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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 -
JAMA Dermatology Jul 2023Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and...
IMPORTANCE
Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and organ transplantation. The pathobiology of GD remains unknown.
OBJECTIVE
To determine if damaging somatic single-nucleotide variants (SNVs) are associated with GD.
DESIGN, SETTING, AND PARTICIPANTS
In this retrospective case series, we identified consecutive patients from a dermatopathology archive over a 4-year period (January 2007 to December 2011) who had 1 biopsy with a clinical diagnosis of GD confirmed via histopathologic findings and another non-GD biopsy. Participant DNA was extracted from both biopsy tissues and sequenced to high depth with a 51-gene panel to screen for SNVs in genes previously associated with acantholysis and Mendelian disorders of cornification. Analysis took place between 2021 and 2023.
MAIN OUTCOMES AND MEASURES
Comparative analysis of sequencing data from paired GD and control tissue was employed to identify SNVs predicted to affect gene function, which were exclusive to, or highly enriched in, GD tissue.
RESULTS
Overall, 12 of 15 cases of GD (12 men and 3 women; mean [SD] age, 68.3 [10.0] years) were associated with C>T or G>A ATP2A2 SNVs in GD tissue; all were predicted to be highly damaging via combined annotation dependent depletion (CADD) scores, and 4 were previously associated with Darier disease. In 9 cases (75%), the GD-associated ATP2A2 SNV was absent from control tissue DNA, and in 3 cases (25%), ATP2A2 SNVs were enriched 4- to 22-fold in GD vs control tissue.
CONCLUSIONS AND RELEVANCE
In this case series study of 15 patients, damaging somatic ATP2A2 SNVs were associated with GD. This discovery expands the spectrum of acantholytic disorders associated with ATP2A2 SNVs and highlights the role of somatic variation in acquired disorders.
Topics: Aged; Female; Humans; Male; Acantholysis; Darier Disease; Ichthyosis; Retrospective Studies; Sarcoplasmic Reticulum Calcium-Transporting ATPases
PubMed: 37195706
DOI: 10.1001/jamadermatol.2023.1139 -
Vancomycin-Induced Leukocytoclastic Vasculitis: A Rare Complication From a Commonly Used Medication.Cureus Mar 2023Leukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis that is characterized by the development of a non-blanching palpable purpura. Diagnosis is made...
Leukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis that is characterized by the development of a non-blanching palpable purpura. Diagnosis is made by skin biopsy and histopathology which shows subepidermal acantholysis with dense neutrophilic infiltrate leading to fibrinoid necrosis of the dermal blood vessels. Etiology is generally idiopathic in most cases but secondary causes include chronic infections, malignancies, systemic autoimmune conditions, and medication use. Treatment involves supportive measures in the case of idiopathic LCV, and treatment of the offending condition or agent in LCV due to a secondary cause. A 59-year-old male presented with purulent ulcers on the plantar surface of the right foot. Radiograph of the right foot showed soft tissue swelling without evidence of osteomyelitis. Empiric antibiotic treatment with vancomycin was initiated. A wound culture was obtained from the purulent drainage which grew positive for methicillin-resistant (MRSA). On the fourth day of treatment with vancomycin, multiple symmetric, purpuric lesions arose on the patient's trunk and extremities. Skin biopsy with histopathology showed subepidermal acantholysis with neutrophil-predominant inflammatory infiltrate consistent with leukocytoclastic vasculitis. Vancomycin was discontinued and the patient's exanthem began to regress, with full resolution after 30 days post withdrawal of the antibiotic.
PubMed: 37102000
DOI: 10.7759/cureus.36532