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Genetic Deficiency of Interferon‐γ Reveals Interferon‐γ–Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis
Author(s) -
Burn Thomas N.,
Weaver Lehn,
Rood Julia E.,
Chu Niansheng,
Bodansky Aaron,
Kreiger Portia A.,
Behrens Edward M.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41076
Subject(s) - immunology , hemophagocytic lymphohistiocytosis , cd8 , cytokine , neutrophilia , immune system , biology , lymphocytic choriomeningitis , interferon , cytotoxic t cell , macrophage activation syndrome , medicine , disease , arthritis , biochemistry , in vitro
Objective Familial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon‐γ (IFNγ) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFNγ‐blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. This study was undertaken to determine the necessity of IFNγ in driving HLH. Methods IFNγ −/− Prf1 −/− mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell–intrinsic role of IFNγ receptor signaling. CD8+ T cell depletion and interleukin‐33 (IL‐33)/ST2 blockade were performed using monoclonal antibodies. Results LCMV infection of IFNγ −/− Prf1 −/− mice resulted in severe HLH‐like disease. CD8+ T cells and the IL‐33/ST2 axis remained essential mediators of disease; however, IFNγ‐independent HLH immunopathology correlated with a 10–15‐fold increase in neutrophilia ( P < 0.001) and an altered cytokine milieu dominated by IL‐6, IL‐1β, and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) ( P < 0.05). Furthermore, IFNγ regulated CD8+ T cell expression of GM‐CSF and neutrophil survival. Conclusion IFNγ is not necessary for the development of fulminant HLH, requiring physicians to consider case‐by‐case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL‐33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ‐dependent and ‐independent manifestations of HLH/MAS.

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