Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
PLoS One. 2010 Nov 30;5(11):e14173. doi: 10.1371/journal.pone.0014173.
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of infancy or early childhood. To clarify the incidence and subtypes of FHL in Japan, we performed genetic and functional analyses of cytotoxic T lymphocytes (CTLs) in Japanese patients with FHL.
Among the Japanese children with hemophagocytic lymphohistiocytosis (HLH) registered at our laboratory, those with more than one of the following findings were eligible for study entry under a diagnosis of FHL: positive for known genetic mutations, a family history of HLH, and impaired CTL-mediated cytotoxicity. Mutations of the newly identified causative gene for FHL5, STXBP2, and the cytotoxicity and degranulation activity of CTLs in FHL patients, were analyzed.
Among 31 FHL patients who satisfied the above criteria, PRF1 mutation was detected in 17 (FHL2) and UNC13D mutation was in 10 (FHL3). In 2 other patients, 3 novel mutations of STXBP2 gene were confirmed (FHL5). Finally, the remaining 2 were classified as having FHL with unknown genetic mutations. In all FHL patients, CTL-mediated cytotoxicity was low or deficient, and degranulation activity was also low or absent except FHL2 patients. In 2 patients with unknown genetic mutations, the cytotoxicity and degranulation activity of CTLs appeared to be deficient in one patient and moderately impaired in the other.
FHL can be diagnosed and classified on the basis of CTL-mediated cytotoxicity, degranulation activity, and genetic analysis. Based on the data obtained from functional analysis of CTLs, other unknown gene(s) responsible for FHL remain to be identified.
家族性噬血细胞性淋巴组织细胞增生症（FHL）是一种罕见的婴儿期或幼儿期疾病。为了阐明日本 FHL 的发病率和亚型，我们对日本 FHL 患者的细胞毒性 T 淋巴细胞（CTL）进行了遗传和功能分析。
在我们实验室登记的患有噬血细胞性淋巴组织细胞增生症（HLH）的日本儿童中，符合以下多项标准的患者可被诊断为 FHL：存在已知基因突变、HLH 家族史和 CTL 介导的细胞毒性受损。分析了新发现的 FHL5 致病基因 STXBP2 的突变以及 FHL 患者 CTL 的细胞毒性和脱颗粒活性。
在符合上述标准的 31 名 FHL 患者中，检测到 PRF1 突变 17 例（FHL2）和 UNC13D 突变 10 例（FHL3）。另外 2 例患者证实存在 3 种新的 STXBP2 基因突变（FHL5）。最后，另外 2 例被归类为具有未知基因突变的 FHL。所有 FHL 患者的 CTL 介导的细胞毒性均降低或缺失，除 FHL2 患者外，脱颗粒活性也降低或缺失。在 2 名具有未知基因突变的患者中，1 名患者的 CTL 细胞毒性和脱颗粒活性似乎受损，另 1 名患者则中度受损。
可以根据 CTL 介导的细胞毒性、脱颗粒活性和遗传分析来诊断和分类 FHL。基于 CTL 功能分析获得的数据，其他未知的 FHL 相关基因有待确定。
