Mechanism s regulating the gene rearrangements in immune system

获得性免疫中最独特的特征是编码抗原受体的基因通过DNA重组而在具有免疫活性的淋巴细胞中获得和扩大其功能。此外，这些重排决定了淋巴细胞的分化阶段。抗原受体基因是通过可变区的重排来完成的，这使得受体能够与抗原特异性结合。通过这种方式，每个单独的淋巴细胞可以识别一种特定的抗原，因此整个免疫系统可以识别各种各样的抗原。此外，抗体还充当消除或中和抗原的效应器。为了根据抗原入侵的途径扩大抗体的效应功能，在B淋巴细胞激活过程中，抗体重链的恒定区基因也会发生重排(类开关重组，CSR)。本研究试图通过分析重排过程中涉及的转录因子来阐明控制重排本身和靶基因特异性的分子机制。我们发现，转录因子Pax5、E2a、SIP、NFKb、IRF4和RUNX1-3参与了靶基因选择和AID基因表达的特异性调控，而AID基因是CSR所必需的。这些因素与Id2一起形成了Tfg-β信号下游的表观遗传调控电路。我们还发现，这些因子的表达受到二级和三级淋巴组织动态重组和新生形成的微环境的影响，在某些情况下，这些因子表现出多余的功能，而在另一些情况下，它们表现出相反的功能。这种机制增加了调控的复杂性。此外，利用多种刺激的组合，我们建立了一种在体外诱导针对IgA的CSR的有效方法，这一方法到目前为止一直是非常困难的。

The most unque character in acquired immunity is that genes encoding receptors for antigen undergo rearrangements by DNA recombination to acquire and expand their function in the immune-competent lymphocytes. Furthermore these rearrangements determine the differentiation stage of the lymphocyte. The antigen receptor genes are completed by the rearrangements of variable regions, and this enables the receptors to bind specifically to the antigen. by this, each individual lymphocyte can recognize a specific antigen and thus immune system as whole can recognize a wide variety of antigens. In addition, antibodies act as effecter to eliminate or neutralize antigens. To expand such effecter function of antibody according to the route through which the antigens invade, the constant region genes of its heavy chain also rearrange during activation of B lymphocyte (class switch recombination, CSR).In this study, we tried to elucidate the molecular mechanisms controlling the rearrangements per se and target gene specificity by analyzing transcription factors involved in the rearrangement process. We found that the transcription factors, Pax5, E2A, SIP, NF_KB, IRF4, and Runx1-3 are involved and important in the specific regulation of target gene selection and expression of AID gene that is essential for CSR. These factors together with Id2 form epigenetic regulatory circuits downstream to TFG-β signal. We also found that expression of these factors is affected by the micro-environment formed by a dynamic reorganization and neogenesis of the secondary and tertiary lymphoid tissues, and in some case these factors showed a redundant function but in other case they Showed opposite function. Such mechanism increases the complexity of the regulation.In addition, using a combination of stimuli we established an efficient method to induce CSR specifically to IgA in vitro that has been very difficult up to now.