Targeting interferon-γ in hyperinflammation: opportunities and challenges

Interferon-gamma (IFN gamma) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFN gamma underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFN gamma in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFN gamma on B cells and T follicular helper cells, a role for IFN gamma in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFN gamma in human disease, IFN gamma-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFN gamma do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFN gamma-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFN gamma production. Interferon-gamma (IFN gamma) is important in innate and adaptive immunity and its overproduction is also implicated in hyperinflammation. Here, De Benedetti and colleagues discuss the evidence for a pathogenetic role of IFN gamma in hyperinflammatory diseases, the search for IFN gamma biomarkers, and the results of clinical trials of IFN gamma-neutralizing therapeutics.

Automated summary

Interferon-gamma (IFN gamma) plays a crucial role in immune responses and its overproduction is associated with hyperinflammation. Research has identified relevant biomarkers related to IFN gamma and shown promising results of IFN gamma-neutralizing agents in the treatment of specific diseases.