小宮根 真弓

Ceramide deficiency in the stratum corneum (SC) is a key etiological factor in atopic dermatitis (AD). To clarify the direct role of SC ceramide depletion in impairing SC barrier and water-holding functions and in initiating AD-like skin symptoms and disease-specific molecular alterations, we generated Tg mice overexpressing a mutant form of acid ceramidase (aCDase) under the control of the involucrin promoter, resulting in targeted expression in the upper epidermis. By 3 weeks of age, Tg mice developed noninflammatory, scaly skin characterized by severely compromised barrier integrity and water-holding capacity, along with significantly elevated epidermal aCDase activity and markedly reduced ceramide levels in the SC. Compared to WT controls, Tg mice also exhibited increased epidermal innervation and reduced intraepidermal semaphorin 3a protein levels. Additionally, Tg skin showed substantial changes in the expression of AD-associated biomarkers involved in barrier impairment, pruritus, and Th2 polarization. These included increased levels of Il10, Il17a, S100a7, S100a8, and S100a9 and decreased levels of Cxcl10, Ifng, Il2, Il13, Il33, Sema3a, and Tlr9. Repeated topical application of mite antigens induced allergic responses in Tg mice, but not in WT mice. These responses were characterized by prominent eosinophil infiltration in the dermis and significantly elevated serum IgE levels. Allergen-challenged ear skin from Tg mice also demonstrated significantly increased expression of inflammatory mediators related to AD, including Ccl17, Ccl22, Ccl26, Ccl27, Il3, Il13, Il22, and Il33. These findings establish Tg mice as a pathophysiologically relevant model of AD, presenting key features such as xerotic, pruritic skin, impaired barrier and water-retention functions, and Th2-dominant allergic inflammation. This model provides important insights into ceramide-dependent mechanisms in AD pathogenesis and offers a useful platform for therapeutic development. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Generalized pustular psoriasis (GPP) is a heterogeneous, systemic neutrophilic inflammatory disease, characterized by chronic symptoms and recurrent flares, which can be potentially life-threatening. Spesolimab, an interleukin-36 receptor antagonist, has been approved to treat GPP flares in many countries including Japan. An expanded access program (EAP) in Japan provided early access to spesolimab for patients aged 18-75 years unable to participate in a clinical trial with no other treatment options. Patients received a single dose of 900 mg intravenous spesolimab for flare treatment, with an optional second dose after 1 week if symptoms persisted. Safety was monitored for 16 weeks post-treatment. Eleven patients (54.5% female; 51 years mean age; 26.7 kg/m2 mean body mass index) received 23 doses of intravenous spesolimab. Nine patients (81.8%) were diagnosed with GPP for > 5 years. Ten patients (90.9%) had ≥ 1 baseline medical condition. All patients used ≥ 1 concomitant medication prior to or during the spesolimab treatment period, most commonly immunosuppressants and non-steroidal anti-inflammatory agents. Seven patients (63.6%) experienced treatment-emergent adverse events, all of mild or moderate intensity, including skin and subcutaneous tissue disorders, general disorders and administration site conditions. No adverse event led to treatment discontinuation or death. A potential hypersensitivity event (face edema) resolved without intervention and was not considered treatment related. Spesolimab was well tolerated in a heterogeneous patient population with GPP, including those with comorbidities and concomitant medication use. The safety profile of spesolimab aligned with the EFFISAYIL 1 clinical trial results.

A chimeric protein of heparanase and Ig-Fc was designed as a novel tool to expand the detection of structurally heterogeneous heparan sulfate (HS) and related glycosaminoglycans. The whole mouse heparanase gene was combined with the gene segment encoding the mouse IgG1 hinge-Fc domain. A point mutation E335A was inserted to disable putative HS degradation activity. Chimeric proteins consisted of the latent form of the enzyme devoid of HS degradation activity. The chimeric proteins bound to heparin, N-desulfated heparin, and O-sulfated N-acetylheparosan. Their binding spectrum to glycosaminoglycans differed from that of anti-HS mAb 10E4. The chimeric proteins bound to Kato III and A549 cell lines. The binding was reduced by knocking down EXT1 gene expression. One of the chimeric proteins stained the epidermal cells in the hyperplastic spinous layer of inflamed atopic dermatitis skin and inflammatory cells in the dermis, which were not stained with mAb 10E4. The protein stained a polarized structure on the surface of monocytic U937 and THP1 cells. Similar polarized structures were observed with anti-syndecan-1 antibody staining. The chimeric protein and anti-syndecan-1 antibody precipitated similar sets of proteins that included syndecan-1 from the lysates of U937 cells. These novel chimeric proteins are useful to detect HS abundant in O-sulfation in histochemical, cytochemical, and biochemical studies.

We present an updated analysis of albinism in Japan, encompassing both oculocutaneous albinism (OCA) and ocular albinism (OA), based on 290 families, which expands our previous study by 100 additional families. The overall frequency distribution of major subtypes remained consistent with our previous findings: OCA4 remains the most prevalent subtype (67 patients, 23.1%), followed by OCA1 (57 patients, 19.7%), Hermansky-Pudlak syndrome (HPS) 1 (35 patients, 12.1%), and OCA2 (30 patients, 10.3%). Notably, our expanded analysis identified patients with rare subtypes, including OCA3, OCA6, HPS2, HPS3, HPS5, and HPS6, as well as OA, further demonstrating the genetic diversity of albinism in the Japanese population. Through comprehensive genetic screening of the additional 100 families, we identified 17 patients harboring previously unreported pathological variants across multiple albinism subtypes. These findings expand the variant spectrum of albinism in Japan, provide valuable insights for genetic counseling, and underscore the critical importance of comprehensive clinical evaluation and long-term multidisciplinary follow-up for patients with albinism, particularly those with HPS subtypes.