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

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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