The role of macrophage migration inhibitory factor in the pathogenesis of granulomatosis with polyangiitis

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Objective: Macrophage Migration Inhibitory Factor (MIF) is an immunoregulatory cytokine that may play a role in the pathogenesis of granulomatous diseases. This study examined the association between two functional promoter polymorphisms [-794 CATT5-8 microsatellite (rs5844572) and a-173 G/C single nucleotide polymorphism (SNP) (rs755622)], MIF plasma levels, and granulomatosis with polyangiitis (Wegener's, GPA) and the role of MIF in an experimental murine model of granulomatous vasculitis. Methods: The study involved 501 patients with GPA and 576 healthy controls. The frequencies of high expression MIF genotypes (>5 CATT repeats and-173 C SNP) together with MIF plasma levels were compared between patients and healthy controls. Granulomatous disease was induced in wild type, MIF knockout, and MIF lungtransgenic C57BL/6 mice by injection of Candida albicans b-glucan; some mice were additionally treated with anti-MIF, and mortality and pulmonary pathology was measured. Granulomas were stained with anti-MIF or control antibodies. Results: The percentage of individuals carrying>5 CATT repeats in each MIF allele (high MIF expressers) was 60.9% in patients with GPA and 53.7% in controls (p=0.05). There was no difference in the frequency of-173 G/C SNP polymorphisms between these groups. Patients with GPA had higher mean plasma MIF levels than controls (15.9 +/-10.4 ng/dl vs. 6.7 +/-5 ng/dl, p<0.0001). A significantly higher percentage of MIF lung-transgenic mice died when injected with Candida albicans b-glucan as compared to MIF-knockout and wild type controls (Figure 1A), and anti-MIF mAb protected against lethal granulomatous disease (Figure 1B). MIF lung-transgenic mice also exhibited more and MIF-knockout mice exhibited fewer pulmonary granulomas than wild type mice (Figure 1C). There was increased immunostaining for MIF in alveolar epithelial cells and infiltrating mononuclear cells in pulmonary granulomas (Figure 1D). Conclusions: Patients with GPA have an increased frequency of highexpression MIF CATT and higher plasma MIF levels when compared to controls. In a murine model of granulomatous vasculitis, higher MIF expression increased mortality and pulmonary granulomas while anti-MIF protected mice from dying. The MIF locus appears to contribute to the pathogenesis of GPA and pharmacologic blockade of MIF may offer potential therapy for GPA (Figure presented).




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