{"title":"Follicular T helper cells in bullous pemphigoid: How polarization affects the pathophysiology of B cell-mediated autoimmune diseases.","authors":"Farzan Solimani, Christian Möbs","doi":"10.1093/bjd/ljae407","DOIUrl":"https://doi.org/10.1093/bjd/ljae407","url":null,"abstract":"","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ChangHyun Son, Sun Mun Jeong, Jang Hwan Jung, Do Ik Kwon, Seol Hwa Seong, Kee Suck Suh, Min Soo Jang
{"title":"Cyphellophora ludoviensis: A new causative species of tinea nigra.","authors":"ChangHyun Son, Sun Mun Jeong, Jang Hwan Jung, Do Ik Kwon, Seol Hwa Seong, Kee Suck Suh, Min Soo Jang","doi":"10.1093/bjd/ljae390","DOIUrl":"https://doi.org/10.1093/bjd/ljae390","url":null,"abstract":"","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qizhang Wang, Guanglin Niu, Zhuang Liu, Maria A Toma, Jennifer Geara, Xiaowei Bian, Letian Zhang, Minna Piipponen, Dongqing Li, Aoxue Wang, Pehr Sommar, Ning Xu Landén
Background: Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process.
Objectives: To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing.
Methods: CircRNA, linear RNA, and miRNA expression in human acute and chronic wounds were analyzed using RNA sequencing and qRT-PCR. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pull-down assays.
Results: We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. TGF-β signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds.
Conclusions: Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.
{"title":"Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing.","authors":"Qizhang Wang, Guanglin Niu, Zhuang Liu, Maria A Toma, Jennifer Geara, Xiaowei Bian, Letian Zhang, Minna Piipponen, Dongqing Li, Aoxue Wang, Pehr Sommar, Ning Xu Landén","doi":"10.1093/bjd/ljae405","DOIUrl":"https://doi.org/10.1093/bjd/ljae405","url":null,"abstract":"<p><strong>Background: </strong>Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process.</p><p><strong>Objectives: </strong>To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing.</p><p><strong>Methods: </strong>CircRNA, linear RNA, and miRNA expression in human acute and chronic wounds were analyzed using RNA sequencing and qRT-PCR. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pull-down assays.</p><p><strong>Results: </strong>We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. TGF-β signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds.</p><p><strong>Conclusions: </strong>Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.</p>","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fazleenah A Hussain, Arti Bakshi, Paul D Yesudian, Stuart N Cohen
{"title":"Overtreatment of dysplastic naevi: results of a multiregional UK questionnaire study.","authors":"Fazleenah A Hussain, Arti Bakshi, Paul D Yesudian, Stuart N Cohen","doi":"10.1093/bjd/ljae382","DOIUrl":"https://doi.org/10.1093/bjd/ljae382","url":null,"abstract":"","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thierry Passeron, Maximilian Reinhardt, Benjamin Ehst, Jonathan Weiss, Jason Sluzevich, Michael Sticherling, Pascal Reygagne, Johannes Wohlrab, Michael Hertl, Nasim Fazel, Elisa Muscianisi, Heng Fan, Isabelle Hampele, Nicolò Compagno
Background: Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden, representing a population with a clear unmet need for new treatments.
Objectives: To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP) that is inadequately controlled by topical corticosteroids.
Methods: PRELUDE was a randomized double-blind placebo-controlled phase II proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomized to either secukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W) or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤ 2 at week 16.
Results: Overall, 111 patients were randomized (n = 37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the three cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤ 2 response at week 16 with SECQ4W vs. placebo in the MLP {37.5% [95% credibility interval (Crl) 20.3-57.2] vs. 23.1% (95% Crl 6.5-49.2)} and LPP cohorts [37.5% (95% Crl 20.2-57.3) vs. 30.8% (95% Crl 10.8-57.6)]. In the LPP cohort, a sustained response for IGA ≤ 2 from week 16 to week 32 was achieved with SECQ4W (week 16, 37.5%; week 32, 45.8%), and a substantial improvement was observed in IGA ≤ 2 response in patients from this cohort who switched from placebo (week 16, 30.8%) to SECQ2W after week 16 (week 32, 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals.
Conclusions: PRELUDE is the first randomized controlled basket trial evaluating interleukin (IL)-17A inhibition with secukinumab across three subtypes of LP. Secukinumab was well tolerated and safe, showing different response rates across the three subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of IL-17A across LP subtypes. The novel IGA score showed significant correlation with both patient- and physician-reported outcome measurements.
{"title":"Secukinumab in adult patients with lichen planus: efficacy and safety results from the randomized placebo-controlled proof-of-concept PRELUDE study.","authors":"Thierry Passeron, Maximilian Reinhardt, Benjamin Ehst, Jonathan Weiss, Jason Sluzevich, Michael Sticherling, Pascal Reygagne, Johannes Wohlrab, Michael Hertl, Nasim Fazel, Elisa Muscianisi, Heng Fan, Isabelle Hampele, Nicolò Compagno","doi":"10.1093/bjd/ljae181","DOIUrl":"10.1093/bjd/ljae181","url":null,"abstract":"<p><strong>Background: </strong>Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden, representing a population with a clear unmet need for new treatments.</p><p><strong>Objectives: </strong>To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP) that is inadequately controlled by topical corticosteroids.</p><p><strong>Methods: </strong>PRELUDE was a randomized double-blind placebo-controlled phase II proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomized to either secukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W) or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤ 2 at week 16.</p><p><strong>Results: </strong>Overall, 111 patients were randomized (n = 37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the three cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤ 2 response at week 16 with SECQ4W vs. placebo in the MLP {37.5% [95% credibility interval (Crl) 20.3-57.2] vs. 23.1% (95% Crl 6.5-49.2)} and LPP cohorts [37.5% (95% Crl 20.2-57.3) vs. 30.8% (95% Crl 10.8-57.6)]. In the LPP cohort, a sustained response for IGA ≤ 2 from week 16 to week 32 was achieved with SECQ4W (week 16, 37.5%; week 32, 45.8%), and a substantial improvement was observed in IGA ≤ 2 response in patients from this cohort who switched from placebo (week 16, 30.8%) to SECQ2W after week 16 (week 32, 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals.</p><p><strong>Conclusions: </strong>PRELUDE is the first randomized controlled basket trial evaluating interleukin (IL)-17A inhibition with secukinumab across three subtypes of LP. Secukinumab was well tolerated and safe, showing different response rates across the three subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of IL-17A across LP subtypes. The novel IGA score showed significant correlation with both patient- and physician-reported outcome measurements.</p>","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":"680-690"},"PeriodicalIF":11.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kristina Hagenström, Theresa Klinger, Katharina Müller, Charlotte Willers, Matthias Augustin
Background: Systemic glucocorticosteroids (SGCs) are used in the short-term treatment of atopic dermatitis (AD), but are not recommended for long-term use because they are associated with severe side-effects.
Objectives: This study aimed to characterize the utilization and potentially negative effects of SGC use for AD in German statutory health insurance (SHI) claims data.
Methods: Cross-sectional and longitudinal analysis of a large nationwide SHI dataset. SGC drug prescriptions and incidences of predefined comorbidities after drug initiation that were known to be potentially harmful side-effects were analysed. SGC use was quantified by (-definition 1) the number of quarters with at least one SGC prescription and (definition 2) the defined daily doses (DDD). Comparisons were adjusted for age, sex and morbidity.
Results: The AD prevalence was 4.07% in 2020 (4.12% women, 3.42% men). During this period 9.91% of people with AD were prescribed SGCs compared with 5.54% in people without AD (P < 0.01). Prescribing of SGCs was significantly higher in women (10.20% vs. 9.42% in men, P < 0.01) and in the elderly. AD and SGC prevalence varied regionally. In a 3-year follow-up period, 58% of people with AD receiving a SGC were prescribed SGCs in > one quarter and 15% in > six quarters. The odds of developing osteoporosis [odds ratio (OR) 3.90 -(definition 1) and 1.80 (definition 2)] and diabetes [OR 1.90 (definition 1) and 1.38 (definition 2)] were significantly higher in people with AD on SGCs, especially in the frequently prescribed group compared with the rarely prescribed group, regardless of quantified use.
Conclusions: A considerable number of people with AD in Germany are prescribed long-term SGCs. The onset of medical conditions known to be harmful effects of steroids was significantly more frequent in those who were frequently prescribed SGCs, indicating the need for optimized healthcare.
{"title":"Utilization and related harms of systemic glucocorticosteroids for atopic dermatitis: claims data analysis.","authors":"Kristina Hagenström, Theresa Klinger, Katharina Müller, Charlotte Willers, Matthias Augustin","doi":"10.1093/bjd/ljae250","DOIUrl":"10.1093/bjd/ljae250","url":null,"abstract":"<p><strong>Background: </strong>Systemic glucocorticosteroids (SGCs) are used in the short-term treatment of atopic dermatitis (AD), but are not recommended for long-term use because they are associated with severe side-effects.</p><p><strong>Objectives: </strong>This study aimed to characterize the utilization and potentially negative effects of SGC use for AD in German statutory health insurance (SHI) claims data.</p><p><strong>Methods: </strong>Cross-sectional and longitudinal analysis of a large nationwide SHI dataset. SGC drug prescriptions and incidences of predefined comorbidities after drug initiation that were known to be potentially harmful side-effects were analysed. SGC use was quantified by (-definition 1) the number of quarters with at least one SGC prescription and (definition 2) the defined daily doses (DDD). Comparisons were adjusted for age, sex and morbidity.</p><p><strong>Results: </strong>The AD prevalence was 4.07% in 2020 (4.12% women, 3.42% men). During this period 9.91% of people with AD were prescribed SGCs compared with 5.54% in people without AD (P < 0.01). Prescribing of SGCs was significantly higher in women (10.20% vs. 9.42% in men, P < 0.01) and in the elderly. AD and SGC prevalence varied regionally. In a 3-year follow-up period, 58% of people with AD receiving a SGC were prescribed SGCs in > one quarter and 15% in > six quarters. The odds of developing osteoporosis [odds ratio (OR) 3.90 -(definition 1) and 1.80 (definition 2)] and diabetes [OR 1.90 (definition 1) and 1.38 (definition 2)] were significantly higher in people with AD on SGCs, especially in the frequently prescribed group compared with the rarely prescribed group, regardless of quantified use.</p><p><strong>Conclusions: </strong>A considerable number of people with AD in Germany are prescribed long-term SGCs. The onset of medical conditions known to be harmful effects of steroids was significantly more frequent in those who were frequently prescribed SGCs, indicating the need for optimized healthcare.</p>","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":"719-727"},"PeriodicalIF":11.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advancing care in epidermolysis bullosa: insights from qualitative research.","authors":"Marjolein Lugtenberg, Marlies Wakkee","doi":"10.1093/bjd/ljae280","DOIUrl":"10.1093/bjd/ljae280","url":null,"abstract":"","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":"655-656"},"PeriodicalIF":11.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"'Live long and prosper': living guidelines for immune-mediated inflammatory diseases.","authors":"Zenas Z N Yiu, Emma McFarlane, Samuel L Whittle","doi":"10.1093/bjd/ljae324","DOIUrl":"10.1093/bjd/ljae324","url":null,"abstract":"","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":"647-649"},"PeriodicalIF":11.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Orsolya Kiss, Rajia Bahri, Rachel E B Watson, Chidera Chike, Abigail K Langton, Victoria L Newton, Mike Bell, Christopher E M Griffiths, Silvia Bulfone-Paus, Suzanne M Pilkington
Background: Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear.
Objectives: To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge.
Methods: Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence.
Results: Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge.
Conclusions: Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair.
{"title":"The impact of irritant challenge on the skin barrier and myeloid-resident immune cells in women who are postmenopausal is modulated by hormone replacement therapy.","authors":"Orsolya Kiss, Rajia Bahri, Rachel E B Watson, Chidera Chike, Abigail K Langton, Victoria L Newton, Mike Bell, Christopher E M Griffiths, Silvia Bulfone-Paus, Suzanne M Pilkington","doi":"10.1093/bjd/ljae226","DOIUrl":"10.1093/bjd/ljae226","url":null,"abstract":"<p><strong>Background: </strong>Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear.</p><p><strong>Objectives: </strong>To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge.</p><p><strong>Methods: </strong>Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence.</p><p><strong>Results: </strong>Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge.</p><p><strong>Conclusions: </strong>Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair.</p>","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":"746-759"},"PeriodicalIF":11.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Rutkowski, Rachel Scholey, John Davies, Derek Pye, Fiona Blackhall, Richard B Warren, Francisco Jimenez, Christopher E M Griffiths, Ralf Paus
Background: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood.
Objectives: To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo.
Methods: Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization.
Results: The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, β2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-β1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs.
Conclusions: The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.
目的:表皮生长因子受体(EGFRi)或丝裂原活化蛋白激酶(MEKi)抑制剂在 75-90% 的患者中会诱发毛囊炎,但对其病理生物学仍缺乏充分了解。目的:(1)描述表皮生长因子受体(EGFRi)治疗患者的皮肤免疫状态和全局转录特征的变化(2)探究表皮生长因子受体(EGFRi)是否会影响毛囊(HF)的免疫特权(IP)(3)确定表皮生长因子受体(EGFRi)/MEKi在体外人类头皮HF中诱导的早期促炎信号:头皮活检取自长期接受表皮生长因子受体(EGFRi)治疗的毛囊炎患者(慢性-EGFRi,n=9)与正常头皮皮肤(n=9),以及开始接受EGFRi治疗前和接受EGFRi治疗两周后的患者(急性-EGFRi,n=5)。健康器官培养的头皮高频暴露于表皮生长因子受体(EGFRi)(厄洛替尼)或MEKi(Cobimetinib)(各5名患者)。样本通过定量免疫组织形态学、RNAseq和原位杂交进行评估:慢性-EGFRi队列显示CD8+ T细胞浸润隆起,同时HF的IP部分塌陷,表现为MHC I类、ß2-微球蛋白和MHC II类上调以及TGF-ß1蛋白表达减少。用表皮生长因子受体i/MEKi体内外治疗的健康高频也显示出高频IP的部分崩溃和HLA-A、HLA-DR、ß2-微球蛋白转录本的增加。RNAseq分析显示,慢性-EGFRi活检组织中趋化因子(CXCL1、CXCL13、CCL18、CCL3、CCL7)和IL-26的转录增加,急性-EGFRi活检组织和器官培养的HF中IL-33的转录增加,IL-37的转录减少:这些数据表明,表皮生长因子受体(EGFRi)/表皮生长因子受体(MEKi)会损害人类头皮毛囊炎的生理性 IP,并表明未来临床治疗表皮生长因子受体(EGFRi)/表皮生长因子受体(MEKi)诱导的毛囊炎需要保护毛囊炎 IP 和抑制 IL-33。
{"title":"Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege.","authors":"David Rutkowski, Rachel Scholey, John Davies, Derek Pye, Fiona Blackhall, Richard B Warren, Francisco Jimenez, Christopher E M Griffiths, Ralf Paus","doi":"10.1093/bjd/ljae243","DOIUrl":"10.1093/bjd/ljae243","url":null,"abstract":"<p><strong>Background: </strong>Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood.</p><p><strong>Objectives: </strong>To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo.</p><p><strong>Methods: </strong>Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization.</p><p><strong>Results: </strong>The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, β2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-β1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs.</p><p><strong>Conclusions: </strong>The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.</p>","PeriodicalId":9238,"journal":{"name":"British Journal of Dermatology","volume":" ","pages":"791-804"},"PeriodicalIF":11.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}