Analysis of the molecular machaism of defective T cell functions in reqularing B cell activation in various autoimmune diseases

虽然人类T细胞已被证明通过直接抑制B细胞来调节体液免疫反应，但抑制机制的确切后遗症尚未被描述。因此，本研究考察了T细胞-B细胞协同抑制B细胞反应的性质。特别关注Fas (CD95)-Fas配体（FasL）相互作用和CD40-CD40配体（CD40L）相互作用的作用。结果表明，通过CD40- cd40l直接相互作用获得的信号对体液免疫应答的结果产生双向影响，这取决于B细胞的激活状态和CD40连接的程度。此外，这些数据表明，CD40-CD40L相互作用而不是Fas-FasL相互作用可能在B细胞和抗cd3刺激的CD4+ T细胞之间的直接细胞协作中发挥更关键的作用，以防止不当活化的B细胞反应的延伸。IL-12是Th1反应的主要诱导剂。CD40L在调节免疫应答中发挥重要作用，包括T细胞依赖的B细胞激活和单核细胞和树突状细胞的细胞因子产生。接下来，我们研究了IL-12对活化的人CD4+ T细胞中CD40L表达的影响。结果表明，IL- 12可增强活化CD4+ T细胞的CD40L表达，而不依赖于IFN-γ的产生。提示IL-12诱导的Th1应答可能通过上调CD40L表达，在调节体液免疫应答中发挥重要作用。米佐比滨已被证明对类风湿关节炎和狼疮性肾炎有有益的治疗作用，这两种疾病都涉及到异常的B细胞功能。先前的研究表明，米佐利滨直接抑制人类B细胞的功能。我们在分子水平上详细探讨了米佐利滨抑制人B细胞反应的机制。结果表明，米佐利滨通过下调细胞周期蛋白A mRNA的稳定性来抑制细胞周期蛋白A mRNA在人B细胞中的表达，从而下调B细胞的应答。少

Although human T cells have been shown to regulate humoral immune responses by directly inhibiting B cells, the precise sequelae for the mechanism of suppression have not yet been delineated. The present study therefore examined the nature of T cell-B cell collaboration to suppress B cell responses. Special attention was directed to the role of Fas (CD95)-Fas ligand (FasL) interactions and CD40-CD40 ligand (CD40L) interactions. The results indicate that signals achieved by direct interactions through CD40-CD40L exert bidirectional effects on the outcome of humoral immune responses depending on the state of activation of B cells and on the extent of CD40 ligation. Moreover, the data suggest that CD40-CD40L interactions rather than Fas-FasL interactions may play more critical roles in direct cellular collaboration between B cells and anti-CD3 stimulated CD4+ T cells to prevent the extention of responses of inappmpriately activated B cells.IL-12 is the prominent inducer of Th1 responses i … More n human and in the mouse. CD40L plays important roles in regulation of immune responses, including T cell-dependent activation of B cells and cytokine production by monocytes and dendritic cells. We next examined the influences of IL-12 on the CD40L expression a activated human CD4+ T cells. The results indicate that IL- 12 enhances the CD40L expression of activated CD4+ T cells independently of the IFN-γ production. The data thus suggest that Th1 responses induced by IL-12 might play an important role in regulation of humoral immune responses through up-regulated CD40L expression.Mizoribine has been shown to have beneficial effects in the treatment of rheumatoid arthritis and lupus nephritis, in which abnormal B cell functions are involved. Previous studies demonstrated that mizoribine directly suppresses the function of human B cells. We explored in detail the mechanism of the suppression of human B cell responses by mizoribine at the molecular level. The results indicate that mizoribine suppresses the expression of cyclin A mRNA in human B cells by downregulating its stability, and thus downregulates their responses. Less