儿童EBV阳性噬血细胞综合征的遗传分析及其与Th1/Th2细胞因子的关系  

A genetic analysis of children with Epstein-Barr virus-positive hemophagocytic lymphohistiocytosis and its association with T-helper type 1/T-helper type 2 cytokines

作　　者：张垚 汤永民[1] ZHANG Yao;TANG Yong-Min(Pediatric Hematology and Oncology Center,Children's Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,Hangzhou 310003,China)

机构地区：[1]浙江大学医学院附属儿童医院血液肿瘤中心/国家儿童健康与疾病临床医学研究中心,浙江杭州310003

出　　处：《中国当代儿科杂志》2020年第6期620-625,共6页Chinese Journal of Contemporary Pediatrics

基　　金：国家自然科学基金(81770202);浙江省自然科学基金重点项目(LZ12H08001)。

摘　　要：目的探讨遗传变异对EBV阳性噬血细胞综合征(HLH)患儿预后的影响及其与细胞因子的关系。方法选取81例EBV阳性且已进行相关基因测序的HLH患儿,根据有无基因突变分为无突变组(n=35)和突变组(n=46),再根据基因突变方式分为单杂合突变(SHM)亚组、双杂合突变(DHM)亚组和纯合或复合杂合突变(H-CHM)亚组。测定各组患儿血清细胞因子水平,分析其与HLH基因突变的关系。结果UNC13D基因突变出现频率最高(13/46,28%)。STXBP2 c.575G>A(p.R192H)和UNC13D c.604C>A(p.L202M)基因突变首次被报道,均判定为"可能致病的"。突变组TNF-α水平高于无突变组,IFN-γ水平低于无突变组(P<0.05)。DHM亚组IL-4水平高于无突变组,H-CHM亚组IL-4水平低于DHM组(P<0.0083)。H-CHM亚组的1年总生存率(39%±15%)低于无突变组、SHM亚组和DHM亚组(分别为85%±6%、86%±7%和91%±9%,P=0.001)。结论具有基因突变的HLH患儿IFN-γ水平显著降低;H-CHM患儿的预后较差,而其他突变对其预后影响不显著,这可能有助于医生进行临床决策。Objective To study the effect of genetic variation on the prognosis of children with Epstein-Barr virus(EBV)-positive hemophagocytic lymphohistiocytosis(HLH)and its association with cytokines.Methods A total of 81 EBV-positive HLH children who received the sequencing of related genes were enrolled.According to the results of gene detection,they were divided into a non-mutation group and a mutation group.According to the pattern of gene mutation,the mutation group was further divided into three subgroups:single heterozygous mutation(SHM),double heterozygous mutation(DHM),and homozygous or compound heterozygous mutation(H-CHM).The serum levels of cytokines were measured and their association with HLH gene mutations was analyzed.Results UNC13D gene mutation had the highest frequency(13/46,28%).The STXBP2 c.575G>A(p.R192H)and UNC13D c.604C>A(p.L202M)mutations(likely pathogenic)were reported for the first time.The mutation group had a significantly higher level of tumor necrosis factor alpha(TNF-α)than the non-mutation group,while it had a significantly lower level of interferon gamma(IFN-γ)than the non-mutation group(P<0.05).The IL-4 level of the DHM subgroup was higher than that of the non-mutation group,while the IL-4 level of the H-CHM subgroup was lower than that of the DHM group(P<0.0083).The H-CHM subgroup had a significantly lower 1-year overall survival rate than the non-mutation group,the SHM subgroup,and the DHM subgroup(39%±15%vs 85%±6%/86%±7%/91%±9%,P=0.001).Conclusions There is a significant reduction in IFN-γlevel in the mutation group.Children with homozygous or compound heterozygous mutation tend to have poorer prognosis,while other mutations do not have a significant impact on prognosis.

关 键 词：噬血细胞综合征 基因突变 细胞因子 儿童 

分 类 号：R725.5[医药卫生—儿科]