Macrophage migration inhibitory factor (MIF) seems to have an important function in the pathogenesis of granulomatosis with polyangiitis (GPA) according to the results of a new study. In patients with GPA, vasculitis is associated with the formation of inflammatory granulomas. “There remains a lack of clear understanding regarding the formation of granulomas in these patients,” explains corresponding author Antoine Sreih.
MIF is implicated in other granulomatous diseases, such as sarcoidosis and tuberculosis. “We used the comprehensive approach of combining a human genetic study with an experimental animal model to understand the role of MIF in GPA,” says Sreih.
Two MIF promoter polymorphisms have been identified: a -794 CATT6–8 microsatellite (rs5844572) and a -173 G/C SNP (rs755662). Thus, the researchers conducted a multicentre, cross-sectional genetic study of 501 patients with GPA and 576 healthy individuals. 60.2% of patients with GPA carried an increased number of -794 CATT6–8 repeats in their genome, compared with 53.9% of healthy individuals. Patients with GPA also had higher plasma levels of MIF than their disease-free counterparts.
“The experimental model is a mouse model of granulomatous vasculitis induced by injection of Candida albicans β-glucan,” explains Sreih. “To mimic the high-expression MIF polymorphisms in humans, we developed tissue-conditional transgenic mouse lines that overexpress MIF in lung epithelium.”
Mice overexpressing lung epithelial MIF developed more pulmonary granulomas than wild-type mice; they also had increased levels of neutrophil and macrophage chemokines and increased mortality. Injection of an anti-MIF monoclonal antibody reduced lung disease and improved survival in these mice.
Injection of an anti-MIF monoclonal antibody … improved survival in these mice
Notably, an anti-MIF receptor antibody is currently in phase II trials for the treatment of systemic lupus erythematosus, which, if successful, could have implications for the treatment of patients with GPA.
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Sreih, A. G. et al. Role of macrophage migration inhibitory factor in granulomatosis with polyangiitis. Arthritis Rheumatol. https://doi.org/10.1002/art.40655 (2018)
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Leake, I. MIF in granulomatosis with polyangiitis. Nat Rev Rheumatol 14, 501 (2018). https://doi.org/10.1038/s41584-018-0059-8
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DOI: https://doi.org/10.1038/s41584-018-0059-8
