痤疮丙酸杆菌通过激活TLR2和TLR4强化天然免疫缓解特性应皮炎的机制研究

Atopic dermatitis (AD) is a chronic refractory inflammatory dermatosis with high incidence. AD often present with inhibition of innate immunity, imbalance of Th1/Th2 immunity, especially activation of Th2 immunity. Our group has found the deficiency of skin microbiota in Han AD patients, the abundance ratio of staphylococcus augment. Resently, quiet a mount of studies proved that the S. aureus take part in the pathogenesis of AD and relate to disease severity. On the other side, abundance ratio of propionibacterium ances (P. acnes) decrease in AD lesions. As vaccination of P. acnes improves AD mouse model, but the pathogenesis remained unknown. As the P. acnes is a Th1-response antigen, promotor of innate immunity by TLR2 and TLR4, activator of AMPs secretion by keratinocyte. This study aims to: 1. Find the purification of P. acnes, observe its influence of normal human keratinocytes and inhibition to staphylococcus aureus toxin; 2. Elaborate the mechanism of P. acnes enhancing innate immunity by up-regulating TLR2 and TLR4 and MyD88-NFκB expression, enhancing secretion of AMPs; 3. The purified P. acnes improves AD mouse model, the clinic manifestation, skin histopathology, regulation of innate immunity deficiency and Th1/Th2 imbalance, and finally discovery of a new AD treatment.

特异型性皮炎（AD）是最常见的慢性复发性炎症性皮肤病。它的免疫学异常主要表现为固有免疫抑制，Th1/Th2型免疫失衡，尤其是Th2免疫亢进。本课题组前期研究发现汉族AD患者的皮损处葡萄球菌属相对丰度上升，且金葡菌参与AD发病，与疾病严重度相关。而AD患者皮损处痤疮丙酸杆菌（P. acnes）丰度下降，有报道称P.ances能够缓解AD鼠皮损，确切机制不明。P.acnes又可激活TLR2和TLR4刺激固有免疫，刺激角质形成细胞分泌抗菌肽，诱导Th1免疫应答。本研究旨在：1、提取P.acnes纯化物，观察其对正常人上皮细胞生长的影响及对金黄色葡萄球菌毒素的抑制作用；2、解释P acnes通过TLR2和TLR4激活MyD88-NFκB通路，促进抗菌肽分泌，强化固有免疫机制；3、证实P.acnes纯化物对AD鼠疾病表型的缓解，探讨其中免疫机制。

特应性皮炎（AD）是最常见的慢性复发性炎症性皮肤病，同时伴有特应性共病，如哮喘、过敏性鼻炎。本课题组前期研究发现汉族AD患者的皮损处痤疮丙酸杆菌（C. acnes）丰度下降，国际报道发现AD患者外用玫瑰单胞菌活菌能够缓解皮损。本研究构建小鼠AD模型，制备痤疮丙酸杆菌和玫瑰单胞菌的菌体裂解物，证明它们对于MC903造模的AD小鼠的皮肤屏障有保护作用，通过下调TLR表达，抑制Th2和Th1型免疫反应，抑制皮损炎症。进一步，发现富含亚油酸-神经酰胺的保湿剂不仅对于AD鼠模型的皮肤炎症具有保护作用，还通过下调Th2型免疫反应和IgE水平，减少嗜碱性粒细胞mRNA表达，达到抑制肺部炎症的作用。证实“细菌裂解物/亚油酸-神经酰胺修护皮肤屏障-抑制皮肤炎症-改善皮损-抑制系统炎症-改善系统炎症-阻断特应性进程”这一理论，为AD外用治疗提供新方法和新的理论依据。