应激对生发中心免疫应答功能的影响及其生物学机制的研究

免疫功能紊乱在应激导致重大疾病发生中具有重要作用，但目前远未能阐明应激致免疫功能紊乱的生物学机制。本项目组前期研究率先发现了应激可导致脾生发中心形成和发育障碍，本研究拟进一步观察应激状态下脾生发中心B细胞克隆扩增、IgV(D)J基因体细胞高频突变、亲和力成熟以及Ig类型转换重组、浆细胞和记忆B细胞分化发育的改变，认识应激抑制生发中心免疫应答的生物学特点；观察应激致生发中心功能障碍进程中糖皮质激素水平的变化规律，采用双向肾上腺切除术和生物化学拮抗术调控应激机体糖皮质激素水平，探讨其在应激致生发中心功能损伤中的作用，认识应激抑制生发中心的神经内分泌机制；研究应激机体STAT3和IL-6的水平变化，探索其对生发中心Bcl-6、IL-17调控通路的影响，认识应激抑制生发中心免疫应答的分子机制；为阐明应激机体免疫机制紊乱的生物学基础提供新的科学依据，为防治应激损伤相关疾病的医学措施研究提供新的思路。

。.Stress is a known risk factor for numerous human diseases, in which the functional disorder of immune system plays important role. Although stress-associated immune suppression is well-established, the mechanisms underlying the suppressive effects of stress on the immune system have remained largely elusive. germinal centers (GCs) are the principal sites of antigen (Ag)-driven clonal expansion, immunoglobulin (Ig) V(D)J gene somatic hypermutation (SHM), affinity-driven clonal selection, and generation of the memory cell compartment. Our preliminary studies have found that chronic restraint stress inhibits GC reaction, leading to reduced GC formation and decreased production of class-switched Abs. This proposal is to systemically examine the effect of chronic restraint stress on GC response and understand the underlying mechanism of stress-induced impairment of GC response. .This project proposes 3 specific aims:. .(1) Define the functional consequences of stress-induced inhibition of GC response, including antigen (Ag)-driven clonal expansion, immunoglobulin (Ig) V(D)J gene somatic hypermutation (SHM), affinity-driven clonal selection, and generation of the memory cell compartment..(2) Determine the glucocorticoid mechanisms responsible for stress-induced inhibition of GC response, including to define the changes of glucocorticoid during stress induced inhibition of GC response, to assess the impacts of the receptor antagonists to glucocorticoid and adrenalectomy on stress-induced inhibition of GC response and to observe the expression and functional changes of Bcl-6 and IL-17 in GC under above conditionings..(3) Explore the molecular mechanisms underlying stress-induced inhibition of GC response, including to define the changes of STAT3 and IL-6 during stress induced inhibition of GC response, and to assess the impact of IL-6/STAT3 on Bcl-6 and IL-17-mediated signaling on stress-induced inhibition of GC response. .The successful completion of this project will validate GC impairment as an important aspect in assessing the impact of stress on immune function and provide potential target for prevention and/or treatment of stress-associated immune suppression.