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Targeting interferon-γ in hyperinflammation: opportunities and challenges

Nature Reviews Rheumatology volume 17, pages 678–691 (2021)Cite this article

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Abstract

Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ 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 IFNγ 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 IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-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 IFNγ production.

Key points

  • Hyperinflammation is characterized by excessive systemic inflammation resulting from an exaggerated immune response to physiological stimuli, which eventually leads to tissue damage.

  • Haemaphagocytic lymphohistiocytoses (HLHs) are hyperinflammatory diseases and are considered canonical cytokine release syndromes.

  • Studies of interferon-γ (IFNγ) biology have shed light on the role of this immune modulator in various hyperinflammatory diseases, such as the different forms of HLH, and also in other immune-mediated diseases.

  • IFNγ hyperproduction is a feature of the different forms of HLH, and IFNγ neutralization decreases disease severity and reverts lethality in mouse models of HLH.

  • As serum IFNγ levels do not always reflect IFNγ overproduction in tissue in patients, efforts are underway to identify biomarkers that are easily measurable in blood and reflect tissue IFNγ activity.

  • Therapeutic IFNγ neutralization shows promising results in early clinical trials in patients with various forms of HLH.

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Fig. 1: The IFNγ signalling pathway.
Fig. 2: Sources and roles of IFNγ in health and disease.

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Acknowledgements

The authors wish to thank Cristina de Min for her expert interèretation of the clinical trials with anti-IFNγ therapies and for critically revising the manuscript.

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Authors and Affiliations

  1. Division of Rheumatology and Laboratory of ImmunoRheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy

    Fabrizio De Benedetti, Giusi Prencipe, Claudia Bracaglia & Emiliano Marasco

  2. Division of Rheumatology, ML 4010, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Alexei A. Grom

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  1. Fabrizio De Benedetti
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  2. Giusi Prencipe
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  3. Claudia Bracaglia
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  4. Emiliano Marasco
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Fabrizio De Benedetti.

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Competing interests

F.D.B. has received research grants from AbbVie, Novartis, Pfizer, Roche, Sanofi, Novimmune and Sobi. A.A.G. has served as a consultant for Sobi, AB2Bio, Juno and Novartis, and has received research support from Novartis, Sobi and AB2Bio. G.P., C.B. and E.M. declare no competing interests.

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Nature Reviews Rheumatology thanks E. Brisse, who co-reviewed with P. Matthys, R. Planas, who co-reviewed with J. Pachlopnik Schmid, and R. Badolato for their contribution to the peer review of this work.

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De Benedetti, F., Prencipe, G., Bracaglia, C. et al. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol 17, 678–691 (2021). https://doi.org/10.1038/s41584-021-00694-z

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