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

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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.