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

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。

Abstract:

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-γ level 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.