A role of CD27/CD70 in immune response: analysis of immunodeficiency

为了产生抗体，需要将B细胞分化为抗体分泌细胞，即浆细胞。我们描述了属于肿瘤坏死因子受体（TNFR）家族并且是B细胞的记忆标志物的CD 27的连接产生积极控制B细胞进入浆细胞通路的关键信号。在白细胞介素-10（IL-10）存在下，纯化的外周血B细胞上的CD 27配体（CD 70）通过CD 27的触发导致浆细胞数量增加。IL-10和CD 70-转染子的组合在CD 27 + B细胞中发生向浆细胞的分化，但在CD 27-B细胞中不发生。另一方面，CD40信号传导增加了来自主要由IL-2、IL-10和抗CD40 mAb激活的外周血B细胞的B细胞池的扩增。这些数据表明，CD 27配体（CD 70）是与IL-10协同指导CD 27+记忆B细胞向浆细胞分化的关键分子。 ...更多信息 免疫球蛋白E（IgE）在B细胞中的转换需要由细胞因子和细胞接触传递信号给出的几个信号。在此，我们研究了CD 27/CD 70相互作用在B细胞IgE合成中的作用。加入CD27配体（CD70）转染子在IL-4+抗CD40 mAb（抗CD40）存在下协同增加IgE合成。CD70转染子的作用呈剂量依赖性，并可被抗CD70 mAb完全阻断。在IL-4或IL-4+抗-CD 40存在下，CD 27/CD 70相互作用增强B细胞增殖。CD 70转染子对CD 27 + B细胞的增殖有促进作用，而对CD 27-B细胞的增殖作用较弱。通过CD27/CD70相互作用的IgE辅助活性不能归因于生殖系e转录物的增强。流式细胞术和形态学分析表明，加入CD 70转染物，我们的研究结果表明，通过B细胞上的CD 27信号转导与IL-4和CD 40信号转导协同诱导IgE合成，通过上调PRDI-BF 1促进浆细胞的产生。在X连锁高IgM综合征（XHIM）患者中，用金黄色葡萄球菌科万菌株（SAC）加IL-2或抗-CD 40 mAb（抗-CD 40）加IL-10共刺激来自大多数患者的单核细胞诱导无至低水平的从IgM到IgG和IgA的类别转换。在用抗CD40加IL-4刺激后，一些患者分泌了可测量水平的IgE。用SAC加IL-2加抗CD40加IL-10共刺激产生除了IgM之外的显著水平的IgG分泌，但不产生IgA。6例患者外周血B细胞均为IgD + CD 27-和IgD + CD 27 + B细胞，IgD-CD 27+记忆B细胞明显减少。来自XHIM患者的IgD + CD 27 + B细胞主要产生IgM。我们的数据表明，XHIM患者中IgG产生的低应答是由于IgD-CD 27+记忆B细胞数量减少。然而，IgG的产生可以通过刺激免疫球蛋白受体和CD 40与细胞因子如IL-2和IL-10在体外协同诱导。少

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