Pub Date : 2025-12-01DOI: 10.1016/j.jdermsci.2025.09.006
Tetsuya Honda
Atopic dermatitis (AD) is a chronic inflammatory skin disorder driven by type 2 cytokines, particularly IL-4, IL-13, and IL-31. CD4⁺ Th2 cells have long been considered the primary producers of these cytokines in AD, but the contribution of CD8⁺ Tc2 cells has received limited attention. Recent advances in single-cell RNA sequencing, which allow for cytokine expression profiling at the single-cell level, challenge this traditional paradigm. This review reappraises the cellular sources of IL-13—a key effector cytokine in AD lesions—by not only summarizing prior studies but also reanalyzing multiple publicly available scRNA-seq datasets. These analyses indicate that Tc2 cells may represent a substantial, and in some cases dominant, source of IL-13 in lesional skin, alongside Th2 cells. This perspective invites a reconsideration of the Th2-centric model and proposes that a broader view—including Tc2 cells—is needed to fully understand type 2 immune responses in AD.
{"title":"A reappraisal of type 2 cytokine-producing cells in atopic dermatitis: Spotlight on Tc2 cells","authors":"Tetsuya Honda","doi":"10.1016/j.jdermsci.2025.09.006","DOIUrl":"10.1016/j.jdermsci.2025.09.006","url":null,"abstract":"<div><div>Atopic dermatitis (AD) is a chronic inflammatory skin disorder driven by type 2 cytokines, particularly IL-4, IL-13, and IL-31. CD4⁺ Th2 cells have long been considered the primary producers of these cytokines in AD, but the contribution of CD8⁺ Tc2 cells has received limited attention. Recent advances in single-cell RNA sequencing, which allow for cytokine expression profiling at the single-cell level, challenge this traditional paradigm. This review reappraises the cellular sources of IL-13—a key effector cytokine in AD lesions—by not only summarizing prior studies but also reanalyzing multiple publicly available scRNA-seq datasets. These analyses indicate that Tc2 cells may represent a substantial, and in some cases dominant, source of IL-13 in lesional skin, alongside Th2 cells. This perspective invites a reconsideration of the Th2-centric model and proposes that a broader view—including Tc2 cells—is needed to fully understand type 2 immune responses in AD.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 3","pages":"Pages 81-87"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277086","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 : 2025-12-01DOI: 10.1016/j.jdermsci.2025.10.003
Miki Hamanaka , Ken Ishii , Mari Urushibata , Kenji Yoshida , Akira Ishiko
Background
Previously, we developed bead aggregation assays with recombinant desmoglein (Dsg) and desmocollin (Dsc) and found that pemphigus autoantibodies directly block the heterophilic trans-interaction of Dsg/Dsc.
Objective
To investigate whether inhibitory activities measured by bead aggregation assays can be used to assess pemphigus disease activity.
Methods
First, we investigated whether the inhibitory activity correlated with patients’ clinical disease activity using sera of 21 pemphigus vulgaris (PV) and 16 pemphigus foliaceus (PF) cases at the time of initial diagnosis. Next, we investigated whether the inhibitory activities reflect disease activities along the time course.
Results
The inhibitory activities were significantly correlated with the pemphigus disease area index (PDAI) (Spearman rank correlation, 0.761, n = 21, p < 0.01) in the PV group. However, no significant correlation was observed between Dsg3 ELISA titers and PDAI (Spearman rank correlation, 0.238, p > 0.05). Similar results were observed in the PF group (0.746, p < 0.01 vs. 0.357, p > 0.05). The inhibitory activities were evaluated using sera from the initial onset, remission, and relapse stages for four PV and four PF cases. The inhibitory activity changed in parallel with the clinical disease activity in seven out of eight cases. In two cases, the inhibitory activity correlated more accurately with disease activity than the Dsg ELISA titers.
Conclusions
Bead assay is useful for assessing disease activity in patients with pemphigus. Furthermore, our findings suggest that the direct inhibition of Dsg/Dsc adhesion is important for pemphigus pathogenesis.
{"title":"Bead aggregation assays with desmoglein and desmocollin for the evaluation of disease activity in pemphigus","authors":"Miki Hamanaka , Ken Ishii , Mari Urushibata , Kenji Yoshida , Akira Ishiko","doi":"10.1016/j.jdermsci.2025.10.003","DOIUrl":"10.1016/j.jdermsci.2025.10.003","url":null,"abstract":"<div><h3>Background</h3><div>Previously, we developed bead aggregation assays with recombinant desmoglein (Dsg) and desmocollin (Dsc) and found that pemphigus autoantibodies directly block the heterophilic trans-interaction of Dsg/Dsc.</div></div><div><h3>Objective</h3><div>To investigate whether inhibitory activities measured by bead aggregation assays can be used to assess pemphigus disease activity.</div></div><div><h3>Methods</h3><div>First, we investigated whether the inhibitory activity correlated with patients’ clinical disease activity using sera of 21 pemphigus vulgaris (PV) and 16 pemphigus foliaceus (PF) cases at the time of initial diagnosis. Next, we investigated whether the inhibitory activities reflect disease activities along the time course.</div></div><div><h3>Results</h3><div>The inhibitory activities were significantly correlated with the pemphigus disease area index (PDAI) (Spearman rank correlation, 0.761, n = 21, p < 0.01) in the PV group. However, no significant correlation was observed between Dsg3 ELISA titers and PDAI (Spearman rank correlation, 0.238, p > 0.05). Similar results were observed in the PF group (0.746, p < 0.01 vs. 0.357, p > 0.05). The inhibitory activities were evaluated using sera from the initial onset, remission, and relapse stages for four PV and four PF cases. The inhibitory activity changed in parallel with the clinical disease activity in seven out of eight cases. In two cases, the inhibitory activity correlated more accurately with disease activity than the Dsg ELISA titers.</div></div><div><h3>Conclusions</h3><div>Bead assay is useful for assessing disease activity in patients with pemphigus. Furthermore, our findings suggest that the direct inhibition of Dsg/Dsc adhesion is important for pemphigus pathogenesis.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 3","pages":"Pages 88-97"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427261","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/j.jdermsci.2025.08.004
Takehiro Takahashi
Fibroblasts are mesenchymal cells that constitute the stroma across tissues. Historically, they have long been perceived as uniform structural cells passively residing in the background during the immune responses within tissues. However, a growing number of recent studies have revealed that fibroblasts are highly heterogeneous and dynamic, responding to various external stimuli with notable plasticity. They exhibit heterogeneity not only across tissues but also within the same organ, and show dynamic changes over time throughout development and aging. As a barrier tissue, the skin is constantly exposed to numerous environmental stressors and pathogens and is capable of mounting diverse yet robust immune responses to these stimuli. Reflecting this inherent nature, skin dermal fibroblasts are remarkably heterogeneous and dynamic. Upon tissue inflammation, they produce and secrete not only inflammatory cytokines and chemokines but also extracellular matrix molecules that critically modulate immune cell infiltration. They also engage in direct mechano-chemical interactions with neighboring cells and actively support neural growth. Furthermore, they function as antigen presenting cells and contribute to the formation of tertiary lymphoid structures. This review highlights recent advances in understanding the heterogeneity of dermal fibroblast subpopulations and their roles in the pathogenesis of major inflammatory and autoimmune skin diseases.
{"title":"Dermal fibroblast subsets and their roles in inflammatory and autoimmune skin diseases","authors":"Takehiro Takahashi","doi":"10.1016/j.jdermsci.2025.08.004","DOIUrl":"10.1016/j.jdermsci.2025.08.004","url":null,"abstract":"<div><div>Fibroblasts are mesenchymal cells that constitute the stroma across tissues. Historically, they have long been perceived as uniform structural cells passively residing in the background during the immune responses within tissues. However, a growing number of recent studies have revealed that fibroblasts are highly heterogeneous and dynamic, responding to various external stimuli with notable plasticity. They exhibit heterogeneity not only across tissues but also within the same organ, and show dynamic changes over time throughout development and aging. As a barrier tissue, the skin is constantly exposed to numerous environmental stressors and pathogens and is capable of mounting diverse yet robust immune responses to these stimuli. Reflecting this inherent nature, skin dermal fibroblasts are remarkably heterogeneous and dynamic. Upon tissue inflammation, they produce and secrete not only inflammatory cytokines and chemokines but also extracellular matrix molecules that critically modulate immune cell infiltration. They also engage in direct mechano-chemical interactions with neighboring cells and actively support neural growth. Furthermore, they function as antigen presenting cells and contribute to the formation of tertiary lymphoid structures. This review highlights recent advances in understanding the heterogeneity of dermal fibroblast subpopulations and their roles in the pathogenesis of major inflammatory and autoimmune skin diseases.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 2","pages":"Pages 45-51"},"PeriodicalIF":4.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214798","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/j.jdermsci.2025.09.007
Shigetoshi Sano
{"title":"A case of metastatic breast carcinoma to the skin expressing SARS-CoV-2 spike protein possibly derived from mRNA vaccine","authors":"Shigetoshi Sano","doi":"10.1016/j.jdermsci.2025.09.007","DOIUrl":"10.1016/j.jdermsci.2025.09.007","url":null,"abstract":"","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 2","pages":"Pages 71-73"},"PeriodicalIF":4.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277080","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/j.jdermsci.2025.09.002
Shiyu Jin , Sheng Wan , Xiuzu Song , Cuiping Guan
{"title":"Foxp3-ablation/melanoma-induced vitiligo: An enhanced mouse model","authors":"Shiyu Jin , Sheng Wan , Xiuzu Song , Cuiping Guan","doi":"10.1016/j.jdermsci.2025.09.002","DOIUrl":"10.1016/j.jdermsci.2025.09.002","url":null,"abstract":"","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 2","pages":"Pages 74-76"},"PeriodicalIF":4.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228691","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/j.jdermsci.2025.09.004
Jing Wang , Fanglan Zha , Simin Lin , Yun Wei , Lingling Xuan , Zhangying Ye , Hu Huang
Background
Excessive melanogenesis in skin melanocytes results in hyperpigmentation disorders.
Objective
This study investigates the combined effects and mechanisms of 3,3,5-trimethylcyclohexanol succinate dimethylamide (335, a succinic acid derivative) and tranexamic acid (TXA) on melanogenesis.
Methods
Skin penetration of 335 was assessed via Raman spectroscopy. Interactions between 335 and TXA were predicted by molecular docking. The anti-melanogenic effect was evaluated by measuring melanin content in human keratinocytes (HaCaT) and mouse melanoma cells (B16). Transcriptome sequencing was performed to identify key pathways by which 335 regulates melanogenesis. Melanosomes were isolated from human melanoma cells (MNT-1) and co-cultured with keratinocytes to validate the specific mechanisms. A 3D melanin skin model was established to evaluate the anti-pigmentation effect of 335 and TXA by analyzing apparent chroma, lightness (L*), and melanin content and distribution.
Results
The skin penetration of 335 was enhanced by the addition of TXA, and the two compounds exhibited hydrogen bonding and hydrophobic interactions. The combination of 335 and TXA (1:10) significantly reduced the melanin content in B16 cells compared to individual treatments. Transcriptomics revealed 335 modulates the ubiquitin-proteasome system (UPS) and autophagy. Experimental validation confirmed that 335 and TXA combination inhibited melanin production by promoting ubiquitination degradation of tyrosinase and autophagic degradation of melanosomes. In the 3D skin model, the combination enhanced skin brightness (apparent chroma and L* value) and reduced melanin deposition.
Conclusion
The combination of 335 and TXA inhibits melanogenesis by UPS-mediated tyrosinase degradation and autophagy-driven melanosome degradation, offering a promising strategy for hyperpigmentation treatment.
{"title":"Regulation of melanogenesis via ubiquitin-proteasome system and autophagy by 3,3,5-trimethylcyclohexyl succinate dimethylamide and tranexamic acid","authors":"Jing Wang , Fanglan Zha , Simin Lin , Yun Wei , Lingling Xuan , Zhangying Ye , Hu Huang","doi":"10.1016/j.jdermsci.2025.09.004","DOIUrl":"10.1016/j.jdermsci.2025.09.004","url":null,"abstract":"<div><h3>Background</h3><div>Excessive melanogenesis in skin melanocytes results in hyperpigmentation disorders.</div></div><div><h3>Objective</h3><div>This study investigates the combined effects and mechanisms of 3,3,5-trimethylcyclohexanol succinate dimethylamide (335, a succinic acid derivative) and tranexamic acid (TXA) on melanogenesis.</div></div><div><h3>Methods</h3><div>Skin penetration of 335 was assessed via Raman spectroscopy. Interactions between 335 and TXA were predicted by molecular docking. The anti-melanogenic effect was evaluated by measuring melanin content in human keratinocytes (HaCaT) and mouse melanoma cells (B16). Transcriptome sequencing was performed to identify key pathways by which 335 regulates melanogenesis. Melanosomes were isolated from human melanoma cells (MNT-1) and co-cultured with keratinocytes to validate the specific mechanisms. A 3D melanin skin model was established to evaluate the anti-pigmentation effect of 335 and TXA by analyzing apparent chroma, lightness (L*), and melanin content and distribution.</div></div><div><h3>Results</h3><div>The skin penetration of 335 was enhanced by the addition of TXA, and the two compounds exhibited hydrogen bonding and hydrophobic interactions. The combination of 335 and TXA (1:10) significantly reduced the melanin content in B16 cells compared to individual treatments. Transcriptomics revealed 335 modulates the ubiquitin-proteasome system (UPS) and autophagy. Experimental validation confirmed that 335 and TXA combination inhibited melanin production by promoting ubiquitination degradation of tyrosinase and autophagic degradation of melanosomes. In the 3D skin model, the combination enhanced skin brightness (apparent chroma and L* value) and reduced melanin deposition.</div></div><div><h3>Conclusion</h3><div>The combination of 335 and TXA inhibits melanogenesis by UPS-mediated tyrosinase degradation and autophagy-driven melanosome degradation, offering a promising strategy for hyperpigmentation treatment.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 2","pages":"Pages 61-70"},"PeriodicalIF":4.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228639","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/j.jdermsci.2025.09.005
James G. Krueger , Akimichi Morita , Mona Uchida-Yamada , Chiharu Tateishi , Eisaku Ogawa , Koji Masuda , Yukie Yamaguchi , Hong Beom Hur , Sandra Garcet , Naomi Shishido-Takahashi , Yasumasa Kanai
Background
Brodalumab, an anti-interleukin-17 receptor A antibody, is effective in psoriasis via action on the IL-17 pathway.
Objective
This analysis of an exploratory intervention study (ESPRIT) in Japanese patients with moderate to severe plaque psoriasis examined the brodalumab efficacy by clinical changes, and modulation of skin inflammation via changes in skin gene expression and blood sample protein expression.
Methods
Primary clinical endpoints were changes in PASI score and PASI score 0 achievement rate at Week 12. For molecular endpoints, biopsies of lesional, non-lesional and healthy volunteer skin were examined by RNA sequencing and RT-PCR. Blood sample serum was analyzed by Olink high-throughput proteomics.
Results
Twenty healthy volunteers and 40 patients were enrolled; 37 underwent molecular profiling. Clinical assessment showed that the median baseline PASI score (19.0) significantly decreased to 0.4 at Week 12 (P < 0.0001), with more rapid decline in higher PASI responders. Molecular assessment demonstrated that differential expressed genes in lesional skin were suppressed equivalently to non-lesional skin, establishing the molecular improvement with brodalumab. The transcriptomes of Japanese and Western patients were similar, and top-upregulated genes included IL-17-inducible and cardiovascular disease-related genes, which were suppressed by brodalumab. Serum protein analysis identified 22 proteins elevated by psoriasis. Several inflammatory and cardiovascular risk proteins correlated with psoriasis severity and BMI, but at lower rates than in Western patients.
Conclusions
In summary, the transcriptome and the proteome characteristics of Japanese and Western psoriasis patients were similar. Brodalumab rapidly improved skin and serum molecular levels and reduced cardiovascular disease risk factor expression.
{"title":"Molecular profile of interleukin-17RA blockade by brodalumab in Japanese patients with psoriasis: Results from the ESPRIT study","authors":"James G. Krueger , Akimichi Morita , Mona Uchida-Yamada , Chiharu Tateishi , Eisaku Ogawa , Koji Masuda , Yukie Yamaguchi , Hong Beom Hur , Sandra Garcet , Naomi Shishido-Takahashi , Yasumasa Kanai","doi":"10.1016/j.jdermsci.2025.09.005","DOIUrl":"10.1016/j.jdermsci.2025.09.005","url":null,"abstract":"<div><h3>Background</h3><div>Brodalumab, an anti-interleukin-17 receptor A antibody, is effective in psoriasis via action on the IL-17 pathway.</div></div><div><h3>Objective</h3><div>This analysis of an exploratory intervention study (ESPRIT) in Japanese patients with moderate to severe plaque psoriasis examined the brodalumab efficacy by clinical changes, and modulation of skin inflammation via changes in skin gene expression and blood sample protein expression.</div></div><div><h3>Methods</h3><div>Primary clinical endpoints were changes in PASI score and PASI score 0 achievement rate at Week 12. For molecular endpoints, biopsies of lesional, non-lesional and healthy volunteer skin were examined by RNA sequencing and RT-PCR. Blood sample serum was analyzed by Olink high-throughput proteomics.</div></div><div><h3>Results</h3><div>Twenty healthy volunteers and 40 patients were enrolled; 37 underwent molecular profiling. Clinical assessment showed that the median baseline PASI score (19.0) significantly decreased to 0.4 at Week 12 (<em>P</em> < 0.0001), with more rapid decline in higher PASI responders. Molecular assessment demonstrated that differential expressed genes in lesional skin were suppressed equivalently to non-lesional skin, establishing the molecular improvement with brodalumab. The transcriptomes of Japanese and Western patients were similar, and top-upregulated genes included IL-17-inducible and cardiovascular disease-related genes, which were suppressed by brodalumab. Serum protein analysis identified 22 proteins elevated by psoriasis. Several inflammatory and cardiovascular risk proteins correlated with psoriasis severity and BMI, but at lower rates than in Western patients.</div></div><div><h3>Conclusions</h3><div>In summary, the transcriptome and the proteome characteristics of Japanese and Western psoriasis patients were similar. Brodalumab rapidly improved skin and serum molecular levels and reduced cardiovascular disease risk factor expression.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"120 2","pages":"Pages 52-60"},"PeriodicalIF":4.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282235","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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