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Frontiers in Immunology 2023Pemphigus vulgaris (PV) is an acquired autoimmune blistering disease characterized by the production of autoantibodies targeting desmosomal cadherins, primarily...
Pemphigus vulgaris (PV) is an acquired autoimmune blistering disease characterized by the production of autoantibodies targeting desmosomal cadherins, primarily desmoglein 1 and desmoglein 3, leading to acantholysis. The etiology of PV is multifactorial, including genetic susceptibility. This retrospective study aimed to evaluate the association of HLA class II alleles and PV and to examine the impact of PV-associated HLA class II alleles on the concentration of anti-desmoglein antibodies. The study group included 30 patients in whom the diagnosis of PV was confirmed by histopathological analysis, immunofluorescence findings, and ELISA testing for detecting antibodies against desmoglein 1 and desmoglein 3. HLA class II alleles were typed by polymerase chain reaction with sequence-specific primers (PCR-SSP). The control group consisted of 190 healthy volunteer blood donors. Data analysis revealed a significantly higher frequency of HLA class II alleles in our population of patients with PV, including HLA-DRB1*04:02, HLA-DRB1*14:54, HLA-DQB1*03:02, HLA-DQB1*05:03, HLA- DQA1*03:01, and HLA-DQA1*01:04, as well as a significantly lower frequency of HLA-DQA1*05:01 compared to the control group. We have also investigated the influence of risk alleles for PV, recognized in almost all study populations, HLA-DRB1*04:02 and HLA-DQB1*05:03, on the concentration of antibodies against desmogleins 1 and 3 in relation to the presence of these alleles. The results showed significantly higher levels of antibodies directed against desmoglein 3 among patients with DRB1*04:02 compared to patients without this allele. No difference was found for anti-desmoglein 1 antibodies. Regarding DQB1*05:03 allele, statistical analysis showed no differences in the concentration of anti-desmoglein antibodies in patients carrying this allele versus those without it.
Topics: Humans; Pemphigus; Desmoglein 3; Retrospective Studies; Croatia; HLA-DRB1 Chains; Autoantibodies; Autoimmune Diseases
PubMed: 37529044
DOI: 10.3389/fimmu.2023.1200992 -
Journal of Translational Autoimmunity Dec 2023Endemic pemphigus foliaceus and endemic pemphigus vulgaris are autoimmune dermatologic disorders endemic to the Peruvian Amazon.
BACKGROUND
Endemic pemphigus foliaceus and endemic pemphigus vulgaris are autoimmune dermatologic disorders endemic to the Peruvian Amazon.
OBJECTIVE
To determine the ultrastructural skin alterations of three healthy subjects with anti DSG-1 antibodies in areas endemic to pemphigus foliaceus and pemphigus vulgaris in the Peruvian Amazon.
PATIENTS AND METHODS
Case series carried out from data of three clinically healthy subjects positive to anti DSG-1 antibodies, from Peru. This study consists of a sub-analysis of data gathered in a previous study.
RESULTS
Ultrastructural results are presented from the skin biopsies of three clinically healthy patients positive to -desmoglein 1 (DSG-1) antibodies. High Resolution Optical Microscopy (HROM) showed the absence of acantholysis. Transmission Electron Microscopy (TEM) showed the widening of intercellular space between keratinocytes, the presence of vacuoles in intercellular space with granular material and cytoplasmic vacuolization, loss of desmosome structure, loss of normal distribution among tonofilaments and lateral separation among cells in the stratum basale.
CONCLUSION
According to our results, healthy subjects that present -desmoglein 1 antibodies can develop ultrastructural alterations that are visible through transmission electron microscopy but not through conventional optical microscopy.
PubMed: 37520889
DOI: 10.1016/j.jtauto.2023.100208 -
International Journal of Molecular... Jul 2023The mucosal-dominant variant of pemphigus vulgaris (MPV) is an autoimmune disease characterized by oral mucosal blistering and circulating pathogenic IgG antibodies...
The mucosal-dominant variant of pemphigus vulgaris (MPV) is an autoimmune disease characterized by oral mucosal blistering and circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3), resulting in life-threatening bullae and erosion formation. Recently, microRNAs (miRNAs) have emerged as promising players in the diagnosis and prognosis of several pathological states. For the first time, we have identified a different expression profile of miRNAs isolated from plasma-derived exosomes (P-EVs) of MPV patients positive for antibodies against Dsg3 (Dsg3-positive) compared to healthy controls. Moreover, a dysregulated miRNA profile was confirmed in MPV tissue biopsies. In particular, a strong downregulation of the miR-148a-3p expression level in P-EVs of MPV patients compared to healthy controls was demonstrated. Bioinformatics prediction analysis identifies metalloproteinase-7 (MMP7) as a potential miR-148a-3p target. An in vitro acantholysis model revealed that the miR-148a-3p expression level was dramatically downregulated after treatment with Dsg3 autoantibodies, with a concomitant increase in MMP7 expression. The increased expression of MMP7 leads to the disruption of intercellular and/or extracellular matrix adhesion in an in vitro cellular model of MPV, with subsequent cell dissociation. Overexpression of miR-148a-3p prevented cell dissociation and regressed MMP7 upregulation. Our findings suggest a pivotal role of P-EV cargo in regulating molecular mechanisms involved in MPV pathogenesis and indicate them as potential MPV therapeutic targets.
Topics: Humans; Pemphigus; Down-Regulation; Matrix Metalloproteinase 7; Desmoglein 3; Autoantibodies; MicroRNAs; Blister; Mouth Mucosa
PubMed: 37511259
DOI: 10.3390/ijms241411493 -
Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.Frontiers in Immunology 2023Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister...
Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister formation occurs upon binding of autoantibodies to their antigen proteins (desmoglein1, DSG1 and desmoglein3, DSG3), current therapies mostly aim to suppress the immune system. To avoid the severe side effects associated with the chronic use of immunosuppressive treatments, we have developed PC111, a fully human monoclonal antibody targeting human Fas ligand (FasL). We have provided a number of and evidences showing that soluble FasL induces keratinocyte apoptosis followed by acantholysis. An anti-murine FasL prevents blister formation in the pemphigus neonatal mouse model. To confirm the mechanism of action (MoA) and the efficacy of PC111 in a human pemphigus context, we used the keratinocyte dissociation assay and two independent Human Skin Organ Cultures (HSOC) pemphigus models. PC111 reduced acantholysis , as shown by the dose-dependent reduction of fragments in the monolayer cultures. In the first HSOC model, normal human skin was subcutaneously injected with a scFv antibody fragment directed against DSG1 and DSG3, resulting in a severe acantholysis (70-100%) after 24 hours. PC111 inhibited blister formation to around 50% of control. In the second model, normal human skin was injected with a mixture of pemphigus patients' autoantibodies resulting in a less severe acantholysis (20-30%). PC111 significantly suppressed blister formation to more than 75% up to 72 hours. These results confirm PC111 MoA and demonstrates the efficacy of the anti-FasL antibody also in a pemphigus setting.
Topics: Humans; Animals; Mice; Pemphigus; Fas Ligand Protein; Blister; Acantholysis; Autoantibodies
PubMed: 37503332
DOI: 10.3389/fimmu.2023.1193032 -
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 -
Transcriptional profiling of rare acantholytic disorders suggests common mechanisms of pathogenesis.JCI Insight Aug 2023Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell...
Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. To better understand the underlying mechanisms leading to disease in these conditions, we performed RNA-seq on lesional skin samples from patients. The transcriptomic profiles of Darier, Hailey-Hailey, and Grover diseases were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases. Analysis of enriched pathways showed a shared increase in keratinocyte differentiation, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grover diseases. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in the acantholytic skin diseases. Furthermore, upstream regulator analysis suggested that a decrease in SRF/MRTF activity was responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared with normal skin. These findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grover diseases, and identify decreases in actin organization pathways as a unique signature present in these conditions.
Topics: Humans; Actins; Skin; Acantholysis; Skin Diseases
PubMed: 37471166
DOI: 10.1172/jci.insight.168955 -
Clinical, Cosmetic and Investigational... 2023Familial dyskeratotic comedones (FDC) is an autosomal dominant inherited skin disorder characterized by generalized multiple discrete comedone-like hyperkeratotic...
Familial dyskeratotic comedones (FDC) is an autosomal dominant inherited skin disorder characterized by generalized multiple discrete comedone-like hyperkeratotic papules. The disease demonstrates a distinct histopathologic feature of dyskeratosis of the crater-like invaginated epidermis or follicle-like structures with or without acantholysis. Despite its asymptomatic and benign course, the condition is refractory to treatment. Herein, we report a case of a 54-year-old female presenting with progressively developed generalized multiple hyperkeratotic papules with central keratin plugs on the trunk and extremities for 20 years. A definite diagnosis was made by clinical manifestations and histopathological examination. The lesions were slightly improved after 3 months of topical retinoids and urea cream treatments. Besides, we first describe dermoscopic findings of FDC and reviewed 21 previously reported FDC cases from 11 families in the literature.
PubMed: 37426083
DOI: 10.2147/CCID.S420723