产生IL-10的调节性B细胞在HIV感染免疫发病机制中的作用

AIDS，which is a serious threat to the health of people and social stability and progress. The pathogenesis of it has been focus on the immunologic mechanism. Immunological impairment is the main characteristic of HIV pathogenesis. With the progressive loss of CD4+ T cells in HIV infection, the dysfunction in the T cell, and dysfunction of immune regulation. Dysfunction of negative immune regulation mechanism play an important roles in the pathogenesis of infectious diseases, however, the exact role and mechanism are not clear yet. Besides regulatory T cells, regulatory B cells (Breg) are newly identified regulatory cells in immune response, which play an important role in T cell-mediated autoimmune disease. Our preliminary study showed that the number of IL-10 and Treg in peripheral blood in HIV-1 infected patients was increase than that of health control, and the ratio of Th1 and Th2 cytokine concentration in HIV-1 infection was higher than that of healthy control too. Breg frequency is correlated with the level of IL-10, imbalance of Th1/Th2 and Th17/Treg. That indicate Breg may participate in the immunological pathogenesis of HIV infection. Based on our previous data, we plan to go further the analysis on the number, function of Breg，and level of IL-10, TGF-βand other cytokine expression levels in HIV-1 infected patients which with different CD4+ T cells count or before and after HAART treatment, and to explore the immune response of Breg to antigen and the mechanism of inhibitory effects. Study the relationship of Breg and HIV-1 infectious progression and the function of Breg in pathogenesis of the immunologic mechanism of HIV-1 infection. The current proposal would uncover a new mechanism for the pathogenesis of HIV infections, and provide new strategy for the treatment of HIV infections.

艾滋病严重威胁人类健康与社会稳定，其免疫发病机制一直是近年研究的热点，而负性免疫调控在疾病发病机制中的作用逐渐受到重视，Breg是Treg之后倍受关注的负性免疫调节细胞。本研究组前期研究发现HIV-1感染后患者外周血IL-10、Treg水平均升高，存在明显的Th1/Th2失衡。而Breg与IL-10、Th1/Th2平衡、Th17/ Treg平衡均密切相关，由此我们推测Breg细胞在HIV感染的T细胞功能紊乱发病机制中可能起到调节作用。在此基础上本研究拟深入分析不同CD4+ T细胞水平以及HIV 抗病毒治疗前后的HIV-1感染患者外周血Breg的数量、功能，IL-10等细胞因子水平，探索Breg对抗原的应答特点及发挥抑制效应的机制，研究Breg与HIV感染疾病进程的关系，以及在HIV感染者免疫调节网络中的作用，以期进一步阐明HIV感染发病的免疫调节机制，为探索新的预防与治疗途径提供理论依据。

艾滋病是由HIV感染引起的一种严重威胁人类健康、社会稳定和经济发展的传染病。 Bregs作为负性调控因子在感染性疾病发病机制中倍受关注。本研究组的前期研究发现感染 HIV -1 后外周血 中IL-10 水平、Treg数目均显著升高，存在明显的 Th1/Th2 失衡。Bregs与 IL-10水平、Th1/Th2 平衡、Th17/Treg平衡均密切相关，由此我们推测Bregs在 HIV感染中对T细胞功能紊乱可能起到免疫调控作用。本课题检测分析了30例未治疗的HIV-1感染者外周血CD1dhiCD5+CD19+B、CD19+CD24hiCD38hiB细胞及其相关细胞因子IL-10的表达水平，并分析了其与患者 CD4+T 细胞数量和HIV病毒载量的关系，以及 ART治疗前后患者外周血Bregs细胞和IL-10表达水平，结果显示HIV-1感染者CD1dhiCD5+CD19+B、CD19+CD24hiCD38hiB细胞数目显著上升，IL-10分泌增高，Bregs水平与CD4+T细胞数量、CD4/CD8比例均呈负相关性，而与HIV病毒载量呈正相关性，提示Bregs细胞比例在HIV感染免疫调控网络中可能发挥重要作用；实施ART治疗12周后患者外周血Bregs比例和IL-10水平较前显著降低，CD4+T细胞数量显著上升，HIV病毒载量已被明显抑制，提示Bregs细胞水平与HIV感染者疾病进展和机体免疫情况密切相关， 且ART治疗可能通过有效抑制病毒和调节Bregs和IL-10水平来改善机体免疫应答功能。进一步检测发现HIV-1感染者PBMC培养液上清中的IL-10的表达水平显著高于健康对照组，且其与CD1dhiCD5+CD19+B细胞水平呈正相关性，同时，CD19+CD24hiCD38hiB细胞与其血浆中IL-10表达水平呈正相关性，提示Bregs可能通过分泌IL-10参与HIV感染者免疫调节。综上所述，本研究表明Bregs细胞与HIV-1感染者疾病进程和机体免疫状态密切相关，且HIV-1感染者外周血中的Bregs水平及其相关细胞因子IL-10的表达水平升高可能是HIV免疫发病机制之一。因此，亟待深入研究Bregs细胞亚群比例、功能变化及其免疫调节机制，为发现更有效的预防与治疗途径提供新策略和理论依据。