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Blood, 1 August 2004, Vol. 104, No. 3, pp. 735-743. Prepublished online as a Blood First Edition Paper on April 6, 2004; DOI 10.1182/blood-2003-10-3413. This Article Full Text (PDF) All Versions of this Article: 2003-10-3413v1 104/3/735    most recent Alert me when this article is cited Alert me if a correction is posted 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 Jordan, M. B Articles by Marrack, P. Search for Related Content PubMed PubMed Citation Articles by Jordan, M. B Articles by Marrack, P. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 6, 2003 Accepted February 4, 2004 An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder Michael B Jordan*, David Hildeman, John Kappler, and Philippa Marrack Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA; Immunology, University of Colorado Health Sciences Center, Denver, CO, USA; Howard Hughes Medical Institute, Denver, CO, USA Immunobiology, Cincinnati Children's Hospital and The University of Cincinnati, Cincinnati, OH, USA Pediatrics, University of Colorado Health Sciences Center, Denver, CO, USA; National Jewish Medical and Research Center, Denver, CO, USA; Howard Hughes Medical Institute, Denver, CO, USA * Corresponding author; email: jordanm{at}njc.org. Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8+ T cells, but not NK cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFN) is uniquely essential as well. Finally, the excessive amount of IFNg seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Bullfight without killers: interferon rules pathology in HLH E. Marion Schneider Blood 2004 104: 600-601. [Full Text] [PDF] This article has been cited by other articles: 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] 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] N. Mahlaoui, M. Ouachee-Chardin, G. de Saint Basile, B. Neven, C. Picard, S. Blanche, and A. Fischer Immunotherapy of Familial Hemophagocytic Lymphohistiocytosis With Antithymocyte Globulins: A Single-Center Retrospective Report of 38 Patients Pediatrics, September 1, 2007; 120(3): e622 - e628. [Abstract] [Full Text] [PDF] K. G. Elpek, C. Lacelle, N. P. Singh, E. S. Yolcu, and H. Shirwan CD4+CD25+ T Regulatory Cells Dominate Multiple Immune Evasion Mechanisms in Early but Not Late Phases of Tumor Development in a B Cell Lymphoma Model J. Immunol., June 1, 2007; 178(11): 6840 - 6848. [Abstract] [Full Text] [PDF] K. Crozat, K. Hoebe, S. Ugolini, N. A. Hong, E. Janssen, S. Rutschmann, S. Mudd, S. Sovath, E. Vivier, and B. Beutler Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis J. Exp. Med., April 16, 2007; 204(4): 853 - 863. [Abstract] [Full Text] [PDF] M. Carneiro-Sampaio and A. Coutinho Immunity to Microbes: Lessons from Primary Immunodeficiencies Infect. Immun., April 1, 2007; 75(4): 1545 - 1555. [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] A. Enders, B. Zieger, K. Schwarz, A. Yoshimi, C. Speckmann, E.-M. Knoepfle, U. Kontny, C. Muller, A. Nurden, J. Rohr, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II Blood, July 1, 2006; 108(1): 81 - 87. [Abstract] [Full Text] [PDF] S.-M. Hsieh and S.-C. Chang Cutting Edge: Insufficient Perforin Expression in CD8+ T Cells in Response to Hemagglutinin from Avian Influenza (H5N1) Virus. J. Immunol., April 15, 2006; 176(8): 4530 - 4533. [Abstract] [Full Text] [PDF] E Rudd, K Goransdotter Ericson, C Zheng, Z Uysal, A Ozkan, A Gurgey, B Fadeel, M Nordenskjold, and J-I Henter Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J. Med. Genet., April 1, 2006; 43(4): e14 - e14. [Abstract] [Full Text] [PDF] M. Ouachee-Chardin, C. Elie, G. de Saint Basile, F. Le Deist, N. Mahlaoui, C. Picard, B. Neven, J.-L. Casanova, M. Tardieu, M. Cavazzana-Calvo, et al. Hematopoietic Stem Cell Transplantation in Hemophagocytic Lymphohistiocytosis: A Single-Center Report of 48 Patients Pediatrics, April 1, 2006; 117(4): e743 - e750. [Abstract] [Full Text] [PDF] P. Storm, C. Bartholdy, M. R. Sorensen, J. P. Christensen, and A. R. Thomsen Perforin-Deficient CD8+ T Cells Mediate Fatal Lymphocytic Choriomeningitis despite Impaired Cytokine Production J. Virol., February 1, 2006; 80(3): 1222 - 1230. [Abstract] [Full Text] [PDF] J. Yang, S. P. Huck, R. S. McHugh, I. F. Hermans, and F. Ronchese Perforin-dependent elimination of dendritic cells regulates the expansion of antigen-specific CD8+ T cells in vivo PNAS, January 3, 2006; 103(1): 147 - 152. [Abstract] [Full Text] [PDF] K. Mazodier, V. Marin, D. Novick, C. Farnarier, S. Robitail, N. Schleinitz, V. Veit, P. Paul, M. Rubinstein, C. A. Dinarello, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome Blood, November 15, 2005; 106(10): 3483 - 3489. [Abstract] [Full Text] [PDF] A. V. Ramanan and A. A. Grom Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology, November 1, 2005; 44(11): 1350 - 1353. [Abstract] [Full Text] [PDF] M. J. Smyth, I. Voskoboinik, and J. A. Trapani Immune surveillance of lymphoma in humans? Blood, June 1, 2005; 105(11): 4159 - 4160. [Full Text] [PDF] R. Clementi, F. Locatelli, L. Dupre, A. Garaventa, L. Emmi, M. Bregni, G. Cefalo, A. Moretta, C. Danesino, M. Comis, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene Blood, June 1, 2005; 105(11): 4424 - 4428. [Abstract] [Full Text] [PDF] M. B. Jordan A series of unfortunate events Blood, February 15, 2005; 105(4): 1372 - 1373. [Full Text] [PDF] A. D. Billiau, T. Roskams, R. Van Damme-Lombaerts, P. Matthys, and C. Wouters Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-{gamma}-producing lymphocytes and IL-6- and TNF-{alpha}-producing macrophages Blood, February 15, 2005; 105(4): 1648 - 1651. [Abstract] [Full Text] [PDF] G. Janka and U. zur Stadt Familial and Acquired Hemophagocytic Lymphohistiocytosis Hematology, January 1, 2005; 2005(1): 82 - 88. 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