ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1861

The Role of Macrophage Migration Inhibitory Factor (MIF) and MIF Gene Polymorphisms in the Pathogenesis of Granulomatosis with Polyangiitis

Antoine G. Sreih1, Rana Ezzeddine2, Juan Fan3, Lin Leng3, Simon Carette4, David Cuthbertson5, Gary S. Hoffman6, Nader A. Khalidi7, Carol A. Langford8, Carol McAlear9, Paul Monach10, Philip Seo11, Ulrich Specks12, Steven R. Ytterberg13, Peter A. Merkel14 and Richard Bucala15, 1Medicine/Division of Rheumatology, The University of Pennsylvania, Philadelphia, PA, 2Biostatistics, Bristol-Myers Squibb, Wallingford, CT, 3Yale University, New Haven, CT, 4Division of Rheumatology, University of Toronto, Toronto, ON, Canada, 5Department of Biostatistics, University of South Florida, Tampa, FL, 6Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH, 7Division of Rheumatology, St. Joseph’s Hospital, McMaster University, Hamilton, ON, Canada, 8Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, OH, 9Division of Rheumatology, Vasculitis Center, University of Pennsylvania, Philadelphia, PA, 10Rheumatology, Boston University, Boston, MA, 11Rheumatology Division, Johns Hopkins Vasculitis Center, Johns Hopkins University, Baltimore, MD, 12Frederichs Dr NW, Mayo Clinic, Rochester, MN, 13Division of Rheumatology, Mayo Clinic, Rochester, MN, 14Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, 15Rheum/Dept of Int Med, Yale University School of Med, New Haven, CT

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: Vasculitis II

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Macrophage Migration Inhibitory Factor (MIF) is an immunoregulatory cytokine that may play a central role in the pathogenesis of granulomatous diseases. Two functional polymorphisms have been identified in the MIF gene promoter that correlate with MIF production in vivo: a -794 CATT repeat (rs5844572) and a -173 G/C SNP (rs755622). This project aimed to study the association of MIF polymorphisms and MIF cytokine in granulomatosis with polyangiitis (Wegener’s, GPA) and to examine the role of MIF in a murine model of granulomatous vasculitis induced by Candida albicans water-soluble fraction (CAWS).

Methods:

The human study involved 488 Caucasian patients with GPA and 551 healthy age- and sex-matched controls. Genotyping for the CATT site was performed by PCR plus capillary electrophoresis; SNP analysis was performed by real-time PCR. The frequencies of high expression MIF genotypes (>5 CATT repeats and -173 C SNP) were compared between patients and controls. MIF plasma levels were measured by ELISA in 78 patients and 45 controls. Wild type C57BL/6 mice and MIF lung-transgenic mice, some treated with anti-MIF, were injected with CAWS and analyzed for survival and for pulmonary pathology.

Results:

The percentage of individuals carrying more than 5 CATT repeats (high MIF expression) was 60.9% in patients with GPA and 53.7% in controls (p=0.02). There was no difference in the -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 transgenic mice died when injected with CAWS as compared to wild type (Figure 1A). Injection of anti-MIF mAb protected transgenic mice from dying (Figure 1B). MIF lung-transgenic mice also exhibited more pulmonary granulomas than wild type mice (Mean number = 11.5 ± 0.8 /mm2 in transgenic vs. 7.9 ± 1.4 /mm2 in controls, p=0.1) (Figure 2A and 2B).

Conclusion:

Compared to controls, patients with GPA have an increased frequency of high-expression MIF CATT, and higher plasma MIF levels. In a murine model of granulomatous vasculitis, higher MIF expression increased mortality and pulmonary granulomas while injection of anti-MIF mAb protected mice from dying. MIF seems to play a critical role in the pathogenesis of GPA. Pharmacologic MIF inhibition may offer a promising therapy for GPA.

 

Disclosure:

A. G. Sreih,
None;

R. Ezzeddine,
None;

J. Fan,
None;

L. Leng,
None;

S. Carette,
None;

D. Cuthbertson,
None;

G. S. Hoffman,
None;

N. A. Khalidi,
None;

C. A. Langford,
None;

C. McAlear,
None;

P. Monach,
None;

P. Seo,
None;

U. Specks,
None;

S. R. Ytterberg,
None;

P. A. Merkel,
None;

R. Bucala,

Yale University,

9.

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