Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalArthritis and Rheumatology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Macrophage Migration-Inhibitory Factors
Granulomatosis with Polyangiitis
Granuloma
Glucans
Lung
Candida albicans
Inbred C57BL Mouse
Chemokines
Knockout Mice
Human Migration
Alleles
Gene Expression
Mortality
Bronchoalveolar Lavage Fluid
Capillary Electrophoresis
Vasculitis
Reporter Genes
Microsatellite Repeats
Therapeutics
Epithelium

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Sreih, A. G., Ezzedine, R., Leng, L., Fan, J., Yao, J., Reid, D., ... Bucala, R. (Accepted/In press). Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis. Arthritis and Rheumatology. https://doi.org/10.1002/art.40655

Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis. / 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 A.; 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.

In: Arthritis and Rheumatology, 01.01.2018.

Research output: Contribution to journalArticle

Sreih, AG, Ezzedine, R, Leng, L, Fan, J, Yao, J, Reid, D, Piecychna, M, Carette, S, Cuthbertson, D, Dellaripa, P, Hoffman, GS, Khalidi, NA, Koening, CL, Langford, CA, Mahr, A, McAlear, CA, Maksimowicz-Mckinnon, K, Monach, PA, Seo, P, Specks, U, St.Clair, EW, Stone, JH, Ytterberg, SR, Edberg, J, Merkel, PA & Bucala, R 2018, 'Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis', Arthritis and Rheumatology. https://doi.org/10.1002/art.40655
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 A. ; 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. / Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis. In: Arthritis and Rheumatology. 2018.
@article{bbab0b3ba9914d0a92bb93e438e9fbba,
title = "Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis",
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.",
author = "Sreih, {Antoine G.} and Rana Ezzedine and Lin Leng and Juan Fan and Jie Yao and Duncan Reid and Marta Piecychna and Simon Carette and David Cuthbertson and Paul Dellaripa and Hoffman, {Gary S.} and Khalidi, {Nader A.} and Koening, {Curry L.} and Langford, {Carol A.} and Alfred Mahr and McAlear, {Carol A.} and Kathleen Maksimowicz-Mckinnon and Monach, {Paul A.} and Philip Seo and Ulrich Specks and St.Clair, {E. William} and Stone, {John H.} and Ytterberg, {Steven R} and Jeffrey Edberg and Merkel, {Peter A.} and Richard Bucala",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/art.40655",
language = "English (US)",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis

AU - Sreih, Antoine G.

AU - Ezzedine, Rana

AU - Leng, Lin

AU - Fan, Juan

AU - Yao, Jie

AU - Reid, Duncan

AU - Piecychna, Marta

AU - Carette, Simon

AU - Cuthbertson, David

AU - Dellaripa, Paul

AU - Hoffman, Gary S.

AU - Khalidi, Nader A.

AU - Koening, Curry L.

AU - Langford, Carol A.

AU - Mahr, Alfred

AU - McAlear, Carol A.

AU - Maksimowicz-Mckinnon, Kathleen

AU - Monach, Paul A.

AU - Seo, Philip

AU - Specks, Ulrich

AU - St.Clair, E. William

AU - Stone, John H.

AU - Ytterberg, Steven R

AU - Edberg, Jeffrey

AU - Merkel, Peter A.

AU - Bucala, Richard

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85050625491&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050625491&partnerID=8YFLogxK

U2 - 10.1002/art.40655

DO - 10.1002/art.40655

M3 - Article

C2 - 29953750

AN - SCOPUS:85050625491

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

ER -