Dynamism of B cell development

到目前为止，所有已确定的基因都是编码Preb细胞受体的组成部分或参与Preb细胞受体信号转导的分子的，哪些突变会导致B细胞缺失的原发免疫缺陷。这清楚地表明，Preb细胞受体在B细胞发育中起着关键作用。然而，Preb细胞受体如何调控骨髓中早期B细胞的发育仍有待确定。在这项研究中，我们使用我们的原始系统来分析B细胞的早期发育，并检测了Preb细胞受体在B细胞前体细胞中的表达模式，Preb细胞受体的信号通路以及通过Preb细胞受体的p11链的质量检查。用高灵敏的免疫荧光清楚地表明，Preb细胞受体的表面表达局限于人和小鼠发育的B细胞的大Preb细胞期。这最终解决了关于Preb细胞受体表达的困惑。鉴定出两条不同的Preb细胞受体信号通路。一种依赖于Src家族的激酶，另一种依赖于Syk。仅在前一途径中可观察到NF-κ-3的激活。命名为TPP36和TPP32的新分子在Preb细胞中被Abl鉴定为酪氨酸磷酸化。为了阐明B细胞发育早期H链选择的机制，我们建立了有Preb细胞受体的Preb细胞和没有Preb细胞受体的Preb细胞的体内实验系统，发现在Preb细胞阶段，多达三分之二的H链Pro(Preb细胞阶段的LuCED是INCAL)能够与代理L链结合形成Preb细胞受体。我们最近的数据表明，μH链质量检查的故障会导致免疫缺陷和自身免疫性疾病。

All the genes so far identified till now, which mutations cause B cell-less primary immunodeficiency encode components of preB cell receptor or molecules involved in preB cell receptor signaling. This clearly indicates that preB cell receptor plays a pivotal role in B cell development. However, it remains to be determined how preB cell receptor regulates early B cell development in bone marrow. In this study, we employed our original system to analyze early B cell development and examined the expression pattern of preB cell receptor in B cell precursors, the signaling pathways of preB cell receptor and the quality check of p11 chain through preB cell receptor. It was clearly demonstrated by using highly sensitive immunofluorescence that the surface expression of preB cell receptor was confined to the large preB cell stage of B cell (levelopment m both humans and mice. This finally settled the confusion regarding the preB cell receptor expression. Two distinct pathways of preB cell receptor signahng were identified. One is dependent on Src family kinases, and the other is dependent on Syk. Activation of NFκ3 was observed only in the former pathway. Novel molecules designated TPP36 and TPP32 were identified as tyrosine-phosphorylated by Abl in preB cells. In order to clarify the mechanism of H chain selection at the early stage of B cell development, we have established a novel system to dlstlngnLsh preB cells with preB cell receptor and those without preB cell receptor ih vivo and found that as much as two-thirds of H chains pro(luced at the preB cell stage are incal)able of associating with surrogate L chain to form preB cell receptor. Our recent data suggest that the malfunction of μH chain quality check results in immunodeficiency and autoimmune diseases.