Sho Hiroyasu

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Background: Vitiligo is an acquired depigmenting disorder characterised by melanocyte loss. While immune responses against melanocytes are implicated in its pathogenesis, melanocyte detachment, melanocyte senescence and aberrant epidermal differentiation are increasingly characterised as additional pathological features. Granzyme B (GzmB), classically recognised as an intracellular effector of perforin-dependent cytotoxicity, is increased in vitiligo lesions; however, its extracellular contribution to vitiligo pathology remains unclear. Objectives: To determine whether extracellular GzmB contributes to depigmentation and epidermal pathological features relevant to vitiligo, and to define its cellular source and underlying mechanisms. Methods: Human vitiligo skin samples, murine depigmentation models and cultured human epidermal cells were analysed. The functional effects of extracellular GzmB were examined by subcutaneous administration of recombinant GzmB in mice. A rhododendrol (RD)-induced leukoderma model was used to evaluate the disease relevance of GzmB and the therapeutic effect of topical GzmB inhibition with VTI-1002. Results: GzmB-positive cells were markedly increased in active vitiligo lesions and were predominantly associated with tryptase-positive cells, with limited co-distribution with CD8 or perforin. Vitiligo lesions also showed melanocyte detachment, increased p16 ^INK4A -positive melanocytes and aberrant keratinocyte differentiation. These pathological features were recapitulated in vivo by extracellular GzmB administration, accompanied by focal depigmentation. In cultured melanocytes, GzmB exerted no cytotoxic effects but reduced attachment strength and induced a senescence-associated phenotype characterised by decreased extracellular matrix- and adhesion-related gene expression, increased p16 ^INK4A level, elevated senescence-associated β-galactosidase activity and activation of transforming growth factor-β/SMAD signalling. In keratinocytes, extracellular GzmB promoted aberrant differentiation associated with activation of p53 signalling. Topical inhibition of GzmB in RD-induced leukoderma attenuated depigmentation progression, melanocyte detachment, melanocyte senescence and abnormal epidermal differentiation. Conclusions: Extracellular GzmB promotes depigmentation associated with inducing melanocyte detachment, melanocyte senescence and aberrant keratinocyte differentiation. These findings identify extracellular GzmB as a previously underrecognised pathogenic mediator and potential therapeutic target in vitiligo-associated depigmentation. What is already known about this topic?: Vitiligo is an acquired depigmenting disorder characterised by melanocyte loss. Although autoreactive immune responses are implicated in vitiligo, melanocyte detachment, melanocyte senescence and keratinocyte abnormalities are increasingly recognised as additional pathological features that may also contribute to depigmentation. Granzyme B is increased in vitiligo lesions, but whether extracellular granzyme B contributes to disease pathology independently of classical perforin-dependent cytotoxicity has not been tested. What does this study add?: In active vitiligo lesions, granzyme B was increased and predominantly distributed to perforin-negative, tryptase-positive mast cells. Extracellular granzyme B induced focal depigmentation, melanocyte detachment, melanocyte senescence and aberrant keratinocyte differentiation. Pharmacological inhibition of extracellular granzyme B attenuated depigmentation progression and associated pathological changes in a rhododendrol-induced vitiligo-like mouse model. What is the translational message?: Granzyme B contributes to melanocyte loss via extracellular mechanisms beyond classical intracellular cytotoxicity. These findings support topical inhibition of extracellular granzyme B as a potential local therapeutic strategy for active vitiligo. Abstract figure: Abbreviated abstract (Teaser Text): In vitiligo, mast cell-associated extracellular granzyme B promotes depigmentation accompanied by melanocyte detachment, melanocyte senescence and aberrant keratinocyte differentiation. Topical granzyme B inhibition attenuates depigmentation and associated pathological changes in a rhododendrol-induced vitiligo-like mouse model, identifying extracellular granzyme B as a potential therapeutic target for depigmenting skin disease.

The advent of immune checkpoint inhibitors (ICIs) and targeted therapeutic agents (TTAs) has improved melanoma treatment. With the ongoing development of novel drugs, treatment options are expected to expand further. However, this is also anticipated to increase the financial burden on patients. Changes in medical costs for melanoma patients have not yet been examined in Japan. Therefore, we herein conducted a retrospective observational study using data from a Japanese nationwide database. The dataset comprised 14 727 patients diagnosed with melanoma between April 2008 and June 2023. The mean monthly cost per patient was calculated and changes were evaluated. The results obtained showed that the mean monthly cost per patient has consistently increased, and a breakdown revealed that drug costs for ICIs and TTAs accounted for a significant percentage of these costs. Furthermore, the usage rates of ICIs and TTAs have steadily increased since their approval in 2014, with a notable rise being observed in 2018 when adjuvant therapies were approved in Japan. An interrupted time series analysis further confirmed a significant increase in medical costs around 2018. While ICIs and TTAs represent major advances in melanoma treatment, their increasing use underscores the need for a careful evaluation of both clinical benefits and economic sustainability.

Neutrophilic skin diseases, including Behçet disease, Sweet syndrome, pyoderma gangrenosum (PG), and epidermolysis bullosa acquisita (EBA), are characterized by an exaggerated inflammatory response following mechanical skin stimulation, yet the underlying mechanisms remain unclear. We identify adenosine triphosphate (ATP) released from keratinocytes as a key mediator of this phenomenon, promoting neutrophil extracellular trap (NET) formation. Using an EBA murine model as a model of neutrophilic skin disease, where scratching (a prototypic mechanical stimulation) exacerbates lesional severity, we observed abundant NET deposition in lesional skin. Degradation of these NETs with DNase1 reduced clinical and histopathological severities. In vitro, purified NET components increased IL-8 secretion from keratinocytes and fibroblasts, suggesting that NETs amplify inflammation via a self-amplifying loop of neutrophil recruitment. In the EBA mouse, scratch restriction with neck collars not only attenuated clinical and histological disease severities but also decreased lesional NETosis and neutrophils. Mechanistically, keratinocytes released ATP in response to mechanical stress in vitro, and pharmacologic purinergic blockade in the EBA mice with suramin phenocopied the protective effects of scratch restriction. While ATP alone did not induce NETosis, ATP enhanced complement component 5a (C5a)-induced NET formation in vitro. These findings indicate that keratinocyte-derived ATP, released in response to mechanical stress, contributes to NETosis in a C5a-dependent manner, thereby exaggerating neutrophilic inflammation, leading to blistering and further NETosis. Histopathological analyses of EBA and PG cases also demonstrated NETs accumulation localized to the upper dermis, suggesting a conserved ATP-NET axis. Targeting this pathway may represent a promising therapeutic strategy for neutrophilic skin diseases.

The skin epidermis is maintained by spatially organized stem cell populations with distinct cellular dynamics; however, how inflammation affects this heterogeneity remains largely unknown. Here, we demonstrate that acute skin inflammation alters epidermal stem cell compartments through IL-1-mediated suppression of canonical Wnt signaling. Lineage tracing in inflamed mouse skin revealed that slow-cycling Dlx1+ epidermal stem cell clones persist, whereas fast-cycling Slc1a3+ clones decline through enhanced differentiation and lineage conversion, driving the reorganization of epidermal stem cell compartments. IL-1 signaling is both necessary and sufficient for this change: administration of IL-1 recapitulates these effects, while transgenic induction of the IL-1 decoy receptor preserves the balance of stem cell populations. IL-1 suppresses canonical Wnt activity in both the mouse epidermis and human keratinocytes, and Wnt ligand administration restores the fast-cycling compartment in vivo. Together, these results identify a reversible IL-1-Wnt axis that governs inflammation-induced stem cell plasticity and spatial tissue remodeling.

Patients with autoimmune bullous disease have their quality of life (QOL) affected by both the disease and its treatment burden. While QOL assessment is clinically important, it is often hindered by limited time in clinical practice, highlighting the need for accurate and efficient QOL evaluation tools. However, no validated QOL questionnaires are currently available in Japan. This study evaluated the validity and reliability of the Japanese versions of the Autoimmune Bullous Disease Quality of Life (ABQOL) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) questionnaires, as well as their practical application in clinical settings. The original questionnaires were forward and back‐translated into Japanese by certified translators according to established guidelines, then their validity and reliability were evaluated using data from 147 patients with autoimmune bullous diseases. Validity was evaluated via confirmatory and exploratory factor analyses, cross‐cultural validation, hypothesis testing, and convergent validity. Reliability was evaluated via test–retest and internal consistency. Although confirmatory factor analysis showed a weak fit and factor structures slightly differed from the original versions, internal consistency was cross‐culturally valid. Also, the Japanese version cohort showed lower mean scores and better QOL outcomes compared with other language versions for similar cohorts. Hypothesis testing revealed a significant positive correlation between ABQOL scores and subjective disease severity; TABQOL scores were significantly correlated with steroid dosage. The mucosal subscale of the ABQOL showed a significant difference based on mucosal lesion status. Bland–Altman plots confirmed approximate agreement between the two sets of measurements: Cronbach's alpha coefficients were 0.872 for ABQOL and 0.903 for TABQOL, verifying reliability. Finally, an expert panel reviewed and agreed on the target population, timing, methods for using the scales, and considerations for scale evaluation. The Japanese versions of the ABQOL and TABQOL are expected to be implemented in clinical practice as reliable and validated tools in Japan.