生命早期分别经皮肤与消化道接触尘螨抗原引起皮肤屏障功能破坏小鼠皮肤与肠道调节性T细胞表达的差异及其机制

Dust mites are the most important allergens in atopic dermatitis (AD). Intestinal tract is the first place for Treg cells to combat exogenous antigen in early life. Langerhans cells (LCs) can activate regulatory T cells (Treg) and induce immune tolerance. We found that the expression of anti-inflammatory factor IFN-γ in early childhood of AD family is lower than that in the middle and elder age. In addition, we also identified that Treg cells could be up-regulated to ameliorate AD lesion via Smad3/TGF-β signaling pathway. Other scholars have already found that dust mites can induce inflammatory response via impaired skin barrier. Can the early sensitization of dust mites via digestive tract activate Treg cells to induce immune tolerance? What is its regulatory effect on the immune response caused by the subsequent dust mite sensitization via skin? Can it interfere with the development of the allergy march? ①We intend to explore the regulatory effects of sensitization via digestive tract on the severity of lesions of mice; ②We attempt to explore the expression of LCs and Treg cells detected in oral cavity and intestinal mucosa, skin and lymph nodes. In addition, we aim to explore whether the regulation above is correlated with Smad3/TGF-β signaling pathway; ③We also aim to identify the effect of early sensitization via digestive tract on airway hyperresponsiveness and provide a reference for the prevention of allergy march.

尘螨是特应性皮炎（AD）最重要的致敏原。生命早期肠道是调节性T细胞（Treg）对抗外源性抗原的首要场所，而朗格汉斯细胞（LCs）可激活Treg细胞，造成免疫耐受。本课题组发现AD家系中幼儿期抑制炎症的IFN-γ表达水平较中老年期低；通过活化Smad3/TGF-β途径上调Treg细胞表达可改善AD症状。已知尘螨可通过受损的皮肤屏障诱发过敏反应。那么生命早期经消化道接触尘螨可否激活肠道Treg细胞诱发免疫耐受及干预过敏进程发展？本研究拟在小鼠模型体内①探究预先消化道接触尘螨抗原对小鼠皮损严重程度的影响；②检测各组小鼠口腔及肠道黏膜、皮肤、淋巴结中LCs和Treg细胞的表达；探索以上调控作用是否与Smad3/TGF-β途径相关；③明确早期消化道接触尘螨抗原对后期气道高反应性的影响，为过敏进程预防提供依据。

本项目明确生命早期口服尘螨能有效预防AD，15-21日龄是口服尘螨预防AD的最佳时间窗，小肠粘膜固有层失能T细胞在其中发挥重要作用。另外，尘螨口服组小鼠可能通过高表达Msi1介导关键炎症因子的翻译抑制，通过IL-17a——S100a8/9——焦亡通路从而减轻AD。另外，项目组研究明确利多卡因抑制感觉神经元活性依赖的降钙素基因相关肽释放从而发挥抗炎和抗瘙痒作用；建立中国婴儿AD诊断标准，发表于国际皮肤病学权威期刊；探索中国早发型AD在12岁时持续发作的危险因素分析等。鉴于项目组长期致力于AD的基础与临床研究，项目负责人以第一完成人获得2020年华夏医学科技奖一等奖。本项目共计发表标注本项目的SCI论文4篇。举办全国性学术会议2次，参加国内学术交流10次以上。培养已毕业博士研究生2名，已毕业硕士研究生4名。