Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis Conference Paper uri icon

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abstract

  • OBJECTIVE: To examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis. METHODS: The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF -794 CATT5-8 promoter microsatellite (rs5844572). MIF promoter, CATT-length-dependent gene expression in response to β-glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β-glucan into wild-type (WT) or Mif-knockout (Mif-KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung-Tg2.1). Mice were treated with a neutralizing anti-MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality. RESULTS: The percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif-KO mice. A significantly higher percentage of Mif lung-Tg2.1 mice, compared to Mif-KO or WT mice, died when injected with Candida albicans β-glucan, and treatment of these mice with an anti-MIF monoclonal antibody protected against a lethal outcome. Levels of MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung-Tg2.1 mice. CONCLUSION: Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung-Tg2.1 mice, while anti-MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.

authors

  • Sreih, Antoine G
  • Ezzedine, Rana
  • Leng, Lin
  • Fan, Juan
  • Yao, Jie
  • Reid, Duncan
  • Piecychna, Marta
  • Carette, Simon
  • Cuthbertson, David
  • Dellaripa, Paul
  • Hoffman, Gary S
  • Khalidi, Nader
  • Koening, Curry L
  • Langford, Carol A
  • Mahr, Alfred
  • McAlear, Carol A
  • Maksimowicz‐Mckinnon, Kathleen
  • Monach, Paul A
  • Seo, Philip
  • Specks, Ulrich
  • St.Clair, E William
  • Stone, John H
  • Ytterberg, Steven R
  • Edberg, Jeffrey
  • Merkel, Peter A
  • Bucala, Richard

publication date

  • December 2018

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