Genetic subtypes of familial hemophagocytic lymphohistiocytosis: Correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions

Eiichi Ishii, Ikuyo Ueda, Ryutaro Shirakawa, Ken Yamamoto, Hisanori Horiuchi, Shouichi Ohga, Kenji Furuno, Akira Morimoto, Miyoko Imayoshi, Yoshiyasu Ogata, Masafumi Zaitsu, Masahiro Sako, Kenichi Koike, Akifumi Sakata, Hidetoshi Takada, Toshiro Hara, Shinsaku Imashuku, Takehiko Sasazuki, Masaki Yasukawa

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Abstract

Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset.

Original languageEnglish
Pages (from-to)3442-3448
Number of pages7
JournalBlood
Volume105
Issue number9
DOIs
Publication statusPublished - 2005 May 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Ishii, E., Ueda, I., Shirakawa, R., Yamamoto, K., Horiuchi, H., Ohga, S., Furuno, K., Morimoto, A., Imayoshi, M., Ogata, Y., Zaitsu, M., Sako, M., Koike, K., Sakata, A., Takada, H., Hara, T., Imashuku, S., Sasazuki, T., & Yasukawa, M. (2005). Genetic subtypes of familial hemophagocytic lymphohistiocytosis: Correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood, 105(9), 3442-3448. https://doi.org/10.1182/blood-2004-08-3296