Experimental Dermatology最新文献

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) is a disorder caused by autosomal-dominant mutations in the TP63 gene. AEC is characterised by the presence of severe and painful skin erosions that can take years to heal. Current treatment options for these devastating lesions are limited, highlighting the need for new therapeutic strategies. We previously generated keratinocytes from patient-derived induced pluripotent stem cells (iPSC-K) and identified defects in several cell adhesion complexes, including desmosomes, hemidesmosomes and focal adhesions. In the present study, we developed a complementary in vitro model using NTERT keratinocytes transduced with lentiviral constructs expressing AEC-related TP63 mutations (N-AEC). This model allows for the large-scale production of disease-relevant material, overcoming the limitations of iPSC-derived keratinocytes, which have the characteristics of primary keratinocytes, including limited cell doublings and lifespan. We demonstrate that N-AEC keratinocytes exhibit key defects observed in AEC iPSC-K and AEC patient skin, including downregulation of cell adhesion proteins. In addition, 3D epidermal equivalents generated from these cells replicate pathological features seen in AEC patient skin, such as intra-epidermal cysts, reduced desmosomal protein expression and altered expression of differentiation markers. Our N-AEC model provides a valuable tool for investigating the mechanisms underlying skin fragility in AEC and other genetic skin disorders and advances the potential for novel therapeutic development.

The composite index lesion severity (CAILS) score is used to monitor disease and therapeutic response in mycosis fungoides (MF), but is limited by interobserver variability and low sensitivity. Emerging imaging techniques, such as multispectral imaging (MSI), colourimetry and laser speckle contrast imaging (LSCI), offer objective alternatives for quantifying CAILS parameters. The aim of this study was to evaluate non-invasive imaging modalities for objective and reliable quantification of disease extent in MF. Sixty-six participants were enrolled in two prospective studies: a cross-sectional discovery cohort to assess baseline characteristics of 35 MF patients (IA-IVB) and 10 healthy controls using CAILS and MSI, and a longitudinal confirmation cohort including 21 early-stage MF patients (IA-IIA) treated with chlormethine gel 0.016% for 16 weeks, in whom lesional and non-lesional skin were assessed using CAILS, MSI, colourimetry and LSCI at multiple time points. Candidate biomarkers were required to meet five clinical validation criteria: disease discrimination, repeatability, treatment responsiveness, correlation with CAILS and patient acceptability. In the discovery cohort, MSI detected significant differences in erythema, pigmentation, elevation and desquamation between healthy, non-lesional and lesional skin. In the confirmation cohort, four candidate biomarkers met all validation criteria: MSI CIELAB a*, MSI average haemoglobin, and colourimetry CIELAB a* (DSMIII) for quantifying erythema, and MSI individual typology angle (ITA) for pigmentation. These biomarkers reliably discriminated lesional from non-lesional skin (p ≤ 0.001), showed strong test-retest reliability (CV < 10%, ICC > 0.84), detected treatment effects, showed moderate concordance with CAILS, and were associated with low patient burden (mean 3.4/100). These findings show that MSI- and colourimetry-derived biomarkers can objectively monitor disease extent in MF and complement existing clinical assessments.

Janus kinase (JAK) inhibitors are commonly used to treat immune-mediated diseases by modulating the JAK-STAT signalling pathway. While these agents are therapeutically effective, they may also impair immunity, including antifungal response. Here, we present five cases of atypical dermatophyte infections in patients treated with baricitinib or upadacitinib. Their clinical presentations and treatment regimens were summarised to highlight the atypical features and the presumed effects of JAK inhibitors. Patients presented with erythematous indurated plaques, clustered firm papules, and widespread thin plaques with scaling and erosions. PCR and fungal cultures confirmed infections with Trichophyton tonsurans, Trichophyton rubrum, Trichophyton verrucosum, and Microsporum canis. Treatment with systemic antifungal agents such as terbinafine, itraconazole, and griseofulvin was effective. In some cases, the dosage of JAK inhibitors was reduced during antifungal therapy. Clinicians should be vigilant for cutaneous fungal infections in JAK inhibitor-treated patients with new rashes. The immunomodulatory effect of JAK inhibitors may attenuate the clinical manifestation and lead to delayed recognition of dermatophytosis.

Keloids (KDs) are a group of fibroproliferative skin diseases characterised by an excess of fibroblasts and the accumulation of extracellular matrix (ECM). In KDs, keloid fibroblasts (KFs) serve as the primary effector cells, playing a pivotal role. By studying the signalling pathways and epigenetic changes of KFs, researchers can elucidate the mechanisms behind the formation of KDs. This understanding is crucial for identifying potential targets for innovative treatments. In this paper, we review the latest progress in KFs research, detailing their abnormal biological characteristics, with some special KFs subgroups deserving particular attention. We also discuss the aberrantly regulated signalling pathways and therapeutic approaches concerning KFs, aiming to provide insights into the pathogenesis of keloid scars and thereby guide future research directions.

The human gut microbiota is involved in immune regulation, metabolism, and skin homeostasis. In recent years, gut microbiota alterations have been linked with several inflammatory skin disorders, such as atopic dermatitis (AD), psoriasis, and hidradenitis suppurativa (HS). This systematic review synthesises current evidence on gut microbiota composition and functional alterations in these dermatoses. A comprehensive literature search was conducted in the PubMed database, identifying studies from inception to January 2025. Eligible studies included human observational, interventional, and genetic studies investigating gut microbiota alterations in AD, psoriasis, or HS, using microbiome profiling or genetic causal-inference approaches. Studies lacking control groups or relying on culture-based techniques were excluded. Sixty-two studies were included: 38 on AD, 22 on psoriasis and 5 on HS, with three addressing more than one disease. In AD, most studies focused on paediatric populations, leaving a knowledge gap regarding adult-specific data. Reduced alpha-diversity and decreased abundance of Faecalibacterium prausnitzii, Bifidobacterium spp., and Akkermansia muciniphila were recurrent findings. In psoriasis, in addition to dysbiosis, microbial metabolic pathways were also found to be altered. In HS, data remain limited, but increased Ruminococcus gnavus and reduced alpha-diversity have been reported, mirroring findings in inflammatory bowel diseases. Gut microbiota has been increasingly implicated in skin inflammation. Despite advances in microbiota analysis, significant gaps remain-especially in adult AD and HS. Future research should prioritize standardised methodologies, larger and more diverse cohorts, and leverage emerging tools such as Mendelian randomization and AI-based models to develop precision medicine interventions.

Chronic inflammatory skin diseases such as psoriasis and hidradenitis suppurativa are driven by cytokines, including IL-17A and TNF. Although biologics targeting these cytokines have transformed therapy, the transcriptional contributions of individual skin-resident cell types remain unclear, and dermal fibroblasts have been largely overlooked compared with keratinocytes. To address this, we compared the transcriptional responses of primary human dermal fibroblasts and keratinocytes following in vitro stimulation with IL-17A, TNF, or both, using bulk RNA sequencing and Western blotting. Dermal fibroblasts mounted a stronger and broader proinflammatory response than keratinocytes. This was particularly evident in response to TNF and combined TNF/IL-17A stimulation, with enrichment for immune signalling and chemotaxis pathways and robust induction of chemokine genes, including CCL20, CXCL8, and IL6. Keratinocytes primarily upregulated genes associated with epithelial differentiation, barrier function, and protein regulation, including IL36G, S100A7A, and DEFB4A. The heightened fibroblast responsiveness correlated with increased TNF sensitivity and substantially higher TNFR2 (TNFRSF1B) expression and signalling compared with keratinocytes, suggesting a fibroblast-specific mechanism amplifying inflammatory responses. These findings challenge the keratinocyte-centric view of skin inflammation and identify dermal fibroblasts as active contributors and potential therapeutic targets in TNF- and Th17-driven skin diseases.

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disease characterised by widespread eruption of sterile, macroscopic pustules. Patients with GPP can present with multiple comorbidities that may influence treatment. This study aimed to assess the frequency of psoriasis-related complications and non-psoriasis-related comorbidities, and clinical laboratory findings, at the time of GPP diagnosis among patients with GPP. This was a retrospective, longitudinal medical chart review of data from patients with a documented GPP diagnosis attending 29 GPP referral hospitals in Japan. Demographics and clinical characteristics were assessed at baseline (within 6 months prior to and 3 months after GPP diagnosis), including psoriasis-related complications, non-psoriasis-related comorbidities, and clinical laboratory findings. Overall, 205 patients with GPP were included; 48.3% were female, and median age at initial diagnosis was 53 years. Similar proportions of patients had mild (36.1%), moderate (30.7%) and severe (33.2%) GPP at baseline, using Japanese Dermatological Association-GPP severity criteria. Most patients (69.8%) had psoriasis-related complications at baseline, with the most common being psoriasis vulgaris (42.9%) and psoriatic arthritis (26.8%). Non-psoriasis-related comorbidities were present in 69.3% of patients with GPP at baseline, with the most common being hypertension (28.3%), dyslipidaemia (16.6%) and diabetes mellitus (16.1%). There was large variability in laboratory test values between patients. These results demonstrated that, at the time of GPP diagnosis, patients with GPP have multiple burdens of both psoriasis-related complications and non-psoriasis-related comorbidities.