Genetic and functional basis of familial hemophagocytic lymphohistiocytosis

噬血细胞淋巴组织细胞增多症是一种免疫调节受损、危及生命的临床综合征。人促黄体生成素是许多遗传性疾病的关键临床表现，其中大多数疾病的特征是与淋巴细胞细胞毒性相关的基因突变。在这里，我们想要进一步阐明遗传性疾病易患HLH的遗传和功能基础。根据越来越多的临床和免疫学特征良好的转诊患者进行HLH评估，我们将重点关注家族性或复发性疾病、EBV引发的疾病或免疫缺陷情况下的HLH患者。功能筛查将确定有细胞毒性和脱颗粒缺陷的患者，对EBV的特殊反应模式和特殊的T细胞分化模式。在这个表型筛选的基础上，我们将使用最先进的遗传工具，包括整个外显子组测序，来识别新的遗传缺陷，并使用细胞生物学和免疫学方法在体外和体内对它们进行表征。这项研究的目的是确定参与细胞器运输、淋巴细胞细胞毒性和免疫调节的未知成分，并改善HLH患者的诊断和治疗选择。

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome of impaired immune regulation. HLH is a key clinical manifestation in a number of genetic diseases, most of which are characterized by mutations in genes relevant for lymphocyte cytotoxicity. Here, we want to further elucidate the genetic and functional basis of inherited diseases predisposing to HLH. Based on a growing, clinically and immunologically well-characterized cohort of patients referred for evaluation for HLH, we will focus on patients with familial or recurrent disease, EBV triggered disease or HLH in the context of an immunodeficiency. Functional screening will identify patients with cytotoxicity and degranulation defects, particular response patterns to EBV and particular T cell differentiation patterns. Based on this phenotypic screen, we will use state of the art genetic tools including whole exome sequencing to identify novel genetic defects and characterize them in-vitro and in-vivo using cell biological and immunological approaches. The study aims to identify unknown components involved in organelle trafficking, lymphocyte cytotoxicity, and immune regulation and to improve the diagnosis and treatment options for patients with HLH.