IFNy in Primary HLH

IFNγ: a key cytokine in primary HLH1,2

IFNγ is a key cytokine in the immune system3,4

Interferon gamma (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.3,4

In primary hemophagocytic lymphohistiocytosis (HLH), the immune system is dysregulated and IFNγ contributes directly to disease pathogenesis.5

Genetic mutations disrupt immune function in primary HLH2

In healthy individuals, antigen-presenting cells (APCs) are recognized by cytotoxic CD8+ T cells, which bind to them to release perforin and granzymes into the immunological synapse space. Perforin creates pores in the target cell's plasma membrane, allowing the cytotoxic granzymes to enter and initiate lysis. In primary HLH, genetic mutations prevent perforin pore formation needed for cell lysis.7

Graphic showing how primary HLH, genetic mutations prevent perforin pore formation needed for cell lysis.

See how IFNγ activates a vicious cycle of hyperinflamation3

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.3

Stage 1 - In primary HLH, genetic mutations
prevent perforin pore formation needed for cell lysis.
Stage 1 - In primary HLH, genetic mutations
prevent perforin pore formation 
needed for cell lysis.
Stage 2 - The failure to kill APCs leads to the proliferation and hyperactivation of T cells.
Stage 2 - The failure to kill APCs leads to the proliferation and hyperactivation of T cells.
Stage 3 - Activated macrophages release
even more T cell and inflammatory cytokines—most notably IFNγ.
Stage 3 - Activated macrophages release even more T cell and inflammatory cytokines—most notably IFNγ.
Stage 4 - Once IFNγ is released, it binds directly to the macrophage’s cell receptors.
Stage 4 - Once IFNγ is released, it binds directly to the macrophage’s cell receptors.
Stage 5 - The activated macrophage releases even more cytokines, such as TNF, IL-1, and IL-6. This dangerous cycle leads to the hyperinflammatory symptoms of primary HLH.
Stage 5 - The activated macrophage releases even more cytokines, such as TNF, IL-1, and IL-6. This dangerous cycle leads to the hyperinflammatory symptoms of primary HLH.

In primary HLH, genetic mutations
prevent perforin pore formation needed for cell lysis.7

The failure to kill APCs leads to the proliferation and hyperactivation of T cells.2

Activated macrophages release even more T cell and inflammatory cytokines—most notably IFNγ.2

Once IFNγ is released, it binds directly to the macrophage’s cell receptors.3,7

The activated macrophage releases even more cytokines, such as TNF, IL-1, and IL-6. This dangerous cycle leads to the hyperinflammatory symptoms of primary HLH.3,7

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

Fever9

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

Cytopenia10

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

Hypertriglyceridemia9,11

  • Activated macrophages release TNF
  • TNF stimulates hepatic lipid synthesis

Hypofibrinogenemia12

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

Hyperferritinemia9,13

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

Elevated soluble CD25 (sCD25)14

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

Hepatosplenomegaly9

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

Elevated liver enzymes9

  • 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

Hemophagocytosis15

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

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, including4,5:

  • 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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