Dynamism of B cell development

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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.