Stch调控生发中心B细胞反应和抗体产生的分子与细胞机制

机体产生的抗体在感染性疾病、肿瘤、移植排斥和自身免疫病中具有重要的作用。研究发现，生发中心（germinal center，GC）反应是影响B细胞分化成分泌抗体的浆细胞的关键事件。然而，关于GC是如何影响抗体产生的这一重要的科学问题目前仍不甚清楚，亟待解答。本课题组在前期研究的基础上，提出以下科学假设：GC反应诱导B细胞增强热休克蛋白70家族分子Stch的表达和功能，Stch阻断GC B细胞中关键蛋白泛素化而导致的降解，上调GC B细胞中关键蛋白的表达，从而增加抗体产生、亲和力或多样性等。本项目拟通过体内外实验，阐明Stch对抗体类别转换、点突变及亲和力等的影响，揭示Stch在GC B细胞调控抗体产生中的作用机制。本课题也将从Stch过度表达诱发自身抗体产生这一新的角度深入了解系统性红斑狼疮的发生、发展的免疫学机制。本项目的研究将有助于发现抗体相关疾病诊疗的潜在靶点。

Antibodies produced by the body play an important role in infectious diseases, tumor, transplant rejection and autoimmune diseases. The previous studies have shown that germinal center (GC) reaction is a critical event in B-cell differentiation into antibody-secreting plasma cells. However, this important scientific question on how the germinal center reaction affects antibody production is still unclear and is urgently needed to be answered. Based on our previous results, we put forward the following scientific hypothesis: GC reaction induces B cells to up-regulate the expression and function of hot shock protein 70 family member Stch; Stch blocks ubiquitination and degradation of key proteins in GC B cells; The expression of key proteins in GC B cells is up-regulated; Accordantly, key proteins induce the antibody production, affinity, diversity, and so on. The effects of Stch on antibody class switch, affinity and point mutation were elucidated by in vivo and in vivo experiments. We will further explore the mechanisms by which Stch regulates GC B cells-controlled antibody production. We will also study that Stch overexpression induces autoantibody production as the new perspective in-depth understanding of the immunological mechanisms underlying occurrence and development of systemic lupus erythematosus. This project will help to identify potential targets for the diagnosis and treatment of antibody-related diseases.