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Role of macrophage migration inhibitory factor in granulomatosis with polyangiitis

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Sreih AG1, Ezzedine R2, Leng L3, Fan J3, Yao J3, Reid D3, Piecychna M3, Carette S4, Cuthbertson D5, Dellaripa P6, Hoffman GS7, Khalidi NA8, Koening CL9, Langford CA7, Mahr A10, McAlear CA1, Maksimowicz-Mckinnon K11, Monach PA12, Seo P13, Specks U14, St Clair W15, Stone JH16, Ytterberg SR14, Edberg J17, Merkel PA1,18, Bucala R3. Arthritis Rheumatol. 2018 Jun 28. doi: 10.1002/art.40655. [Epub ahead of print]

Abstract

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1 Division of Rheumatology, University of Pennsylvania, Philadelphia, USA.

2 Department of Biostatistics, Bristol-Myers Squibb, Wallingford, USA.

3 Section of Rheumatology, Yale School of Medicine, New Haven, USA.

4 Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

5 Health Informatics Institute, University of South Florida, Tampa, USA.

6 Division of Pulmonology, Brigham and Women's Hospital, Harvard University, Boston, USA.

7 Department of Rheumatology, Cleveland Clinic Foundation, Cleveland, USA.

8 Division of Rheumatology, St. Joseph's Healthcare, McMaster University, Hamilton, Canada.

9 Division of Rheumatology, University of Utah, Salt Lake City, USA.

10 Division of Rheumatology, Department of Medicine and Epidemiology, Hôpital Saint Louis, Paris, France.

11 Division of Rheumatology, Henry Ford Hospital, Wayne State University, Detroit, USA.

12 Section of Rheumatology, Boston University, Boston, USA.

13 Division of Rheumatology, Johns Hopkins University, Baltimore, USA.

14 Division of Rheumatology and Pulmonary, Mayo Clinic College of Medicine, Rochester, USA.

15 Division of Rheumatology, Duke University, Durham, USA.

16 Division of Rheumatology, Massachusetts General Hospital, Harvard University, Boston, USA.

17 Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA.

18 The Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Abstract

OBJECTIVE: This study examined the association between Macrophage Migration Inhibitory Factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA), and MIF's role in a murine model of granulomatous vasculitis.

METHODS: The human study involved 1077 patients with GPA and controls. Genotyping for the MIF -794 CATT5-8 promoter microsatellite (rs5844572) was performed by capillary electrophoresis. MIF promoter CATT-length dependent expression in response to β-glucan was assessed by gene reporter assays. Granulomatous disease was induced in wild type (WT), Mif -/- (Mif-KO), and Mif lung-transgenic (Mif lung-Tg2.1) C57BL/6 mice by injection of Candida albicans β-glucan (CAG). Mice were treated with a neutralizing anti-MIF and analyzed for lethality, pulmonary granulomas and inflammatory chemokine expression.

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 (adjusted p=0.049). Human MIF gene expression increased proportionally by CATT-length in response to granulomatous stimulation. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT, which in turn showed more granulomas than Mif-KO. A significantly higher percentage of Mif lung-Tg2.1 mice died when injected with CAG when compared to Mif-KO or WT, and anti-MIF protected against lethal disease. MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage or plasma of Mif lung-Tg2.1 mice.

CONCLUSION: Patients with GPA have an increased frequency of high-expression MIF CATT alleles. Higher MIF expression increased mortality and pulmonary granulomas while anti-MIF protected mice from lethal disease. MIF blockade in high genotypic MIF expressers may offer a selective pharmacologic therapy for GPA.