Open AccessDual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus
Author(s) -
Sreih Antoine,
Ezzeddine Rana,
Leng Lin,
LaChance Avery,
Yu Geraldine,
Mizue Yuka,
Subrahmanyan Lakshman,
PonsEstel Bernardo A.,
Abelson AnnaKarin,
Gunnarsson Iva,
Svenungsson Elisabet,
Cavett Joshua,
Glenn Stuart,
Zhang Lin,
Montgomery Ruth,
Perl Andras,
Salmon Jane,
AlarcónRiquelme Marta E.,
Harley John B.,
Bucala Richard
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30624
Subject(s) - macrophage migration inhibitory factor , immunology , proinflammatory cytokine , medicine , genotype , population , cytokine , lupus nephritis , inflammation , biology , gene , genetics , environmental health , disease
Abstract Objective To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients. Methods Two functional polymorphisms in the MIF gene, a −794 CATT 5–8 microsatellite repeat ( rs5844572 ) and a −173 G/C single‐nucleotide polymorphism ( rs755622 ), were assessed for association with SLE in 3,195 patients and healthy controls. We also measured MIF plasma levels in relation to genotypes and clinical phenotypes, and assessed Toll‐like receptor 7 (TLR‐7)–stimulated MIF production in vitro. Results Both Caucasians and African Americans with the high‐expression MIF haplotype −794 CATT 7 /−173*C had a lower incidence of SLE (in Caucasians, odds ratio [OR] 0.63, 95% confidence interval [95% CI] 0.53–0.89, P = 0.001; in African Americans, OR 0.46, 95% CI 0.23–0.95, P = 0.012). In contrast, among patients with established SLE, reduced frequencies of low‐expression MIF genotypes (−794 CATT 5 ) were observed in those with nephritis, those with serositis, and those with central nervous system (CNS) involvement when compared to patients without end‐organ involvement ( P = 0.023, P = 0.005, and P = 0.04, respectively). Plasma MIF levels and TLR‐7–stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. Conclusion These findings suggest that MIF, which has both proinflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High‐expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops, however, low‐expression MIF genotypes may protect from ensuing inflammatory end‐organ damage.