Blimp-1: a master regulator of B-lymphocyte terminal differentiation?

B淋巴细胞是免疫系统中产生抗体的细胞。它们在骨髓中形成，然后输出到体内循环，寻找感染的迹象。这些循环细胞还没有完全成熟，但当它们遇到入侵者时，在其他免疫细胞的帮助下，它们就会发生变化。大多数会变成产生抗体的细胞，即B细胞谱系中最后的可操作细胞。一些细胞被留作记忆细胞，一旦同样的感染再次发生，它们可以迅速变成产生抗体的细胞。这是疫苗接种的基础。B淋巴细胞的主要功能是将抗体分泌到血清中（可以结合并消除体内任何部位的入侵者）。该项目将研究允许B细胞变成抗体分泌细胞（称为ASC）的基因。我们将重点研究Blimp-1基因，这是一种B淋巴细胞诱导的成熟蛋白，被称为ASC形成的主要调节因子。这种说法在很大程度上是基于间接证据，并没有经过直接的基因测试。我们已经制造了一只老鼠，其中的Blimp-1基因已经被改变，因此我们可以通过精心控制的方式使其失效。利用这种敲除小鼠，我们可以直接测试ASC和其他细胞类型对Blimp-1的需求。我们将研究这些动物，使用许多可以精确测量分离细胞行为或动物免疫反应的测试。我们将检查其他被认为是ASC形成或发挥作用所必需的基因，看看Blimp-1（一种已知的基因沉默者）的缺失是否影响了这些其他基因。通过这种方式，我们期望确定驱动B细胞成为成熟ASC的遗传程序。利用这些知识，我们希望最终能够研究人类的ASC疾病（如过敏、哮喘、类风湿关节炎和白血病）。这些信息也可用于改善疫苗接种的结果。

B lymphocytes are the antibody-producing cells of the immune system. They are formed in the bone marrow, and are exported to the body to circulate, searching for signs of infection. These circulating cells are not fully mature, but when they encounter an invader, with the help of other immune cells, they change. Most become antibody-producing cells, the final, operational cells of the B cell lineage. A few cells are set aside as memory cells that can rapidly become antibody-producing cells should the same infection occur again. This is the basis of vaccination. The secretion of antibodies into the serum (that can bind to and eliminate an invader anywhere in the body) is the main function of B lymphocytes. This project will study the genes that allow B cells to become antibody-secreting cells (called ASC). We will focus on the gene for Blimp-1, the B lymphocyte-induced maturation protein, which has been called the master regulator of ASC formation. This claim is based largely on circumstantial evidence, and has not been directly tested genetically. We have made a mouse in which the Blimp-1 gene has been altered so that we can disable it in carefully controlled way. Using this knockout mouse, we can directly test the requirement for Blimp-1 in ASC and in other cell types. We will study these animals, using many tests that can accurately measure the behaviour of isolated cells, or the immune responses of the animals. We will examine other genes that are thought to be required for ASC to form or to perform their work, to see if loss of Blimp-1 (a known gene silencer) has impacted on these other genes. In this way, we expect to identify the genetic program that drives a B cell to become a mature ASC. Using this knowledge, we hope eventually to be able to study diseases of ASC in humans (as occur in allergy, asthma, rheumatoid arthritis and leukaemia). This information may also be used to improve the outcome of vaccination.