| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥2,300,000 (Direct Cost: ¥2,300,000)
|
|---|
| Research Abstract |
To produce antibodies, the differentiation of B cells into antibody-secreting cells, plasma cell, is required. We describe that a ligation of CD27, which belongs to the tumor necrosis factor receptor (TNFR) family and is memory marker of B cells, yield crucial signals that positively control the entry of B cells into the pathway to plasma cells. The triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). The differentiation into plasma cells by a combination of IL-10 and CD70-transfectants occurred in CD27+ B cells, but not in CD27-B cells. On the other hand, CD40 signaling increased the expansion of a B cell pool from peripheral blood B cells primarily activated by IL-2, IL-10 and anti-CD40 mAb. These data demonstrate that CD27 ligand (CD70) is a key molecule to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.
The induction
… More
of immunoglobulin E (IgE) switching in B cells requires several signals given by cytokines and cell contact-delivered signals. Here, we investigated the role in CD27/CD70 interaction in B cell IgE synthesis. The addition of CD27 ligand (CD70) transfectants increased IgE synthesis synergistically in the presence of IL-4 plus anti-CD40 mAb (anti-CD40). The effect of CD70 transfectants was in a dose dependent manner and which was completely blocked by anti-CD70 mAb. CD27/CD70 interaction enhanced the B cell proliferation in the presence of IL-4 or IL-4 plus anti-CD40. The augmentation of proliferation by CD70 transfectants was obtained in CD27+ B cells, but mild in CD27- B cells. The IgE helper activity by CD27/CD70 interaction could not be attributed to the enhancement of germline e transcripts. Flow cytometric and morphological analyses demonstrated that the addition of CD70 transfecta Taken together, our findings indicate that signaling via CD27 on B cells induces IgE synthesis in cooperation with IL-4 and CD40 signaling by promoting the generation of plasma cells through up-regulation of PRDI-BF1.
In the patients with X-linked hyper-IgM syndrome (XHIM), costimulation of mononuclear cells from most of the patients induced no to low levels of class switching from IgM to IgG and IgA with Staphylococcus aureus Cowan strain (SAC) plus IL-2 or anti-CD40 mAb (anti-CD40) plus IL-10. Measurable levels of IgE were secreted in some of the patients after stimulation with anti-CD40 plus IL-4. Costimulation with SAC plus IL-2 plus anti-CD40 plus IL-10 yielded secretion of significant levels of IgG in addition to IgM, but not IgA. The most striking finding was that peripheral blood B cells from all of the six patients were composed of only IgD+ CD27- and IgD+ CD27+ B cells; IgD- CD27+ memory B cells were greatly decrease. IgD+ CD27+ B cells from an XHIM patient produced IgM predominantly. Our data indicate that the low response of IgG production in XHIM patients is due to reduced numbers of IgD- CD27+ memory B cells. However, the IgG production can be induced by stimulation of immunoglobulin receptors and CD40 in cooperation with such cytokines as IL-2 and IL-10 in vitro. Less
|
