峠岡 理沙

Ikaros, which is encoded by the Ikaros family zinc finger 1 (IKZF1) gene, is a zinc finger transcription factor. We have previously generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the IKZF1 isoform into epithelial cells expressing keratin 5, which develop patchy alopecia. However, there has been no detailed in vivo investigation of the function of IKZF1 in alopecia or of Ikaros expression in hair follicles of alopecia patients. Our aim was to investigate whether IKZF1 overexpression is involved in the pathogenesis of alopecia areata (AA) using Ikzf1 Tg and to examine Ikaros expression in human scalp skin. We grossly and histologically examined the alopecic lesions of Ikzf1 Tg and the skin of wild-type (WT) mice and the associated mRNA expression of inflammatory mediators. We also examined Ikaros' expression in human scalp skin. Grossly and histologically, we found that the Ikzf1 Tg developed AA-like lesions. Immunohistochemically, the hair follicles of the Ikzf1 Tg expressed high levels of the NKG2D ligand H60 and contained infiltrating CD8+NKG2D+ T cells. Interleukin 15, tumour necrosis factor-α, CXC chemokine ligand (Cxcl)1, Cxcl10, Cxcl11, signal transducer and activator of transcription (STAT)1, STAT3, Janus kinase (JAK)1 and JAK3 mRNA expression were significantly higher in the alopecic lesions of the Ikzf1 Tg than in the WT mice. Ikzf1 Tg given corticosteroid injections exhibited hair regrowth. Immunohistochemical analysis of scalp hair follicles showed that Ikaros was more highly expressed in AA patients than in non-AA controls. Our study suggests that IKZF1 and Ikaros are involved in the pathogenesis of AA.

Atopic dermatitis (AD) is a common skin disease. Although AD pathogenesis has been widely researched, inhibitory mechanisms in AD are still unclear. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors recognising sialic acids; most Siglecs work as inhibitory receptors. Among Siglecs, Siglec-E is expressed on dendritic cells (DCs) and eosinophils, important immune cells in AD. Although Siglec-E inhibits Type 1 inflammatory diseases, how it influences AD is unknown. Thus, we investigated the role of Siglec-E in AD mouse model by using Siglec-E knockout (KO) mice. We demonstrated that Siglec-E attenuated AD-like inflammation of mice caused by topical application of MC903 on ear skin (MC903-induced AD). To reveal the role of Siglec-E in MC903-induced AD, we focused on Siglec-E on DCs and eosinophils. We first showed that Sigle-E was expressed on cutaneous DCs and migratory DCs of draining lymph nodes. Moreover, OX40L expression on cutaneous DCs was reduced in the presence of Siglec-E. In vitro experiments using cultured spleen DCs (SpDCs), highly expressing Siglec-E, revealed that IL-33 was involved in the induction of Siglec-E and confirmed that Siglec-E inhibited OX40L expression on SpDCs induced by IL-33. Moreover, CD4+ T cell-SpDC coculture revealed that Siglec-E inhibited Th2 polarisation under IL-33 stimulation. We finally revealed that Siglec-E was expressed on eosinophils and reduced the eosinophils infiltration to the MC903-treated ear skin with the suppression of CD49d, a necessary integrin for eosinophil migration to skin tissue [1], expression on eosinophils. These findings elucidated the inhibitory role of Siglec-E in MC903-induced AD.

BACKGROUND: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti-IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. OBJECTIVE: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. METHODS: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. RESULTS: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. CONCLUSION: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation.