Pub Date : 2025-12-05DOI: 10.1016/j.xjidi.2025.100438
Fiona Chan-Pak-Choon , Andrew Y. Shuen , Evan Weber , Lili Fu , Barbara Rivera , William D. Foulkes
Whole-genome sequencing can uncover clinically significant noncoding variants missed by standard germline testing, as demonstrated in this report in a patient with Muir–Torre syndrome, a subtype of Lynch syndrome. In this case, despite a convincing clinical phenotype and immunohistochemical loss of MSH2/MSH6 in 1 of the patient’s tumors, conventional gene panel testing failed to detect a germline pathogenic variant. Whole-genome sequencing identified a deep intronic MSH2 variant, and tumor sequencing revealed somatic MSH2 mutations (second hits) across multiple tumors, confirming mismatch repair deficiency and establishing a Muir-Torre syndrome diagnosis. This report underscores the limitations of routine genetic testing and highlights the clinical utility of whole-genome sequencing in identifying pathogenic variants in noncoding regions. It also emphasizes the role of dermatologists in recognizing cutaneous markers of hereditary cancer syndromes and the importance of interdisciplinary evaluation in guiding both patient care and familial risk assessment.
{"title":"Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome","authors":"Fiona Chan-Pak-Choon , Andrew Y. Shuen , Evan Weber , Lili Fu , Barbara Rivera , William D. Foulkes","doi":"10.1016/j.xjidi.2025.100438","DOIUrl":"10.1016/j.xjidi.2025.100438","url":null,"abstract":"<div><div>Whole-genome sequencing can uncover clinically significant noncoding variants missed by standard germline testing, as demonstrated in this report in a patient with Muir–Torre syndrome, a subtype of Lynch syndrome. In this case, despite a convincing clinical phenotype and immunohistochemical loss of MSH2/MSH6 in 1 of the patient’s tumors, conventional gene panel testing failed to detect a germline pathogenic variant. Whole-genome sequencing identified a deep intronic <em>MSH2</em> variant, and tumor sequencing revealed somatic <em>MSH2</em> mutations (second hits) across multiple tumors, confirming mismatch repair deficiency and establishing a Muir-Torre syndrome diagnosis. This report underscores the limitations of routine genetic testing and highlights the clinical utility of whole-genome sequencing in identifying pathogenic variants in noncoding regions. It also emphasizes the role of dermatologists in recognizing cutaneous markers of hereditary cancer syndromes and the importance of interdisciplinary evaluation in guiding both patient care and familial risk assessment.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100438"},"PeriodicalIF":0.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.xjidi.2025.100437
Minxue Shen , Zhiwei Wang , Danrong Jing , Songchun Yang , Yi Xiao , Xiang Chen
Whether the levels of circulating fatty acids (FAs) are associated with psoriasis and psoriatic arthritis remains unknown. To examine the measured and predicted levels of circulating FAs in association with incident psoriatic disease, 2-sample Mendelian randomization analysis was performed to examine the causal relationship between monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs) and psoriasis, and a cohort study of the UK Biobank participants was conducted to validate the findings, in terms of the measured and dietarily predicted levels of FAs. Mendelian randomization analysis identified a positive association of genetically predicted MUFAs% but inverse associations of PUFAs% and PUFAs/MUFAs with psoriasis and psoriatic arthritis. In the cohort, higher MUFAs% was associated with increased risks of psoriasis (relative risk = 1.109, P = .004) and psoriatic arthritis (relative risk = 1.188, P = .016), whereas higher PUFAs% and PUFAs/MUFAs were associated with lower risks of psoriasis (relative risk = 0.891, P = .001) and psoriatic arthritis (relative risk = 0.874, P = .051). Dietary scores that predict PUFAs% and MUFAs% showed consistent results with larger effect sizes. The effects of PUFAs% and MUFAs% were not significant in under- or normal-weighted participants. In conclusion, circulating PUFAs% and MUFAs% are causal factors for incident psoriatic diseases, and the effects might be modified by obesity.
{"title":"Abundances but not concentrations of circulating unsaturated fatty acids are associated with incident psoriatic diseases: Evidence from cohort and Mendelian randomization studies","authors":"Minxue Shen , Zhiwei Wang , Danrong Jing , Songchun Yang , Yi Xiao , Xiang Chen","doi":"10.1016/j.xjidi.2025.100437","DOIUrl":"10.1016/j.xjidi.2025.100437","url":null,"abstract":"<div><div>Whether the levels of circulating fatty acids (FAs) are associated with psoriasis and psoriatic arthritis remains unknown. To examine the measured and predicted levels of circulating FAs in association with incident psoriatic disease, 2-sample Mendelian randomization analysis was performed to examine the causal relationship between monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs) and psoriasis, and a cohort study of the UK Biobank participants was conducted to validate the findings, in terms of the measured and dietarily predicted levels of FAs. Mendelian randomization analysis identified a positive association of genetically predicted MUFAs% but inverse associations of PUFAs% and PUFAs/MUFAs with psoriasis and psoriatic arthritis. In the cohort, higher MUFAs% was associated with increased risks of psoriasis (relative risk = 1.109, <em>P</em> = .004) and psoriatic arthritis (relative risk = 1.188, <em>P</em> = .016), whereas higher PUFAs% and PUFAs/MUFAs were associated with lower risks of psoriasis (relative risk = 0.891, <em>P</em> = .001) and psoriatic arthritis (relative risk = 0.874, <em>P</em> = .051). Dietary scores that predict PUFAs% and MUFAs% showed consistent results with larger effect sizes. The effects of PUFAs% and MUFAs% were not significant in under- or normal-weighted participants. In conclusion, circulating PUFAs% and MUFAs% are causal factors for incident psoriatic diseases, and the effects might be modified by obesity.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100437"},"PeriodicalIF":0.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145841217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1016/j.xjidi.2025.100436
Aaroh Joshi , Altan Cornu , Josefa Luxner , Gernot Zarfel , Camille Braun , Jean-Francois Nicolas , Richard L. Gallo , Marc Vocanson , Peter Wolf , Vijaykumar Patra
Staphylococcus aureus (S. aureus) worsens atopic dermatitis (AD), but how individual strains differ in pathogenicity remains unclear. Mouse models that mimic AD and allow direct manipulation of S. aureus in early stages of disease are limited. Moreover, these models rarely incorporate clinical S. aureus strains isolated from patients with AD. In this study, we investigated the inflammatory potential of clinical S. aureus and S. epidermidis isolates from patients with AD in a mouse model. Clinical S. aureus strains showed significant variability in their ability to elicit inflammation. The inflammation was associated with differences in virulence factor expression and, to a lesser extent, with genomic variation. In contrast, S. epidermidis strains (taken from the same lesional skin sites of patients) induced only mild but consistent inflammation, with less variability at the strain level. Next, we examined the impact of a pathogenic clinical S. aureus strains in the presence of an MC903-induced type 2 immune environment. Under these conditions, S. aureus enhanced colonization; increased inflammation; and promoted type 1, type 2, and type 17/22 immune responses. These responses were less evident with either treatment alone. Our findings suggest that clinical S. aureus strains from patients with AD differ in their capacity to modulate skin inflammation, particularly within a type 2–skewed environment. These results highlight the potential value of incorporating clinically relevant S. aureus isolates into early-stage in vivo models to better understand AD immunopathology and to inform microbiome-targeted therapeutic strategies.
{"title":"Atopic Dermatitis–like mouse model using early inoculation of patient-derived S. aureus together with MC903","authors":"Aaroh Joshi , Altan Cornu , Josefa Luxner , Gernot Zarfel , Camille Braun , Jean-Francois Nicolas , Richard L. Gallo , Marc Vocanson , Peter Wolf , Vijaykumar Patra","doi":"10.1016/j.xjidi.2025.100436","DOIUrl":"10.1016/j.xjidi.2025.100436","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> (<em>S. aureus</em>) worsens atopic dermatitis (AD), but how individual strains differ in pathogenicity remains unclear. Mouse models that mimic AD and allow direct manipulation of <em>S. aureus</em> in early stages of disease are limited. Moreover, these models rarely incorporate clinical <em>S. aureus</em> strains isolated from patients with AD. In this study, we investigated the inflammatory potential of clinical <em>S. aureus</em> and <em>S. epidermidis</em> isolates from patients with AD in a mouse model. Clinical <em>S. aureus</em> strains showed significant variability in their ability to elicit inflammation. The inflammation was associated with differences in virulence factor expression and, to a lesser extent, with genomic variation. In contrast, <em>S. epidermidis</em> strains (taken from the same lesional skin sites of patients) induced only mild but consistent inflammation, with less variability at the strain level. Next, we examined the impact of a pathogenic clinical <em>S. aureus</em> strains in the presence of an MC903-induced type 2 immune environment. Under these conditions, <em>S. aureus</em> enhanced colonization; increased inflammation; and promoted type 1, type 2, and type 17/22 immune responses. These responses were less evident with either treatment alone. Our findings suggest that clinical <em>S. aureus</em> strains from patients with AD differ in their capacity to modulate skin inflammation, particularly within a type 2–skewed environment. These results highlight the potential value of incorporating clinically relevant <em>S. aureus</em> isolates into early-stage in vivo models to better understand AD immunopathology and to inform microbiome-targeted therapeutic strategies.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100436"},"PeriodicalIF":0.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145747576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1016/j.xjidi.2025.100435
Matthew J. Yan BS, BA , Yuan Chun Jiang BS , Shannon Wongvibulsin MD, PhD , Steven T. Chen MD, MPH, MS-HPEd
Artificial intelligence (AI) is rapidly transforming dermatology, particularly through diagnostic imaging and enhancing patient management. Despite expanding clinical applications, public engagement with AI in dermatology remains underexplored. This study addresses this gap by analyzing public interest in AI dermatology over the past decade using Google Trends. Search terms were categorized into groups of “AI dermatology,” “general AI,” “AI nondermatology,” “general dermatology,” and “general nondermatology.” Monthly Search Volume Index values from January 2015 to January 2025 were collected, and linear and exponential regression models quantified temporal trends. Geographic analysis evaluated the frequency of countries appearing in the top five search volumes for each term. Public interest in AI dermatology terms increased markedly after 2022, with growth of 73.6%, 143.6%, and 59.1% in 2022, 2023, and 2024, respectively. AI dermatology terms demonstrated a steeper linear slope (6.212) compared with general AI (6.181) and dermatology terms (1.61), and an exponential growth factor of 0.551. Interest was highest in Singapore, Ireland, Australia, the Philippines, New Zealand, and the United Arab Emirates. These findings indicate a substantial rise in global engagement with AI in dermatology and highlight the importance of integrating public interest considerations into AI tool development, clinical practice, patient safety, and equitable access.
{"title":"Assessing public interest in artificial intelligence in dermatology: A Google Trends analysis","authors":"Matthew J. Yan BS, BA , Yuan Chun Jiang BS , Shannon Wongvibulsin MD, PhD , Steven T. Chen MD, MPH, MS-HPEd","doi":"10.1016/j.xjidi.2025.100435","DOIUrl":"10.1016/j.xjidi.2025.100435","url":null,"abstract":"<div><div>Artificial intelligence (AI) is rapidly transforming dermatology, particularly through diagnostic imaging and enhancing patient management. Despite expanding clinical applications, public engagement with AI in dermatology remains underexplored. This study addresses this gap by analyzing public interest in AI dermatology over the past decade using Google Trends. Search terms were categorized into groups of “AI dermatology,” “general AI,” “AI nondermatology,” “general dermatology,” and “general nondermatology.” Monthly Search Volume Index values from January 2015 to January 2025 were collected, and linear and exponential regression models quantified temporal trends. Geographic analysis evaluated the frequency of countries appearing in the top five search volumes for each term. Public interest in AI dermatology terms increased markedly after 2022, with growth of 73.6%, 143.6%, and 59.1% in 2022, 2023, and 2024, respectively. AI dermatology terms demonstrated a steeper linear slope (6.212) compared with general AI (6.181) and dermatology terms (1.61), and an exponential growth factor of 0.551. Interest was highest in Singapore, Ireland, Australia, the Philippines, New Zealand, and the United Arab Emirates. These findings indicate a substantial rise in global engagement with AI in dermatology and highlight the importance of integrating public interest considerations into AI tool development, clinical practice, patient safety, and equitable access.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100435"},"PeriodicalIF":0.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anti–IL-23 antibody therapies improve the underlying immunopathology of psoriasis. Immune profile dynamics after anti–IL-23 treatment and their association with the treatment response are unclear. Focusing on guselkumab, an anti–IL-23p19 antibody, we comprehensively analyzed immune cells, serum inflammatory molecules, and CD4+ T-cell transcriptomics to identify drug effects in psoriasis. Peripheral and lesional skin blood samples were collected from 24 biologic-naïve patients at baseline and after treatment with guselkumab. We conducted FACS analysis of regulatory T cells, resident memory T cells, and dendritic cells; measured serum cytokine and chemokine levels; and analyzed RNA-sequencing data for gene expression changes in peripheral CD4+ T cells. Guselkumab administration increased regulatory T cells and decreased resident memory T cells. Gene expression differences at baseline defined 2 groups on the basis of the treatment response: transcriptomic profile–based high responders and transcriptomic profile–based moderate responders. Expression of certain chemokines, such as CXCL1 and CXCL5, was higher in the moderate responders, suggesting their association with a lower treatment response. RNA-sequencing analysis revealed gene expression changes related to T helper 17 cells and regulatory T cell activity. We observed alterations in regulatory T cells and resident memory T cells in response to guselkumab treatment that may contribute to the long-term suppression of the IL-23–driven inflammatory pathology in psoriasis. Furthermore, baseline peripheral blood transcriptomic immune findings may predict therapeutic outcomes. The G-Grope trial was registered as jRCTs041200070 with the Japan Registry of Clinical Trials on December 8, 2020.
{"title":"Assessing T-Cell Profile Shifts through IL-23 Inhibition by Guselkumab on Psoriasis","authors":"Yoshifumi Kanayama , Oki Watanabe , Mai Sakurai , Yuki Enomoto , Aya Yamamoto , Shunya Mashiko , Yukako Sugiura , Masahiko Miyashiro , Junya Masuda , Akimichi Morita","doi":"10.1016/j.xjidi.2025.100433","DOIUrl":"10.1016/j.xjidi.2025.100433","url":null,"abstract":"<div><div>Anti–IL-23 antibody therapies improve the underlying immunopathology of psoriasis. Immune profile dynamics after anti–IL-23 treatment and their association with the treatment response are unclear. Focusing on guselkumab, an anti–IL-23p19 antibody, we comprehensively analyzed immune cells, serum inflammatory molecules, and CD4<sup>+</sup> T-cell transcriptomics to identify drug effects in psoriasis. Peripheral and lesional skin blood samples were collected from 24 biologic-naïve patients at baseline and after treatment with guselkumab. We conducted FACS analysis of regulatory T cells, resident memory T cells, and dendritic cells; measured serum cytokine and chemokine levels; and analyzed RNA-sequencing data for gene expression changes in peripheral CD4<sup>+</sup> T cells. Guselkumab administration increased regulatory T cells and decreased resident memory T cells. Gene expression differences at baseline defined 2 groups on the basis of the treatment response: transcriptomic profile–based high responders and transcriptomic profile–based moderate responders. Expression of certain chemokines, such as CXCL1 and CXCL5, was higher in the moderate responders, suggesting their association with a lower treatment response. RNA-sequencing analysis revealed gene expression changes related to T helper 17 cells and regulatory T cell activity. We observed alterations in regulatory T cells and resident memory T cells in response to guselkumab treatment that may contribute to the long-term suppression of the IL-23–driven inflammatory pathology in psoriasis. Furthermore, baseline peripheral blood transcriptomic immune findings may predict therapeutic outcomes. The G-Grope trial was registered as jRCTs041200070 with the Japan Registry of Clinical Trials on December 8, 2020.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 2","pages":"Article 100433"},"PeriodicalIF":0.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145697920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.xjidi.2025.100432
Shirin Emtenani , Salam Alfarsi , Philip Curman , Henning Olbrich , Rengin Melis Engin , Ralf J. Ludwig , Enno Schmidt
Pemphigus is a rare, severe autoimmune blistering disease caused by autoantibodies targeting desmosomal proteins, leading to intraepithelial blistering and painful erosions of the skin and mucous membranes. Although 10–15% of dermatology patients are diagnosed with psychiatric disorders, the association between pemphigus and psychiatric disorders remains unclear owing to limited large-scale evidence. We conducted a retrospective cohort study using the United States TriNetX Collaborative Network, analyzing data from over 120 million electronic health records. Adults (aged ≥18 years) with pemphigus were identified and matched 1:1 with comparators (n = 5753 individuals per group) using propensity score matching for age, sex, ethnicity, and major comorbidities. Outcomes were the incidence of psychiatric disorders diagnosed after the index event, including suicidal ideation, suicide attempts, depression, psychotic disorders, bipolar disorder, substance use disorders, anxiety, eating disorders, borderline personality disorder, attention-deficit hyperactivity disorder, and stress-related disorders, defined by International Classification of Diseases, Tenth Revision, Clinical Modification codes. Three sensitivity analyses addressed variations in follow-up time, baseline data completeness, and long-term outcome stability. No increased risk of psychiatric disorders was observed in patients with pemphigus over the course of the disease, with consistent results across all sensitivity analyses. In conclusion, these findings challenge prior assumptions and highlight the importance of large-scale, well-controlled studies in clarifying psychiatric comorbidities in autoimmune blistering diseases.
{"title":"Pemphigus Is not Associated with an Increased Risk of Psychiatric Disorders during the Course of the Disease","authors":"Shirin Emtenani , Salam Alfarsi , Philip Curman , Henning Olbrich , Rengin Melis Engin , Ralf J. Ludwig , Enno Schmidt","doi":"10.1016/j.xjidi.2025.100432","DOIUrl":"10.1016/j.xjidi.2025.100432","url":null,"abstract":"<div><div>Pemphigus is a rare, severe autoimmune blistering disease caused by autoantibodies targeting desmosomal proteins, leading to intraepithelial blistering and painful erosions of the skin and mucous membranes. Although 10–15% of dermatology patients are diagnosed with psychiatric disorders, the association between pemphigus and psychiatric disorders remains unclear owing to limited large-scale evidence. We conducted a retrospective cohort study using the United States TriNetX Collaborative Network, analyzing data from over 120 million electronic health records. Adults (aged ≥18 years) with pemphigus were identified and matched 1:1 with comparators (n = 5753 individuals per group) using propensity score matching for age, sex, ethnicity, and major comorbidities. Outcomes were the incidence of psychiatric disorders diagnosed after the index event, including suicidal ideation, suicide attempts, depression, psychotic disorders, bipolar disorder, substance use disorders, anxiety, eating disorders, borderline personality disorder, attention-deficit hyperactivity disorder, and stress-related disorders, defined by International Classification of Diseases, Tenth Revision, Clinical Modification codes. Three sensitivity analyses addressed variations in follow-up time, baseline data completeness, and long-term outcome stability. No increased risk of psychiatric disorders was observed in patients with pemphigus over the course of the disease, with consistent results across all sensitivity analyses. In conclusion, these findings challenge prior assumptions and highlight the importance of large-scale, well-controlled studies in clarifying psychiatric comorbidities in autoimmune blistering diseases.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100432"},"PeriodicalIF":0.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 10.1016/S2667-0267(25)00083-9
{"title":"Cover","authors":"","doi":"10.1016/S2667-0267(25)00083-9","DOIUrl":"10.1016/S2667-0267(25)00083-9","url":null,"abstract":"","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"5 6","pages":"Article 100427"},"PeriodicalIF":0.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Psoriasis is a chronic inflammatory skin disease with recurrence that often reappears at previously affected sites, suggesting an epigenetic imprint in healed skin. However, the chromatin landscape of clinically healed psoriatic keratinocytes remains uncharacterized. We performed Assay for Transposase-Accessible Chromatin using sequencing on epidermal keratinocytes isolated from psoriasis-affected, clinically healed, and control skin samples. Compared with those of healthy skin, psoriasis-affected keratinocytes exhibited widespread alterations in chromatin accessibility. Although most of these disease-associated changes resolved after clinical remission, 152 peaks remained differentially accessible, particularly at NF-κB–associated immune-regulatory loci, including S100A7/A8/A9 and IL36G. Despite this residual chromatin accessibility, immunohistochemistry revealed a lack of detectable protein expression in healed keratinocytes, reflecting a transcriptionally poised but translationally inactive state. Pathway analysis revealed 2 recovery patterns: low-recovery peaks enriched for inflammatory pathways and high-recovery peaks linked to cytoskeletal remodeling and metabolism. These findings demonstrate that postremission keratinocytes retain a chromatin signature distinct from both affected and healthy skin. A limitation of this study is the absence of never-involved skin in assessing whether the chromatin changes identified are specific to previously affected skin. Nevertheless, this study provides insight into the molecular basis of disease memory that may underlie the skin’s susceptibility to relapse in psoriasis.
{"title":"Chromatin Accessibility Profiling of Keratinocytes from Clinically Healed Psoriatic Skin Reveals Epigenetic Alterations","authors":"Sayaka Shibata , Kentaro Awaji , Asumi Koyama , Haruka Taira , Toyoki Yamamoto , Lixin Li , Yukiko Ito , Shunsuke Miura , Takashi Yamashita , Takuya Miyagawa , Shinichi Sato","doi":"10.1016/j.xjidi.2025.100430","DOIUrl":"10.1016/j.xjidi.2025.100430","url":null,"abstract":"<div><div>Psoriasis is a chronic inflammatory skin disease with recurrence that often reappears at previously affected sites, suggesting an epigenetic imprint in healed skin. However, the chromatin landscape of clinically healed psoriatic keratinocytes remains uncharacterized. We performed Assay for Transposase-Accessible Chromatin using sequencing on epidermal keratinocytes isolated from psoriasis-affected, clinically healed, and control skin samples. Compared with those of healthy skin, psoriasis-affected keratinocytes exhibited widespread alterations in chromatin accessibility. Although most of these disease-associated changes resolved after clinical remission, 152 peaks remained differentially accessible, particularly at NF-κB–associated immune-regulatory loci, including <em>S100A7</em>/<em>A8/A9</em> and <em>IL36G</em>. Despite this residual chromatin accessibility, immunohistochemistry revealed a lack of detectable protein expression in healed keratinocytes, reflecting a transcriptionally poised but translationally inactive state. Pathway analysis revealed 2 recovery patterns: low-recovery peaks enriched for inflammatory pathways and high-recovery peaks linked to cytoskeletal remodeling and metabolism. These findings demonstrate that postremission keratinocytes retain a chromatin signature distinct from both affected and healthy skin. A limitation of this study is the absence of never-involved skin in assessing whether the chromatin changes identified are specific to previously affected skin. Nevertheless, this study provides insight into the molecular basis of disease memory that may underlie the skin’s susceptibility to relapse in psoriasis.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100430"},"PeriodicalIF":0.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1016/j.xjidi.2025.100426
Graham A. Johnston , Gareth Squire , Shaun Barber , David Fairlamb , Christine E. Pullar
Background
Salbutamol is a well-established β2-adrenergic receptor agonist used clinically for the reversal of bronchospasm. A functional β2-adrenergic receptor agonist network exists in the skin, which can alter skin cell migration and proliferation, inhibit angiogenesis, and alter wound re-epithelialization, suggesting a potential role for a β2-adrenergic receptor agonist applied topically for the prevention and treatment of scarring. Reduced scarring has been observed in an in vivo pig model, whereby a 50% reduction in skin scar area and hyperpigmentation was observed after topical application of salbutamol. Objectives: We conducted a double-blind, placebo-controlled, randomized, dose-escalation clinical trial. This was designed to investigate both the safety and efficacy of topical salbutamol for the improvement of scar appearance when applied as a cutaneous gel to sutured wound margins on the arms of healthy volunteers. Methods: In a phase I, single-center, double-blind, placebo (vehicle) controlled, randomized, dose-escalation trial on 45 healthy human volunteers, 1 ml salbutamol topical gel was administered once daily to one 2-cm full-thickness incision site on each arm of the trial participants for 60 days. Each participant was allocated to only 1 dosing group (group 1: 2.5 mM, group 2: 5 mM, and group 3: 10 mM). Pharmacokinetic and clinical assessments of safety and efficacy were performed over a 12-month period. Scarring was assessed by validated clinical scoring systems by both investigator and participant over 12 months. Results: In healthy human volunteers, tolerability assessments indicated zero incidences of edema, exudate, bleeding, or infection at any salbutamol-treated site irrespective of dose. All participants at every time point had peak plasma levels of salbutamol below the prespecified limit of 30 ng/ml. In efficacy assessments of the scars, no statistically significant improvements were noted in the mean difference between salbutamol-treated scars at any dose compared with placebo at months 7, 9, or 12 for either the investigator or participants’ assessments. Conclusions: There are no clinically significant safety signals after the cutaneous administration of salbutamol gel (0.2–10 mM) in humans either local to the site of injury and drug administration or arising from systemic exposure to salbutamol, but the extent of salbutamol absorption decreases as the wound heals, confirming that re-epithelialization of the wound limits the potential for systemic absorption. This trial was prospectively registered with the Medicines and Healthcare products Regulatory Agency with the European Union Drug Regulating Authorities Clinical Trials (EudraCT number: 2017-003118-15).
{"title":"Topical Salbutamol Cutaneous Gel Is Safe in a Double-Blind, Placebo-Controlled, Randomized Trial of Scarring from Sutured Wound Margins on the Arms of Healthy Human Volunteers","authors":"Graham A. Johnston , Gareth Squire , Shaun Barber , David Fairlamb , Christine E. Pullar","doi":"10.1016/j.xjidi.2025.100426","DOIUrl":"10.1016/j.xjidi.2025.100426","url":null,"abstract":"<div><h3>Background</h3><div>Salbutamol is a well-established β2-adrenergic receptor agonist used clinically for the reversal of bronchospasm. A functional β2-adrenergic receptor agonist network exists in the skin, which can alter skin cell migration and proliferation, inhibit angiogenesis, and alter wound re-epithelialization, suggesting a potential role for a β2-adrenergic receptor agonist applied topically for the prevention and treatment of scarring. Reduced scarring has been observed in an in vivo pig model, whereby a 50% reduction in skin scar area and hyperpigmentation was observed after topical application of salbutamol. Objectives: We conducted a double-blind, placebo-controlled, randomized, dose-escalation clinical trial. This was designed to investigate both the safety and efficacy of topical salbutamol for the improvement of scar appearance when applied as a cutaneous gel to sutured wound margins on the arms of healthy volunteers. Methods: In a phase I, single-center, double-blind, placebo (vehicle) controlled, randomized, dose-escalation trial on 45 healthy human volunteers, 1 ml salbutamol topical gel was administered once daily to one 2-cm full-thickness incision site on each arm of the trial participants for 60 days. Each participant was allocated to only 1 dosing group (group 1: 2.5 mM, group 2: 5 mM, and group 3: 10 mM). Pharmacokinetic and clinical assessments of safety and efficacy were performed over a 12-month period. Scarring was assessed by validated clinical scoring systems by both investigator and participant over 12 months. Results: In healthy human volunteers, tolerability assessments indicated zero incidences of edema, exudate, bleeding, or infection at any salbutamol-treated site irrespective of dose. All participants at every time point had peak plasma levels of salbutamol below the prespecified limit of 30 ng/ml. In efficacy assessments of the scars, no statistically significant improvements were noted in the mean difference between salbutamol-treated scars at any dose compared with placebo at months 7, 9, or 12 for either the investigator or participants’ assessments. Conclusions: There are no clinically significant safety signals after the cutaneous administration of salbutamol gel (0.2–10 mM) in humans either local to the site of injury and drug administration or arising from systemic exposure to salbutamol, but the extent of salbutamol absorption decreases as the wound heals, confirming that re-epithelialization of the wound limits the potential for systemic absorption. This trial was prospectively registered with the Medicines and Healthcare products Regulatory Agency with the European Union Drug Regulating Authorities Clinical Trials (EudraCT number: 2017-003118-15).</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100426"},"PeriodicalIF":0.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-17DOI: 10.1016/j.xjidi.2025.100425
Namya Nanda , Chloe Kim , Ishita Jain , Charlene Cai , Martin P. Alphonse
Mucosal-associated invariant T (MAIT) cells are a unique subset of innate-like T lymphocytes that recognize microbial-derived vitamin B metabolites presented by the nonpolymorphic MR1 (major histocompatibility complex class I–related protein). These cells comprise about 1–10% of circulating T cells in humans and are abundant at mucosal surfaces, including the skin. MAIT cells possess a semi-invariant TCR (typically, TRAV1-2/TRAJ33 in humans) and can be activated by riboflavin metabolites such as 5-OP-RU (5-[2-oxopropylideneamino]-6-d-ribitylaminouracil) and 5-OE-RU (5-2-oxoethylideneamino]-6-d-ribitylaminouracil) as well as through cytokine-mediated pathways independent of MR1. Upon activation, MAIT cells quickly produce proinflammatory cytokines, including IFN-γ, TNF-α, and IL-17, and perform cytotoxic functions by releasing granzyme B and perforin. This review thoroughly explores the role of MAIT cells in skin immunity and skin diseases. We detail their involvement in inflammatory skin conditions such as psoriasis, atopic dermatitis, and hidradenitis suppurativa, where alterations in MAIT cell numbers and functions have been observed. The review also addresses MAIT cells’ roles in wound healing, tissue repair, and antimicrobial defense within the skin. Furthermore, we evaluate the potential of targeting MAIT cells for therapy, including how current treatments affect them and the development of new immunometabolic strategies. Gaining a better understanding of MAIT cell biology in skin contexts could provide new insights into the development of skin diseases and lead to innovative dermatological treatments.
粘膜相关不变T （MAIT）细胞是先天样T淋巴细胞的一个独特子集，可识别微生物来源的维生素B代谢物，这些代谢物由非多态性MR1（主要组织相容性复合体i类相关蛋白）呈现。这些细胞约占人体循环T细胞的1-10%，大量存在于包括皮肤在内的粘膜表面。MAIT细胞具有半不变的TCR（在人类中通常为TRAV1-2/TRAJ33），可以被核黄素代谢产物如5- op - ru（5-[2-氧丙基氨基]-6-d-ribitylaminouracil）和5- oe - ru（5-2-氧乙基氨基]-6-d-ribitylaminouracil）激活，也可以通过独立于MR1的细胞因子介导途径激活。激活后，MAIT细胞迅速产生促炎细胞因子，包括IFN-γ、TNF-α和IL-17，并通过释放颗粒酶B和穿孔素发挥细胞毒性功能。本文综述了MAIT细胞在皮肤免疫和皮肤病中的作用。我们详细描述了它们在炎症性皮肤状况中的作用，如牛皮癣、特应性皮炎和化脓性汗腺炎，在这些情况下，MAIT细胞数量和功能的改变已经被观察到。该综述还讨论了MAIT细胞在皮肤伤口愈合、组织修复和抗菌防御中的作用。此外，我们评估了靶向MAIT细胞治疗的潜力，包括当前治疗如何影响它们以及新的免疫代谢策略的发展。更好地了解皮肤环境中的MAIT细胞生物学可以为皮肤病的发展提供新的见解，并导致创新的皮肤病学治疗。
{"title":"Mucosal-Associated Invariant T (MAIT) Cells in Skin Immunity: Metabolic Regulation, Tissue Adaptation, and Roles in Skin Inflammation and Disease","authors":"Namya Nanda , Chloe Kim , Ishita Jain , Charlene Cai , Martin P. Alphonse","doi":"10.1016/j.xjidi.2025.100425","DOIUrl":"10.1016/j.xjidi.2025.100425","url":null,"abstract":"<div><div>Mucosal-associated invariant T (MAIT) cells are a unique subset of innate-like T lymphocytes that recognize microbial-derived vitamin B metabolites presented by the nonpolymorphic MR1 (major histocompatibility complex class I–related protein). These cells comprise about 1–10% of circulating T cells in humans and are abundant at mucosal surfaces, including the skin. MAIT cells possess a semi-invariant TCR (typically, TRAV1-2/TRAJ33 in humans) and can be activated by riboflavin metabolites such as 5-OP-RU (5-[2-oxopropylideneamino]-6-d-ribitylaminouracil) and 5-OE-RU (5-2-oxoethylideneamino]-6-d-ribitylaminouracil) as well as through cytokine-mediated pathways independent of MR1. Upon activation, MAIT cells quickly produce proinflammatory cytokines, including IFN-γ, TNF-α, and IL-17, and perform cytotoxic functions by releasing granzyme B and perforin. This review thoroughly explores the role of MAIT cells in skin immunity and skin diseases. We detail their involvement in inflammatory skin conditions such as psoriasis, atopic dermatitis, and hidradenitis suppurativa, where alterations in MAIT cell numbers and functions have been observed. The review also addresses MAIT cells’ roles in wound healing, tissue repair, and antimicrobial defense within the skin. Furthermore, we evaluate the potential of targeting MAIT cells for therapy, including how current treatments affect them and the development of new immunometabolic strategies. Gaining a better understanding of MAIT cell biology in skin contexts could provide new insights into the development of skin diseases and lead to innovative dermatological treatments.</div></div>","PeriodicalId":73548,"journal":{"name":"JID innovations : skin science from molecules to population health","volume":"6 1","pages":"Article 100425"},"PeriodicalIF":0.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145571759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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