LAMP-2促进自身免疫性肝脏损伤的作用及机制

Primary biliary cirrhosis (PBC) is a slowly progessive autoimmune liver disease of unknown etiology. In our previous study, we found the expression of LAMP-2 significantly increased in PBC livers compared with control groups. What and how should the relationship between LMAP-2 increase and PBC initiation be? Zhou et al demenstrated that overexpression of LAMP-2 enhanced MHC class II presentation of cytoplasmic autoantigen presentation. It is well known that autoantigen presentation by MHC molecules is critical for the induction of self tolerance. Whether the increased LAMP-2 are critical factors of deficiency in autoimmune tolerance in PBC? In our study, C57BL/6 mice injected with adeno-associated virus 8 expressing LAMP-2, had a substantial number of lymphocytes infiltrated in livers. Therefore, the present study aims to clarify the potential roles and mechanisms of LAMP-2 in PBC, identify the autoantigen presented by hepatocytes vio class II proteins, which may help illuminate the mechanisms of PBC and find the novel therapeutic targets in PBC patients.

PBC是一种自身免疫性肝病，发病机制至今不清。在国科金资助下，本课题组在国际上率先发现PBC患者肝细胞中LAMP-2高表达，但PBC患者肝细胞中LMAP-2高表达是否与PBC发病有关？有研究发现LAMP-2过表达可以增强MHC II类途径对自身抗原的提呈。那么，LAMP-2是否是通过增强肝细胞对某些自身抗原的提呈，诱发自身免疫性肝损伤，导致PBC发生呢？我们前期工作证实肝细胞LAMP-2过表达可以诱发小鼠肝脏组织淋巴细胞浸润。本课题拟在前期工作基础上，明确LAMP-2过表达对肝脏的损伤作用；研究LAMP-2增强肝细胞自身抗原提呈，对淋巴细胞活化、增殖的影响；筛选并验证肝细胞异常提呈的自身抗原肽；研究新鉴定的自身抗原与PBC发病的相关性。该项目是本课题组既往对LAMP-2与PBC相关研究的深入，有助于进一步阐明LAMP-2参与PBC免疫损伤的分子机制，对于理解PBC发生具有重要意义。

原发性胆汁性胆管炎（PBC）是一种免疫介导的慢性胆汁淤积性肝病。本研究利用TALENs技术构建了溶酶体相关膜蛋白2（LAMP-2）基因敲除大鼠模型，利用该动物模型我们的研究发现LAMP-2基因敲除大鼠肝脏表现有肝内胆汁淤积现象，且对胆汁淤积的耐受性降低，更易发生胆汁排泄障碍。进一步研究发现，LAMP-2可能通过调控肝细胞胆管膜胆汁转运体多药耐药相关蛋白2（Mrp2）在肝细胞毛细胆管膜上的定位，影响肝细胞胆汁排泄过程。进一步借助RNA-seq技术，探讨了LAMP-2分子在免疫等方面的可能作用，GO分析和Pathway分析均提示，LAMP-2分子在免疫、代谢等方面的可能作用，为后续深入研究提供了突破口。