). However, the specific mechanism of action remains unclear.
PURPOSE
Thalidomide (Tha) can be used as a selective treatment for mild pemphigus vulgaris (PV). However, the specific mechanism of action remains unclear.
PATIENTS AND METHODS
PV IgG extracted from patients' serum was cocultured with HaCaT cells to construct a PV cell model, and different concentrations of Tha were used to screen the drug effect. The expression level of MYD88 was assessed in skin lesions of PV patients. Intracellular Ca concentration, reactive oxygen species level, DSG3, PG, MYD88, apoptosis-related proteins (Caspase-3, Bcl-2, and Bax), NF-κB pathway-related proteins (IκBα, p-IκBα, p50, and p65), NLRP3, IFN-γ, TNF-α, IL-6, and IL-8 levels were measured. PV IgG was subcutaneously injected into C57BL/6 neonatal mice to construct the animal model. Immunofluorescence was used to detect IgG deposition in the mouse epidermis, whereas immunohistochemistry and TUNEL methods were used to detect the expression of MYD88 and NLRP3 as well as cell apoptosis level in the mouse epidermis.
RESULTS
Tha reversed the decrease in Dsg3 and PG caused by PV IgG. The expression of MyD88 increased in the patients' skin, PV cell model, and PV mouse model. The increase in MyD88 expression level in PV cell models and PV newborn mouse models was inhibited by Tha. Overexpression of MyD88 induced a decrease in the expression levels of Dsg3 and PG in Hacat cells. Overexpression of MyD88 inhibited Tha effects on Dsg3 and PG expressions and blocked Tha effects on Ca, apoptosis, Bax, Bcl-2, and Caspase-3 expressions, oxidative damage, and inflammatory response in HaCat cells. Tha alleviated acantholysis induced by PV IgG in model mice.
CONCLUSION
Through MYD88, Tha attenuated apoptosis of HaCat cells, modulated NF-κB to hamper the oxidative damage and inflammatory response in the PV cell models, and alleviated acantholysis, IgG deposition, and epidermal cell apoptosis induced by PV IgG in model mice.
Topics: Animals; Humans; Mice; Acantholysis; Animals, Newborn; Apoptosis; bcl-2-Associated X Protein; Caspase 3; HaCaT Cells; Immunoglobulin G; Inflammation; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; NF-kappa B; NF-KappaB Inhibitor alpha; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Pemphigus; Thalidomide
PubMed: 37719363
DOI: 10.2147/DDDT.S407242 -
BMC Immunology Nov 2023Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has...
BACKGROUND
Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has been reported to have an adjuvant treatment effect against PV. However, the mechanism underlying the inhibitory effect of FK506 on PV-IgG-induced acantholysis is unclear.
OBJECTIVE
The objective of this study was to explore the effect of FK506 on desmoglein (Dsg) expression and cell adhesion in an immortalized human keratinocyte cell line (HaCaT cells) stimulated with PV sera.
METHODS
A cell culture model of PV was established by stimulating HaCaT cells with 5% PV sera with or without FK506 and clobetasol propionate (CP) treatment. The effects of PV sera on intercellular junctions and protein levels of p38 mitogen-activated protein kinase (p38MAPK), heat shock protein 27 (HSP27), and Dsg were assayed using western blot analysis, immunofluorescence staining, and a keratinocyte dissociation assay.
RESULTS
PV sera-induced downregulation of Dsg3 was observed in HaCaT cells and was blocked by FK506 and/or CP. Immunofluorescence staining revealed that linear deposits of Dsg3 on the surface of HaCaT cells in the PV sera group disappeared and were replaced by granular and agglomerated fluorescent particles on the cell surface; however, this effect was reversed by FK506 and/or CP treatment. Furthermore, cell dissociation assays showed that FK506 alone or in combination with CP increased cell adhesion in HaCaT cells and ameliorated loss of cell adhesion induced by PV sera. Additionally, FK506 noticeably decreased the PV serum-induced phosphorylation of HSP 27, but had no effect on p38MAPK phosphorylation.
CONCLUSION
FK506 reverses PV-IgG induced-Dsg depletion and desmosomal dissociation in HaCaT cells, and this effect may be obtained by inhibiting HSP27 phosphorylation.
Topics: Humans; Pemphigus; Tacrolimus; HSP27 Heat-Shock Proteins; HaCaT Cells; Phosphorylation; Keratinocytes; Desmoglein 3; Immunoglobulin G; Autoantibodies
PubMed: 37940861
DOI: 10.1186/s12865-023-00582-z -
BioMed Research International 2021Apoptotic events mediated by mitochondrial injury play an important role on the onset of Pemphigus vulgaris (PV). The thioredoxin-2 (Trx2)/apoptosis signal-regulating...
OBJECTIVE
Apoptotic events mediated by mitochondrial injury play an important role on the onset of Pemphigus vulgaris (PV). The thioredoxin-2 (Trx2)/apoptosis signal-regulating kinase 1 (ASK1) signaling pathway is considered a key cascade involved on the regulation of mitochondrial injury. Hence, we have investigated the regulatory mechanism of the Trx2/ASK1 signaling in PV-induced mitochondrial injury.
METHODS
Serum and tissue samples were collected from clinical PV patients to detect the oxidative stress factors, cell apoptosis, and expression of members from Trx2/ASK1 signaling. HaCaT cells were cultured with the serum of PV patients and transfected with Trx2 overexpression or silencing vector. Changes in the levels of reactive oxygen species (ROS), mitochondrial membrane potential (△m), and apoptosis were further evaluated. A PV mouse model was established and administered with Trx2-overexpressing plasmid. The effect of ectopic Trx2 expression towards acantholysis in PV mice was observed.
RESULTS
A series of cellular and molecular effects, including (i) increased levels of oxidative stress products, (ii) destruction of epithelial cells in the skin tissues, (iii) induction of apoptosis in keratinocytes, (iv) reduction of Trx2 protein levels, and (v) enhanced phosphorylation of ASK1, were detected in PV patients. experiments confirmed that Trx2 can inhibit ASK1 phosphorylation, alleviate ROS release, decrease △m, and lower the apoptotic rate. Injection of Trx2-overexpressing vectors could also relieve acantholysis and blister formation in PV mice.
CONCLUSION
The Trx2/ASK1 signaling pathway regulates the incidence of PV mediated by mitochondrial injury.
Topics: Cell Line; Humans; Keratinocytes; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proteins; Oxidative Stress; Pemphigus; Reactive Oxygen Species; Thioredoxins
PubMed: 33763469
DOI: 10.1155/2021/2471518