EAF2在清除自身反应性生发中心B细胞中的作用和机制

High-affinity antibodies (Abs) are the most important effector molecules for host defense against bacterial and virial infections. High-affinity Abs are generated during the germinal center (GC) reaction where B cells undergo enormous expansion, accompanied by Ig gene somatic hypermutation (SHM) and class switch recombination. SHM alters the Ab specificity of GCB and those with high affinity for the foreign antigen are selected to differentiate into antibody-secreting plasma cells or memory B cells. SHM also generates low affinity and auto-reactive GCB cells, the later must be eliminated by apoptosis to avoid the production of autoantibodies and the development of autoimmune diseases. We have recently found that the transcription elongation-associated factor EAF2 is highly expressed in GCB and specifically induces their apoptosis. Absence of EAF2 results in autoantibody production and elevated susceptibility to autoimmune diseases, suggesting that EAF2 is involved in the elimination of autoreactive GCB. In the current project, we aim to prove that EAF2 indeed mediates the apoptosis of GCB using both in vivo and in vitro experiments. In addition, we will elucidate the functional interactions between EAF2 and BCL-2 family in regulating apoptosis. Furthermore, we hope to elucidate the gene transcription network mediated by EAF2 in GCB cells. Our results will provide important insights in understanding the mechanism of autoantibody production and autoimmune diseases.

高亲和力抗体是感染防御的最重要效应分子。B细胞在抗原刺激和T细胞辅助下快速分裂形成生发中心（Germinal center, GC），通过体细胞超突变（SHM）产生高亲和力GCB。SHM同时还会产生自身反应性GCB，机体通过诱导凋亡将其清除，从而防止自身抗体的产生和自身免疫性疾病。我们课题组首次发现转录延伸因子EAF2在GCB高表达，并特异性调控GCB的凋亡，EAF2缺失会导致自身抗体的产生及自身免疫疾病的发生，提示EAF2可能在清除自身反应性GCB中发挥作用。围绕这一现象，为阐明EAF2在自身反应性GCB凋亡中的作用及机制，我们拟做以下研究： 1）在体外及体内实验中分别探索EAF2在介导自身反应性GCB凋亡中的作用。2）明确EAF2与BCL-2家族分子之间的功能性的相互作用关系。3）解明EAF2在GCB的基因调控网络中发挥的作用。4）探索EAF2在抑制B淋巴瘤发生中的作用和机制。