CARD10突变所致单核细胞缺陷在原发性免疫缺陷病的机制研究

原发性免疫缺陷病(PID)是一类主要由单基因突变导致的免疫细胞或分子缺陷性疾病。我们前期通过全外显子测序结合纯合子定位方法在近亲家系的一对PID兄妹中鉴定到CARD10纯合突变(p.R420C)，并证实CARD10可能是PID新致病基因，但其具体机制尚未明确。有研究表明Card10敲除鼠的单核-树突细胞功能缺陷，我们前期亦发现CARD10突变患者单核-树突细胞减少，而单核-树突细胞减少或功能缺陷均可致PID的发生，因此我们推测CARD10突变可能通过影响单核-树突细胞参与PID的发病。本研究拟结合CARD10突变患者、CARD10敲除人单核细胞系及条件性敲除单核细胞Card10基因小鼠，探讨CARD10突变是否导致单核树突细胞功能缺陷，参与PID的发病，并探索可能涉及的下游通路。本研究拓宽了PID的基因谱，为PID的临床诊治及机制研究提供新的理论依据。

Primary immunodeficiency disease (PID) is a class of immune cell or immune factor defect diseases mainly caused by single gene mutations. We previously identified a CARD10 homozygous mutation (p.R420C) in two PID siblings in a consanguineous family by whole-exome sequencing, and confirmed CARD10 may be a new pathogenic gene for PID, but the mechanism remains unknown. Studies have shown monocyte-dendritic cell function defects in Card10 knockout mice, and our patients also have decreased monocyte-dendritic cells. Considering monocyte-dendritic cell deficient or dysfunction can cause PID, we speculated that CARD10 mutation may be involved in the pathogenesis of PID by affecting monocyte-dendritic cells. In this study, we aim to investigate whether CARD10 mutations cause PID by changing monocyte-dendritic cell function. We will detect the function of monocyte-dendritic cells from CARD10 mutated patients, CARD10 knockout human monocyte cell lines, and conditionally knockout monocyte Card10 gene mice and further explore its mechanisms. This study will broaden the gene spectrum of PID, give an insight into its mechanism research, and provide a new theoretical basis for clinical diagnosis and treatment of PID.