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

家族性噬血细胞淋巴组织细胞病（FHL）是一种常染色体隐性遗传病，发生在婴儿期。在我们的研究中，在FHL患者和scid小鼠的各种器官中都观察到T淋巴细胞的克隆性增殖，这些T淋巴细胞对靶细胞的毒性通常受损，因此可以假设对靶细胞具有细胞毒性缺陷的T淋巴细胞在FHL中会积累、增殖并获得克隆性。1999年，穿孔素基因（PRF1）突变被确定为FHL2亚型的一个原因。在日本，FHL2的发病率可计算为所有FHL病例的20-30%。此外，2003年，在一些非fhl2患者（FHL3亚型）中发现了MUNC13-4突变。我们在FHL中发现了几种新的MUNC13-4突变，这种突变的发生率约为FHL病例的30%。在FHL2和FHL3亚型之间可以观察到表型发现的差异。因此，鉴定导致剩余病例的其他基因是一个主要问题。虽然造血干细胞移植被认为是FHL唯一可接受的治疗方法，但对FHL患者进行适当的诊断和决定适当的治疗是必要的。在不久的将来，为了建立适当的治疗方法，包括免疫治疗、干细胞移植和基因治疗，应该阐明整个发病机制。

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.