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 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.

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综合征（NS）是一种由SPINK5基因突变导致的罕见的常染色体隐性遗传性皮肤屏障功能受损伴免疫缺陷的皮肤病。目前我们已经收集15例NS患儿，是病例数较大的单中心数据库。NS患儿表现为反复上呼吸道感染，IVIG可以减少感染，提示免疫记忆缺陷。我们研究发现在抗感染中至关重要的记忆B细胞（MBC）数量下降，MBC分化发育异常，对临床治疗具有指导意义，为IVIG提供理论支持。凋亡及增殖实验、BCR信号分子功能的研究因小婴儿血液采样困难，细胞稀缺，数据还在完善中。Spink5基因B细胞条件性敲除小鼠构建耗时长，目前小鼠模型已经成功构建，记忆B细胞缺陷机制研究正在完善中，机制的阐明或将为临床治疗提供一些思路。

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