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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3442-3448. Prepublished online as a Blood First Edition Paper on January 4, 2005; DOI 10.1182/blood-2004-08-3296. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-08-3296v1 105/9/3442    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ishii, E. Articles by Yasukawa, M. Search for Related Content PubMed PubMed Citation Articles by Ishii, E. Articles by Yasukawa, M. Related Collections Immunobiology Phagocytes Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS 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, and Masaki Yasukawa From the Department of Pediatrics, Saga University, Saga, Japan; Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Pediatrics, Graduate School of Medicine, Kyushu University, Fukuoka, Japan; Division of Molecular Population Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Division of Pediatrics, Osaka General Hospital, Osaka, Japan; Department of Pediatrics, Shinshu University, Matsumoto, Japan; Division of Pediatrics, Okinawa Central Hospital, Okinawa, Japan; Research Institute, International Medical Center of Japan, Tokyo, Japan; First Department of Internal Medicine, Ehime University, Ehime, Japan. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Chia, K. P. Yeo, J. C. Whisstock, M. A. Dunstone, J. A. Trapani, and I. Voskoboinik Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer PNAS, June 16, 2009; 106(24): 9809 - 9814. [Abstract] [Full Text] [PDF] R. Urrea Moreno, J. Gil, C. Rodriguez-Sainz, E. Cela, V. LaFay, B. Oloizia, A. B. Herr, J. Sumegi, M. B. Jordan, and K. A. Risma Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function Blood, January 8, 2009; 113(2): 338 - 346. [Abstract] [Full Text] [PDF] J. K. C. Chan, L. Lamant, E. Algar, G. Delsol, W. Y. W. Tsang, K. C. Lee, K. Tiedemann, and C. W. Chow ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy Blood, October 1, 2008; 112(7): 2965 - 2968. [Abstract] [Full Text] [PDF] E Rudd, Y T Bryceson, C Zheng, J Edner, S M Wood, K Ramme, S Gavhed, A Gurgey, M Hellebostad, A G Bechensteen, et al. Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis J. Med. Genet., March 1, 2008; 45(3): 134 - 141. [Abstract] [Full Text] [PDF] Y. T. Bryceson, E. Rudd, C. Zheng, J. Edner, D. Ma, S. M. Wood, A. G. Bechensteen, J. J. Boelens, T. Celkan, R. A. Farah, et al. Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients Blood, September 15, 2007; 110(6): 1906 - 1915. [Abstract] [Full Text] [PDF] K. Nagafuji, A. Nonami, T. Kumano, Y. Kikushige, G. Yoshimoto, K. Takenaka, K. Shimoda, S. Ohga, M. Yasukawa, H. Horiuchi, et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis Haematologica, July 1, 2007; 92(7): 978 - 981. [Abstract] [Full Text] [PDF] M.-T. Lin, H.-M. Chang, C.-J. Huang, W.-L. Chen, C.-Y. Lin, C.-Y. Lin, and S.-S. Chuang Massive expansion of EBV+ monoclonal T cells with CD5 down regulation in EBV-associated haemophagocytic lymphohistiocytosis J. Clin. Pathol., January 1, 2007; 60(1): 101 - 103. [Abstract] [Full Text] [PDF] A Santoro, S Cannella, G Bossi, F Gallo, A Trizzino, D Pende, F Dieli, G Bruno, J C Stinchcombe, C Micalizzi, et al. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis J. Med. Genet., December 1, 2006; 43(12): 953 - 960. [Abstract] [Full Text] [PDF] S. Marcenaro, F. Gallo, S. Martini, A. Santoro, G. M. Griffiths, M. Arico, L. Moretta, and D. Pende Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease Blood, October 1, 2006; 108(7): 2316 - 2323. [Abstract] [Full Text] [PDF] P. F. Moore, V. K. Affolter, and W. Vernau Canine Hemophagocytic Histiocytic Sarcoma: A Proliferative Disorder of CD11d+ Macrophages. Vet. Pathol., September 1, 2006; 43(5): 632 - 645. [Abstract] [Full Text] [PDF]

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