调节性B细胞在银屑病发病中的保护作用及机制研究

Psoriasis has high prevelence and is hard to treat, which has been a serious threat to the health of tens of millions of people around the world. The pathogenesis of psoriasis has been the focus of extensive research for years. Many experiments have showed that the pathological changes of psoriasis were induced by abberant activiation of Th1/Th17 under certain genetic and environmental background. Dysfunction of negative immune regulation mechanism play important roles in the pathogenesis of psoriasis, however, the exact role and mechanissm are not clear yet. Besides regulatory T cells, regulatory B cells (Breg) are newly identified regulatory cells in immune response, which play important roles in T cell-mediated autoimmune disease. Our preliminary experiments showed that the number of Breg in psoriasis patients was significantly lower than that of control, and the inhibitory effect on T cells was alleivated，indicating that Breg may participated in the pathogenisis pf psoriasis. However, the exact role and the mechanism are not clear. Based on our previous data, the current proposal plan to further the analysis on the number, function of Breg in psoriasis patient, and to explore the immune response of Breg to antigen and the mechanism of inhibitory effects. The psoriasis-SCID mice model will be applied to elucidate the role of Breg in the pathogenesis of psoriasis. The current proposal would uncover a new mechanism for the pathogenesis of psoriasis, and privide new strategy for the treatment of autoimmune disease such as psoriasis.

银屑病高发而难治，严重影响患者身心健康，其发病机制一直是皮肤病及相关学科研究的热点。诸多研究证实Th1/Th17异常活化介导了银屑病多种病理改变的形成；负向免疫调控功能障碍是导致T细胞异常活化的重要因素，然而其确切的细胞和分子机制尚未完全阐明。调节性B细胞(Breg)是继调节性T细胞之后倍受关注的负向免疫调节细胞，在多种T细胞介导的自身免疫性疾病中发挥重要的负向调节作用。本研究在前期工作中发现银屑病患者的Breg数显著降低、对T细胞应答的抑制作用减弱，提示Breg很可能参与银屑病发病，但其确切作用及其机制尚不明确。在此基础上本研究拟深入分析银屑病患者Breg的数量、功能情况，探索Breg对抗原的应答特点及发挥抑制效应的机制，进一步观察Breg对银屑病-SCID鼠模型的影响，阐明Breg在银屑病发病中的作用。本研究有望揭示银屑病发病的新机制，为银屑病等自身免疫性疾病的免疫治疗提供积极的思路。

银屑病高发而难治，严重影响患者身心健康，其发病机制一直是皮肤病及相关学科研究的热点。诸多研究证实Th1/Th17异常活化介导了银屑病多种病理改变的形成；负向免疫调控功能障碍是导致T细胞异常活化的重要因素，然而其确切的细胞和分子机制尚未完全阐明。调节性B细胞(Breg)是继调节性T细胞之后倍受关注的负向免疫调节细胞，在多种T细胞介导的自身免疫性疾病中发挥重要的负向调节作用，本项目对Breg在银屑病中的作用及机制进行了深入的研究。我们发现经PIB+CD40L+CpG、PIB+CD40L及PIB+CpG刺激5h后，银屑病患者外周血CD19+IL-10+B细胞比例明显低于正常对照，表明银屑病患者外周血B10细胞数量下降；相同刺激作用48小时后，银屑病患者外周血CD19+IL-10+B细胞比例高于正常对照，表明银屑病患者外周血B10前体细胞数量增高。对于Breg发挥作用的机制研究发现，银屑病患者PBMC中CD19+CD24hiCD38hiB细胞对T细胞分泌IFN-γ、TNF-α的抑制能力低于正常人。进一步应用天然抗体3B4转基因小鼠，发现3B4小鼠的脾和腹腔Breg数量增多，利用3B4小鼠制备咪喹模特银屑病模型，发现3B4小鼠的咪喹莫特炎症显著弱于对照小鼠，提示Breg在银屑病小鼠模型中发挥了抑制作用。我们还发现B细胞特异性敲除Notch信号通路的小鼠(CD19-cre-RBP-Jflox)的Breg细胞数量降低，利用这一小鼠制备了皮肤炎症模型，发现其炎症强度强于对照小鼠，提示Breg发挥了对炎症的抑制作用。综上，本项目揭示了Breg在银屑病患者的作用和初步的机制，为下一步有针对性地调节Breg的功能用于银屑病的治疗奠定了基础。