牛痘样水疱病样淋巴细胞增生性疾病（HV-like LPD）是由于慢性活动性EB病毒感染导致的皮肤T/NK细胞克隆性增生。该病可迁延多年，发展为淋巴瘤或死于噬血细胞综合征。目前仍不清楚该病的遗传学背景、EB病毒通过何种通路导致了淋巴细胞克隆性增生。本研究旨在研究HV-like LPD是否存在基因突变导致的PI3K/Akt受体通路激活，发生噬血细胞综合征的患儿是否存在相关免疫缺陷基因突变。本课题将研究患者EB病毒感染状况，分析皮损增生性细胞是否为单克隆增殖，采用全外显子测序的方法，研究患儿是否存在噬血细胞综合征相关的免疫缺陷基因以及导致EB病毒活化及淋巴细胞增生的PI3K/Akt通路基因突变、活化，并进行验证。本课题结论有助于研究免疫缺陷在HV-like LPD发病中的作用，探索噬血细胞综合征相关基因突变是否可成为疾病转归信号，也为患者是否适于使用PI3K/Akt通路抑制剂治疗提供理论依据。

Hydroa vacciniforme lymphoproliferative disorder (HV-like LPD) is caused by Epstein-Barr virus infection, and chronic active Epstein-Barr virus (CAEBV) infection leads to T/NK cell clonal proliferation. Patients with HV-like LPD may have a refractory clinical course or die of hemophagocytosis. The genetic background of HV-like LPD and the pathway of lymphocyte proliferation remain unclear. The aim of this research project is to analyze the gene mutations of PI3K/Akt pathway and determine whether patients with hemophagocytosis carrying immunodeficiency-related gene mutations. The background of EB virus infection of all collected cases will be determined, and the clonal analysis of skin lesions will be studied based on the results of T-cell receptor analysis and EB virus terminal repeats analysis. Meanwhile, the high-throughout sequencing platform will be used to detect whether the patients have PI3K/Akt pathway-associated mutations or those with hemophagocytosis have immunodeficiency-related genetic defects. This study will explore the mechanism of immunodeficiency in HV-like LPD, evaluate the significance of hemophagocytosis-related gene mutation in prognosis, and explore the possibility of PI3K/Akt inhibitor in treating HV-like LPD.

EB病毒感染可致疾病呈病谱性分布，其一端为良性HV，另一端为HV-like LPD。虽然部分HV-like LPD患者可进展为牛痘样水疱病样淋巴瘤（HVLL），但大多数患儿长期处于淋巴细胞增生状态，病程迁延，并不发展为淋巴瘤。在长期的慢性活动性EB病毒感染状态下，部分患儿却发展为EB病毒相关的噬血细胞综合征。噬血细胞综合征是慢性活动性EB病毒感染、HV-like LPD严重合并症，也是主要的死亡原因。另外，有研究表明EB病毒进入细胞之后可激活PI3K/Akt通路，而该通路的激活进一步促进了EB病毒的再活化、复制，导致与活化相关的基因BRLF的过度表达。但尚不清楚HV-like LPD患儿是否存在发生噬血细胞综合征相关的基因缺陷，以及HV-like LPD中患者是否存在基因突变导致的PI3K/Akt通路活化。本研究对HV-like LPD患儿行基因测序并初步探索与噬血细胞综合征相关基因及PI3K/Akt通路基因突变，发现两例患儿存在CUBN基因突变，丰富了该病的病因学研究，为进一步研究奠定基础。