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A correction to this article has been published: Crozat et al., J. Exp. Med. 205 (3) 737
Published online
doi:10.1084/jem.20062447
The Journal of Experimental Medicine, Vol. 204, No. 4, 853-863
The Rockefeller University Press, 0022-1007 $30.00
© Crozat et al.
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ARTICLE

 Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

Karine Crozat1, Kasper Hoebe1, Sophie Ugolini2,3,4, Nancy A. Hong5, Edith Janssen6, Sophie Rutschmann1, Suzanne Mudd1, Sosathya Sovath1, Eric Vivier2,3,4, and Bruce Beutler1

1 The Scripps Research Institute (TSRI), La Jolla, CA 92037
2 Centre d'Immunologie de Marseille-Luminy (CIML), Université de la Méditerranée, Marseille 13288, France
3 Institut National de la Santé et de la Recherche Médicale (INSERM), U631, Marseille 13288, France
4 Centre National de la Recherche Scientifique (CNRS), UMR6102, Marseille 13288, France
5 Phenomix Corporation, San Diego, CA 92121
6 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

CORRESPONDENCE Bruce Beutler: bruce{at}scripps.edu

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.

Abbreviations used: ß2m, ß2-microglobulin; C2, Ca2+-binding; ENU, N-ethyl-N-nitrosourea; FHL3, type 3 familial hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; LCMV, lymphocytic choriomeningitis virus; Mb, million basepair; MCMV, mouse cytomegalovirus; MHD, MUNC homology domain.

S. Rutschmann's present address is Dept. of Immunology, Faculty of Medicine, Imperial College London SW7 2AZ, London, UK.


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