Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis.

Authors:
Antoine G Sreih
Antoine G Sreih
University of Ottawa
Rana Ezzedine
Rana Ezzedine
University of Pittsburgh
United States
Lin Leng
Lin Leng
Yale University School of Medicine
New Haven | United States
Juan Fan
Juan Fan
Second Military Medical University
Jie Yao
Jie Yao
Institute for Translational Genomics and Population Sciences
Los Angeles | United States
Duncan Reid
Duncan Reid
Auckland University of Technology
Marta Piecychna
Marta Piecychna
Yale University School of Medicine
United States
Simon Carette
Simon Carette
Mount Sinai Hospital
New York | United States

Arthritis Rheumatol 2018 Dec 22;70(12):2077-2086. Epub 2018 Oct 22.

Yale School of Medicine, New Haven, Connecticut.

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 CATT 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.

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.40655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261690PMC

Still can't find the full text of the article?

We can help you send a request to the authors directly.
December 2018
65 Reads

Publication Analysis

Top Keywords

mif lung-tg21
20
mif
17
lung-tg21 mice
16
pulmonary granulomas
12
patients gpa
12
mice
11
candida albicans
8
mice anti-mif
8
high genotypic
8
gene expression
8
c57bl/6 mice
8
human subjects
8
genotypic mif
8
mif promoter
8
albicans β-glucan
8
migration inhibitory
8
mif expressers
8
macrophage migration
8
mif expression
8
mif-ko mice
8

References

(Supplied by CrossRef)
Mechanisms accounting for granulomatous responses in hypersensitivity pneumonitis
Suga M et al.
Sarcoidosis Vasc Diffuse Lung Dis 1997
Macrophage migration inhibitory factor gene polymorphism is associated with sarcoidosis in biopsy proven erythema nodosum
Amoli MM et al.
J Rheumatol 2002

Similar Publications