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Cited by 712Autoimmune and Inflammatory Disorders ResearchImmunodeficiency and Autoimmune DisordersInflammasome and immune disorders

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

Jordan, Michael B., Hildeman, David, Kappler, John, Marrack, Philippa·2004·Blood
DOI 10.1182/blood-2003-10-3413
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Abstract

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.

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Crossref · 10.1182/blood-2003-10-3413

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  • Data from mouse models of HLH and patients with cytokine storm indicate that the inability of CTLs to kill efficiently leads to prolonged activation of T cells, triggering a cascade of inflammatory tissue damage.

    “Data from mouse models of HLH and patients with cytokine storm indicate that the inability of CTLs to kill efficiently leads to prolonged activation of T cells, triggering a cascade of inflammatory tissue damage.”

    From Cytokine storm (2020) · cites this paper as [21]

  • Attempting to recapitulate HLH by continuous antigen exposure does not completely recreate the disease process, suggesting that persistent antigenemia is not sufficient.

    “However, attempting to recapitulate HLH by continuous antigen exposure does not completely recreate the disease process, suggesting that persistent antigenemia is not sufficient (8).”

    From Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice (2011) · cites this paper as [8]

  • The severity of MAS in this model is less than that seen in the perforin-deficient model.

    “The severity of MAS in this model is less than that seen in the perforin-deficient model (8).”

    From Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice (2011) · cites this paper as [8]

  • In murine models of primary HLH, IFN-γ plays a role and CD8+ T cells are required.

    “Because of the role of IFN-γ and the requirement for CD8 + T cells in murine models of primary HLH (8), there has been much attention given to the antigen-specific receptors in cytokine storm.”

    From Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice (2011) · cites this paper as [8]

  • In primary familial HLH, antigen-driven CD8+ T cells are the major disease-inducing compartment.

    “It is interesting to speculate whether the same process might also play some role in primary familial HLH, in which antigen-driven CD8 + T cells are clearly the major disease-inducing compartment (8).”

    From Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice (2011) · cites this paper as [8]

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Authors
Jordan, M. B., Hildeman, D., Kappler, J., & Marrack, P.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2004-08-01
Volume
104
Issue
3
Pages
735-743
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2003-10-3413
OpenAlex
W1983067071
Cited by
712
References
49
Citations by year
2026: 18 · 2025: 35 · 2024: 48 · 2023: 47 · 2022: 45 · 2021: 51 · 2020: 51 · 2019: 46 · 2018: 22 · 2017: 45 · 2016: 43 · 2015: 37 · 2014: 28 · 2013: 23 · 2012: 27
FWCI
11.29
Type
journal article
Language
en
Open access
closed
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1k08ai050802-01a1)
  • National Institute of Allergy and Infectious Diseases (AI-18785, AI 17134, AI-52225, R01AI052225, AI-50802)
Topics
  • Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
hemophagocytic lymphohistiocytosis, perforin-deficient mice, CD8+ T cells, interferon-gamma, lymphocytic choriomeningitis virus, hemophagocytosis, natural killer cells, antigen presentation, cytokine neutralization, lymphocyte cytotoxicity, hypertriglyceridemia, hypofibrinogenemia, pancytopenia, splenomegaly, animal models
MeSH terms
Animals, beta 2-Microglobulin, Disease Models, Animal, Humans, Interferon-gamma, Killer Cells, Natural, Mice, Inbred C57BL, Histiocytosis, Non-Langerhans-Cell, Immunophenotyping, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice

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