An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder

• Published in: Blood 2004-08, Vol.104 (3), p.735-743
• Main Authors: Jordan, Michael B., Hildeman, David, Kappler, John, Marrack, Philippa
• Format: Article
• Language: English
• Subjects: Animals; beta 2-Microglobulin - deficiency; beta 2-Microglobulin - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Disease Models, Animal; Hematologic and hematopoietic diseases; Histiocytosis, Non-Langerhans-Cell - immunology; Humans; Immunophenotyping; Interferon-gamma - immunology; Killer Cells, Natural - immunology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Other diseases. Hematologic involvement in other diseases
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-10-3413

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, and 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 natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFNγ) is uniquely essential as well. Finally, the excessive amount of IFNγ 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.