Netherton综合征SPINK5基因突变对记忆性B细胞的影响及其机制研究

Netherton综合征（NS）是SPINK5基因突变导致的调节罕见的常染色体隐性遗传性皮肤屏障功能受损相关性皮肤病。研究发现NS患者外周血记忆性B细胞（MBCs）数量减少，且NS患儿再次感染同一抗原不能有效产生保护性抗体，提示NS患儿MBCs功能亦受损。免疫记忆是机体适应性免疫应答的核心，也是预防接种产生长期保护效应的根本基础，MBCs是介导体液免疫记忆的关键细胞。生发中心（GC）是MBCs产生的场所，MBCs功能依赖于B细胞正常活化和BCR信号通路正常调控，BCR聚集簇形成和B细胞扩张是启动B细胞活化的关键早期活化事件。本课题立足于临床问题，研究NS患者SPINK5基因缺陷如何影响MBCs在GC内的分化和外周维持，及MBCs BCR信号及B细胞早期活化事件，以揭示SPINK5基因突变导致MBCs功能缺陷的分子机制，为NS早诊断、精准治疗提供依据，为MBCs的分化维持及功能研究提供数据。

Netherton syndrome is a severe, autosomal recessive form of ichthyosis associated with mutations in the SPINK5 gene. Number of memory B cells (MBCs) in peripheral blood of patients with NS has been reported reduced. Also, protective type-specific antibodies were reduced in NS children infected with the same antigen again, suggesting that function of MBCs was impaired. Immune memory, whose key cells are MBCs, is the core of adaptive immune response, and is also the fundamental basis of long-term protective effect. MBCs are generated in germinal center (GC), and depend on B cell activation and BCR signaling to work. BCR cluster formation and B cell expansion are the key events to active B cells. Based on clinical problems, this project will explore how SPINK5 affects the differentiation of MBCs in GC and the maintaining in peripheral immunity, and the molecular mechanism by which SPINK5 affects the function of MBCs. The results of this original research will contribute to the knowledge basis for developing better, precise therapy for NS patients.