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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 -
Journal of Cutaneous Pathology Oct 2023A 61-year-old African-American female with moderately controlled Hailey-Hailey disease (HHD) presents to the emergency department with a rash and fever. One day prior to...
A 61-year-old African-American female with moderately controlled Hailey-Hailey disease (HHD) presents to the emergency department with a rash and fever. One day prior to her presentation, she was started on oral clindamycin for a tooth extraction procedure. Her physical examination shows diffuse erythema on the trunk and extremities with multiple nonfollicular pustules. A punch biopsy of her upper extremity revealed intraepidermal acantholysis, neutrophilic spongiosis, and subcorneal pustules. The perivascular and interstitial superficial dermal infiltrate is mixed and composed of predominantly neutrophils, with lymphocytes and rare eosinophils. These findings suggest a superimposed acute generalized exanthematous pustulosis (AGEP) in the background of HHD. AGEP is a potentially severe cutaneous condition characterized by the abrupt onset of numerous nonfollicular pustules in a background of pruritic edematous erythroderma. To date, only two case reports have described AGEP in patients with HHD. Early diagnosis of AGEP is essential to initiate prompt and aggressive systemic therapy, prompt medication cessation, close monitoring for end-organ damage, and improve overall morbidity and mortality.
Topics: Humans; Female; Middle Aged; Acute Generalized Exanthematous Pustulosis; Clindamycin; Pemphigus, Benign Familial; Exanthema; Skin
PubMed: 37430411
DOI: 10.1111/cup.14488 -
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 -
The American Journal of Dermatopathology Oct 2023
Topics: Humans; Isotretinoin; COVID-19 Vaccines; COVID-19; Keratosis; Acantholysis
PubMed: 37335843
DOI: 10.1097/DAD.0000000000002473 -
Indian Journal of Dermatology,... 2023
Topics: Humans; Acanthoma; Skin Neoplasms; Acantholysis
PubMed: 37317765
DOI: 10.25259/IJDVL_970_2022 -
Veterinary Dermatology Oct 2023While the clinical features were described recently, the histopathological characterisation of trunk-dominant canine pemphigus foliaceus (PF) is lacking, and whether it...
BACKGROUND
While the clinical features were described recently, the histopathological characterisation of trunk-dominant canine pemphigus foliaceus (PF) is lacking, and whether it differs from classic facial or insecticide-triggered PF is unknown.
HYPOTHESIS/OBJECTIVES
This study describes the histopathological findings of trunk-dominant PF, and compares the results to classic facial and insecticide-triggered PF.
ANIMALS
Skin biopsies from 103 dogs with clinically characterised trunk-dominant (n = 33), classic facial (n = 26) and insecticide-triggered PF (n = 44) were included.
MATERIALS AND METHODS
Histological sections, randomised and blinded, were scored for over 50 morphological parameters of pustules, epidermis, dermis, adnexa and crusts. Intact pustule area and width were measured by digital microscopy.
RESULTS
In trunk-dominant PF, 77 intact pustules were predominantly subcorneal (0.0019-1.940 mm area, 0.0470-4.2532 mm wide), and contained from one to over 100 acantholytic keratinocytes. Pustules had boat acantholytic cells, corneocytes, perinuclear eosinophilic rings, neutrophil rosettes, acantholytic cell necrosis, rafts, cling-ons and/or eosinophils. Peripustular epidermal spongiosis, necrosis and lymphocyte exocytosis occurred, as did follicular pustules. Mixed dermal inflammation often contained eosinophils. Trunk-dominant PF did not differ from the other PF groups except for few parameters, such as having fewer rafts (p = 0.003). Additional autoimmune inflammatory patterns occurred in all PF groups.
CONCLUSIONS AND CLINICAL RELEVANCE
Trunk-dominant PF and other canine PF variants are histologically similar, which indicates shared pathomechanisms. The identification of common boat acantholytic cells and corneocyte separation has implications for the mechanisms of acantholysis. The diversity of histopathological and polyautoimmunity features support complicated immune mechanisms. Finally, results indicate that diagnostic biopsies cannot differentiate between these PF variants in dogs.
Topics: Dogs; Animals; Pemphigus; Insecticides; Skin; Epidermis; Blister; Necrosis
PubMed: 37316895
DOI: 10.1111/vde.13174 -
Journal of the European Academy of... Sep 2023Pemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease primarily caused by acantholysis of keratinocytes attributed to pathogenic desmoglein-3 (Dsg3)...
BACKGROUND
Pemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease primarily caused by acantholysis of keratinocytes attributed to pathogenic desmoglein-3 (Dsg3) autoantibodies. Interleukin-37 (IL-37) reportedly plays important roles in a variety of autoimmune diseases, but its role in PV is not clear.
OBJECTIVES
To investigate whether IL-37 plays a role in the occurrence and progression of PV.
METHODS
HaCaT keratinocytes were stimulated with anti-Dsg3 antibody to establish an in vitro PV model, which was defined as anti-Dsg3 group. Cells incubated with medium without anti-Dsg3 treatment were used as control. IL-37 was cultured with these cells infected with or without lentiviral vector shRNA-Caveolin-1 (sh-Cav-1-LV). Cell dissociation assay and immunocytofluorescence were performed to assess keratinocyte dissociation, keratin retraction and Dsg3 endocytosis. Real-time PCR was used to detect the mRNA level of Cav-1, and western blot was used to determine the protein expression of Cav-1, Dsg3, STAT3 and phosphorylated-STAT3 (p-STAT3).
RESULTS
The anti-Dsg3 group showed more cell debris, increased keratin retraction, increased Dsg3 endocytosis, reduced Cav-1 expression and co-localization than the control group, while IL-37 treatment neutralized all of these changes. Interestingly, Cav-1 knockdown supressed the inhibitory effect of IL-37 on keratinocyte dissociation and Dsg3 internalization. The protein expression of p-STAT3 was increased in keratinocytes of the PV model but decreased by IL-37. Re-activation of the STAT3 pathway by colivelin supressed the inhibitory effect of IL-37 on keratinocyte dissociation and Dsg3 internalization, along with upregulation of Cav-1 and Dsg3.
CONCLUSIONS
IL-37 inhibited keratinocyte dissociation and Dsg3 endocytosis in an in vitro PV model through the upregulating Cav-1 and inhibiting STAT3 pathway.
Topics: Humans; Autoantibodies; Caveolin 1; Desmoglein 3; Endocytosis; Interleukins; Keratinocytes; Keratins; Pemphigus; STAT3 Transcription Factor; Up-Regulation
PubMed: 37262304
DOI: 10.1111/jdv.19239 -
Animal Genetics Aug 2023Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca pump ATP2A2. Defective...
Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine.
Topics: Animals; Dogs; Darier Disease; Mutation, Missense; Heterozygote; Calcium; Pedigree; Dog Diseases
PubMed: 36883421
DOI: 10.1111/age.13314 -
Journal of Cutaneous Pathology Aug 2023Pemphigus is a potentially life-threatening autoimmune blistering disease. To date, studies assessing the association of histopathology with clinical phenotype are...
INTRODUCTION
Pemphigus is a potentially life-threatening autoimmune blistering disease. To date, studies assessing the association of histopathology with clinical phenotype are lacking. We sought to evaluate the main histopathologic findings and, also, the potential links between cutaneous inflammatory infiltrates and clinical characteristics in pemphigus.
METHODS
We conducted a retrospective cohort study in patients diagnosed with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) in a referral center for autoimmune blistering diseases.
RESULTS
A total of 124 patients were included in the study (97 had PV and 27 had PF). On biopsy specimens, PV was more frequently associated with the "row of tombstones" feature (36.1% vs. 11.1%, p = 0.013), and PF was associated with acanthosis (44.4% vs. 23.7%, p = 0.034). Acantholysis was found in the upper half of the epidermis in PF (96.3% vs. 5.15%, p < 0.001), as opposed to the lower half in PV (75.2% vs. 0%, p = 0.002). Patients with lymphocyte-predominant inflammatory infiltrates in lesional skin specimens presented with a higher frequency of the mucosal-dominant phenotype (25.5% vs. 9.1%, p = 0.014), higher-density cellular infiltrate (100% vs. 41.6%, p < 0.001), and more frequent acantholytic cells (42.6% vs. 23.4%, p = 0.025). Neutrophil-predominant infiltrates in specimens from lesional skin were linked to a milder disease based on median Pemphigus Disease Area Index (38.9% vs. 13.2%, p = 0.036) and Autoimmune Bullous Skin Disorder Intensity Score (20.2 vs. 36.3, p = 0.019), while eosinophil-predominant inflammatory infiltrates were more often associated with eosinophilic spongiosis (100% vs. 23.1%, p = 0.014).
CONCLUSIONS
Lymphocyte-predominant infiltrates in lesional skin specimens of pemphigus patients predict a mucosal-dominant phenotype, while neutrophil-predominant infiltrates are associated with a milder disease.
Topics: Humans; Pemphigus; Retrospective Studies; Skin; Skin Diseases; Blister; Phenotype; Lymphocytes; Autoantibodies
PubMed: 36680509
DOI: 10.1111/cup.14395