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Background Alopecia areata (AA) is considered a highly heritable, T-cell-mediated autoimmune disease of the hair follicle. However, no convincing susceptibility gene has yet been pinpointed in the major histocompatibility complex (MHC), a genome region known to be associated with AA as compared to other regions. Methods We engineered mice carrying AA risk allele identified by haplotype sequencing for the MHC region using allele-specific genome editing with the CRISPR/Cas9 system. Finally, we performed functional evaluations in the mice and AA patients with and without the risk allele. Findings We identified a variant (rs142986308, p.Arg587Trp) in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene as the only non-synonymous variant in the AA risk haplotype. Furthermore, mice engineered to carry the risk allele displayed a hair loss phenotype. Transcriptomics further identified CCHCR1 as a novel component interacting with hair cortex keratin in hair shafts. Both, these alopecic mice and AA patients with the risk allele displayed morphologically impaired hair and comparable differential expression of hair-related genes, including hair keratin and keratin-associated proteins (KRTAPs). Interpretation Our results implicate CCHCR1 with the risk allele in a previously unidentified subtype of AA based on aberrant keratinization in addition to autoimmune events. Funding This work was supported by JSPS KAKENHI (JP16K10177) and the NIHR UCLH Biomedical Research center (BRC84/CN/SB/5984).

Background: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. Objective: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) Methods: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0–30) and clinical ichthyosis score (range of 0–100). Results: Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8–71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearman’s correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P, ファイル公開：2019-11-01

Background: Epicutaneous sensitization to allergens is important in the pathogenesis of not only skin inflammation such as atopic dermatitis but also "atopic march" in allergic diseases such as asthma and food allergies. We here examined antibody production and skin barrier dysfunction in mice epicutaneously administered papain, a plant-derived occupational allergen belonging to the same family of cysteine proteases as mite major group 1 allergens. Methods: Papain and Staphylococcus aureus V8 protease were patched on the backs of hairless mice. Tran- sepidermal water loss was measured to evaluate the skin barrier dysfunction caused by the proteases. Papain or that treated with an irreversible inhibitor specific to cysteine proteases, E64, was painted onto the ear lobes of mice of an inbred strain C57BL/6. Serum total IgE levels and papain-specific IgE and IgG antibodies were measured by ELISA. Results: Papain and V8 protease patched on the backs of hairless mice caused skin barrier dysfunction and increased serum total IgE levels, and papain induced the production of papain-specific IgG1, IgG2a, and IgG2b. Papain painted onto the ear lobes of C57BL/6 mice induced papain-specific IgE, IgG1, IgG2c, and IgG2b, whereas papain treated with E64 did not. IgG1 was the most significantly induced papain-specific IgG subclass among those measured. Conclusions: We demonstrated that the epicutaneous administration of protease not only disrupted skin barrier function, but also induced IgE and IgG responses in a manner dependent on its protease activity. These results suggest that protease activity contained in environmental sources contributes to sensitization through an epicutaneous route.

The skin epidermis and mucosal epithelia (airway, ocular tissues, gut, and so on) are located at the interface between the body and environment and have critical roles in the response to various stimuli. Thymic stromal lymphopoietin (TSLP), a cytokine expressed mainly by epidermal keratinocytes (KCs) and mucosal epithelial cells, is a critical factor linking the innate response at barrier surfaces to Th2-skewed acquired immune response. TSLP is highly expressed in skin lesions of atopic dermatitis patients. Here, we describe on Toll-like receptor (TLR)-mediated induction of TSLP expression in primary cultured human KCs, placing emphasis on experimental methods used in our studies. Double-stranded RNA (TLR3 ligand), flagellin (TLR5 ligand), and diacylated lipopeptide (TLR2-TLR6 ligand) stimulated human KCs to express TSLP and Staphylococcus aureus membranes did so via the TLR2-TLR6 pathway. Atopic cytokine milieu upregulated the TLR-mediated induction of TSLP. Culturing in the absence of glucocorticoid before stimulation enhanced the TSLP expression. Extracellular double-stranded RNA induced TSLP via endosomal acidification- and NF-κB-dependent pathway. Specific measurement of the long TSLP transcript, which contributes to the production of the TSLP protein, rather than total or the short transcript is useful for accurate detection of functional human TSLP gene expression. The results suggest that environment-, infection-, and/or self-derived TLR ligands contribute to the initiation and/or amplification of Th2-type skin inflammation including atopic dermatitis and atopic march through the induction of TSLP expression in KCs and include information helpful for understanding the role of the gene-environment interaction relevant in allergic diseases.