Analysis of the pathogenesis and identification of candidate genes in familial hemophagocytic lymphohistiocytosis

家族性噬血细胞性淋巴组织细胞增多症发病机制分析及候选基因鉴定

• 批准号: 14370248
• 负责人: ISHII Eiichi
• 金额: $ 8.51万
• 依托单位: Saga University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370248/
• 关键词: Familial hemophagocytic lymphohistiocytosis; Performn gene; MUNC13-4 gen; NK activity; Cytotoxicity of Tlymphocytes; Linkage analysis; 遺伝子導入; 細胞障害活性; マイクロサテライトマーカー; 原発性血球貪食症候群; マウスモデル

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder occurring in infancy. In our study, clonal proliferation of T lymphocytes has been observed in FHL patients and also various organs of scid mice Cytotoxicity of these T lymphocytes for target cells is usually impaired, consequently, it may be hypothesized that T lymphocytes with cytotoxic defects for target cells will accumulate, proliferate and acquire clonality in FHL. In 1999, perforin gene (PRF1) mutation was identified as a cause of FHL2 subtype. In Japan, the incidence of FHL2 can be calculated as 20-30% of all FHL cases. Furthermore, in 2003, MUNC13-4 mutations were identified in some non-FHL2 patients (FHL3 subtype). We identified several new mutations of MUNC13-4 in FHL, and the incidence of this mutaions was approximately 30% of FHL cases. The difference of phenotypic findings can be observed between FHL2 and FHL3 subtypes. Identification of other genes responsible for remaining cases is therefore a major concern. Althogh it is considered that hematopoietic stem cell transplantation is an only accepted curative therapy for FHL, appropriate diagnosis and decision of appropriate treatment is necessary for FHL patients. In the near future, an entire pathogenesis should be clarified in order to establish appropriate therapies including immunotherapy, stem cell transplantation and gene therapy.

家族性噬血细胞性淋巴组织细胞增生症（FHL）是一种常染色体隐性遗传疾病，发生于婴儿期。在我们的研究中，在FHL患者和scid小鼠的各种器官中观察到T淋巴细胞的克隆性增殖，这些T淋巴细胞对靶细胞的细胞毒性通常受损，因此，可以假设具有靶细胞毒性缺陷的T淋巴细胞将在FHL中积累、增殖并获得克隆性。1999年，穿孔素基因（PRF 1）突变被确定为FHL 2亚型的原因。在日本，FHL 2的发病率可计算为所有FHL病例的20-30%。此外，2003年，在一些非FHL 2患者（FHL 3亚型）中发现了MUNC 13 -4突变。我们在FHL中发现了几个新的MUNC 13 -4突变，这种突变的发生率约为FHL病例的30%。FHL 2和FHL 3亚型间的表型差异显著。因此，鉴定其他与剩余病例有关的基因是一个主要问题。尽管造血干细胞移植是目前公认的FHL唯一有效的治疗方法，但对FHL患者进行正确的诊断和选择合适的治疗方案是必要的。在不久的将来，一个完整的发病机制应澄清，以建立适当的治疗，包括免疫治疗，干细胞移植和基因治疗。

项目成果

Yanai F, Ishii E, Yasukawa M, et al.: "Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4+ T lymphocytes : analysis using the combination of hereditary perforin-deficient effector cells and Fas-deficient target cells."J Imm

Yanai F、Ishii E、Yasukawa M 等人：“穿孔素在人 CD4 T 淋巴细胞介导的抗原特异性细胞毒性中的重要作用：使用遗传性穿孔素缺陷效应细胞和 Fas 缺陷靶细胞的组合进行分析。”J

Ueda I, Ishii E, Imashuku S, et al.: "Characteristic perform gene mutations of haemophagocytic lymphohistiocytosis patients in Japan."Br J Haematol. 121. 503-510 (2003)

Ueda I、Ishii E、Imashuku S 等人：“日本噬血细胞性淋巴组织细胞增多症患者的基因突变特征。”Br J Haematol。

Suga N, Ohga S, Ishii E, et al.: "Perforin defects of primary haemophagocytic lymphohistiocytosis in Japan"Br J Haematol. 116. 346-349 (2002)

Suga N、Ohga S、Ishii E 等人：“日本原发性噬血细胞性淋巴组织细胞增多症的穿孔素缺陷”Br J Haematol。

Yamamoto K, Ishii E, Ohga S, Imashuku S, Sasazuki T, Yasukawa M, et al.: "Identification of novel MUNC13-4 mutations in familial hemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes."J Med Genet. (In pre

Yamamoto K、Ishii E、Ohga S、Imashuku S、Sasazuki T、Yasukawa M 等人：“家族性噬血细胞性淋巴组织细胞增多症中新型 MUNC13-4 突变的鉴定以及 MUNC13-4 缺陷型细胞毒性 T 淋巴细胞的功能分析。”J Med

Imashuku S, Ishii E, et al.: "Low natural killer activity and central nervous system disease as a high-risk prognostic indicators in young patients with hemophagocytic lymphohistiocytosis."Cancer. 94. 3023-3031 (2003)

Imashuku S、Ishii E 等人：“低自然杀伤活性和中枢神经系统疾病是年轻噬血细胞性淋巴组织细胞增多症患者的高风险预后指标。”癌症。