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Science 3 December 1999:
Vol. 286. no. 5446, pp. 1957 - 1959
DOI: 10.1126/science.286.5446.1957
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Reports

Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis

Susan E. Stepp, 1 Rémi Dufourcq-Lagelouse, 2 Françoise Le Deist, 23 Sadhna Bhawan, 1 Stéphanie Certain, 2 Porunelloor A. Mathew, 4 Jan-Inge Henter, 5 Michael Bennett, 1 Alain Fischer, 23 Geneviève de Saint Basile, 2*dagger Vinay Kumar 1*

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-linked FHL. Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation.

1 Department of Pathology and the Graduate Program in Immunology, University of Texas Southwestern Medical School, Dallas, TX 75235, USA.
2 Unité de Recherches sur le Dévelopment Normal et Pathologique du Système Immunitaire INSERM U429, 75015 Paris, France.
3 Unité d'Immunologie et d'Hématologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
4 Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
5 Child Cancer Research, Karolinska Institutet, Department of Pediatric Hematology and Oncology, Karolinska Hospital, Stockholm S-17177, Sweden.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: sbasile{at}necker.fr

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Selective Inhibition of Dipeptidyl Peptidase I, Not Caspases, Prevents the Partial Processing of Procaspase-3 in CD3-activated Human CD8+ T Lymphocytes.
N. Bidere, M. Briet, A. Durrbach, C. Dumont, J. Feldmann, B. Charpentier, G. de Saint-Basile, and A. Senik (2002)
J. Biol. Chem. 277, 32339-32347
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Surface Cathepsin B Protects Cytotoxic Lymphocytes from Self-destruction after Degranulation.
K. N. Balaji, N. Schaschke, W. Machleidt, M. Catalfamo, and P. A. Henkart (2002)
J. Exp. Med. 196, 493-503
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Suppression of Lymphoma and Epithelial Malignancies Effected by Interferon {gamma}.
S. E.A. Street, J. A. Trapani, D. MacGregor, and M. J. Smyth (2002)
J. Exp. Med. 196, 129-134
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A Role for IFN-{gamma} in Primary and Secondary Immunity Generated by NK Cell-Sensitive Tumor-Expressing CD80 In Vivo.
J. M. Kelly, K. Takeda, P. K. Darcy, H. Yagita, and M. J. Smyth (2002)
J. Immunol. 168, 4472-4479
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Autoimmunity in human primary immunodeficiency diseases.
P. D. Arkwright, M. Abinun, and A. J. Cant (2002)
Blood 99, 2694-2702
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