IFNy in Primary HLH

Interferon gamma (IFNγ): a key cytokine in primary HLH1,2

Watch the mechanism of disease (MOD) video

IFNγ is a key cytokine in the immune system1,2

IFNγ is the only type II interferon and plays an important role in cell communication during immune responses. During innate immune responses, IFNγ helps eliminate intracellular pathogens by activating macrophages and natural killer (NK) cells. During adaptive immune responses, IFNγ is responsible for both the differentiation and overproliferation of activated T cells.1,2

In primary hemophagocytic lymphohistiocytosis (HLH), the immune system is dysregulated and IFNγ contributes directly to disease pathogenesis.3

Genetic mutations disrupt immune function in primary HLH1

Under normal conditions, the immune system is tightly regulated. The presence of infected or abnormal cells triggers the activation of CD8+ T cells and NK cells. These cells identify and bind to the abnormal target cells, releasing perforin and granzymes to destroy them. In primary HLH, genetic mutations prevent the normal functioning of perforin and granzymes in cell destruction.1

How IFNγ drives macrophage activation and hyperinflammation

Click through or use the slider to see how IFNγ-activated macrophages trigger the downstream release of proinflammatory cytokines—including additional IFNγ—perpetuating hypercytokinemia and hyperinflammation in an aggressive continuum.1

How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 1
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 1
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 2
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 2
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 3
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 3
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 4
How Interferon Gamma Drives Macrophage Activation and Hyperinflammation – Frame 4

In primary HLH, abnormal target cells are not effectively eliminated because genetic mutations prevent perforin pore formation needed for cell lysis.1

The failure to kill antigen presenting cells leads to the proliferation and hyperactivation of T cells, which produce excessive amounts of IFNγ.1

IFNγ amplifies immune signaling by binding to and activating macrophages.1

The activated macrophages release additional proinflammatory cytokines, such as IL-1, IL-6, and TNF. This self-amplifying feedback loop, sometimes referred to as a "cytokine storm," leads to the dangerous hyperinflammatory symptoms of primary HLH.1

IFNγR=interferon gamma receptor; IL=interleukin; TNF=tumor necrosis factor.

For more information about the critical role of IFNγ in primary HLH, download this guide.

Download the IFNγ guide

Damaging effects of downstream cytokines

See how IFNγ triggers clinical and laboratory manifestations of disease.

Signs and symptoms of primary HLH

Drivers

Persistent/unremitting fever of unknown origin4

  • Activated macrophages release pyrogenic IL-6, IL-1, and TNF

Cytopenia5

  • Activated macrophages can lead to the destruction of bone marrow
  • Decreased stem cell proliferation and hypercytokinemia result in cytopenia

Hypertriglyceridemia4,6

  • Activated macrophages release TNF
  • TNF stimulates hepatic lipid synthesis

Hypofibrinogenemia7

  • IFNγ stimulates macrophages to release plasminogen activator
  • Plasminogen activator produces plasmin, the predominant enzyme responsible for fibrinolysis

Hyperferritinemia4,8

  • Activated macrophages release TNF, which upregulates ferritin synthesis in hepatocytes and other macrophages

Elevated soluble CD25 (sCD25)9

  • sCD25 levels are elevated during T-cell activation and production of IFNγ

Hepatosplenomegaly4

  • Activated macrophages release IL-6 and TNF
  • Increased acute inflammatory response, lymphocyte infiltration, and activation

Elevated liver enzymes4

  • IL-1β, IL-6, and TNF released from IFNγ-activated macrophages drive acute phase protein production in liver
  • Activated hepatic macrophages can also cause liver damage

Hemophagocytosis10

  • Overactive macrophages lead to hemophagocytosis in the liver, spleen, and bone marrow

CD=cluster of differentiation.

The critical role of IFNγ in primary HLH

IFNγ was found to be essential for the development of HLH-like pathology. In murine models, inhibition of this cytokine led to an improvement of known features of HLH, including2,3:

  • Increased blood cell counts (hemoglobin, platelets, and/or neutrophils)
  • Significant reduction of triglyceride and ferritin levels
  • Normalization of histopathological features of the spleen
  • Reduction of macrophage activation, as evidenced by the reduction of hemophagocytosis in the liver
Interferon gamma (IFNγ)
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