IFNG dimer binds IFNG inhibitors

Stable Identifier
R-HSA-9689680
Type
Reaction [binding]
Species
Homo sapiens
Compartment
extracellular region
ReviewStatus
5/5
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IFNG dimer binds IFNG inhibitors
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Interferons (IFNs) are cytokines that play a central role in initiating immune responses, especially antiviral and antitumor effects. The proinflammatory interferon-gamma (INFG) exerts its effect on cells by interacting with its specific IFN-gamma receptor (IFNGR) complex. Aberrant IFNG expression is associated with a number of autoinflammatory and autoimmune diseases. IFNG inhibitors such as the monoclonal antibodies emapalumab and fontolizumab bind and inhibit INFG, preventing it binding to its endgenous receptor and damping down the immune response in some autoinflammatory and autoimmune diseases.

INFG has a strong causal role in the pathogenesis of the fatal inflammatory disease Hemophagocytic lymphohistiocytosis (HLH). Schmid et al. demonstrated that blocking IFNG had a therapeutic effect in two different murine models of human hereditary HLH (Schmid et al. 2009). Targeted therapy with emapalumab can improve survival in patients with HLH (Lounder et al. 2019). Fontolizumab is a humanized monoclonal antibody and an immunosuppressive drug for the treatment of autoimmune diseases like Crohn's disease (Reinisch et al. 2010, Hommes et al. 2006). Fontolizumab binds to and inhibits human IFNG (Bourne et al. 2004), resulting in inhibition of expression of IFNG-regulated genes known to be upregulated in Crohn’s disease.
Literature References
PubMed ID Title Journal Year
15388922 Three-dimensional structures of a humanized anti-IFN-gamma Fab (HuZAF) in two crystal forms

Edmundson, AB, Terzyan, SS, Landolfi, NF, Bourne, PC, Vásquez, M, Cloud, G

Acta Crystallogr. D Biol. Crystallogr. 2004
20049711 Neutralization of IFNgamma defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice

Ferlin, W, Fischer, A, Geissmann, F, Kosco-Vilbois, M, Chrétien, F, Pachlopnik Schmid, J, de Saint Basile, G, Pivert, G, Ho, CH, Lefebvre, JM

EMBO Mol Med 2009
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Orthologous Events
IFNG dimer binds IFNG inhibitors (Bos taurus)
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IFNG dimer binds IFNG inhibitors (Danio rerio)
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IFNG dimer binds IFNG inhibitors (Rattus norvegicus)
IFNG dimer binds IFNG inhibitors (Sus scrofa)
Authored
Jassal, B  (2021-03-25)
Reviewed
Huddart, R  (2022-03-01)
Created
Jassal, B  (2020-05-21)
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