title: Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus.
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.
  
  
  CONCLUSIONS
  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.
authors: Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors: Antoine
authors: A
authors: Sreih
authors: Rana
authors: R
authors: Ezzeddine
authors: Lin
authors: L
authors: Leng
authors: Avery
authors: A
authors: LaChance
authors: Geraldine
authors: G
authors: Yu
authors: Yuka
authors: Y
authors: Mizue
authors: Lakshman
authors: L
authors: Subrahmanyan
authors: Bernardo A
authors: BA
authors: Pons-Estel
authors: Anna-Karin
authors: AK
authors: Abelson
authors: Iva
authors: I
authors: Gunnarsson
authors: Elisabet
authors: E
authors: Svenungsson
authors: Joshua
authors: J
authors: Cavett
authors: Stuart
authors: S
authors: Glenn
authors: Lin
authors: L
authors: Zhang
authors: Ruth
authors: R
authors: Montgomery
authors: Andras
authors: A
authors: Perl
authors: Jane
authors: J
authors: Salmon
authors: Marta E
authors: ME
authors: Alarcón-Riquelme
authors: John B
authors: JB
authors: Harley
authors: Richard
authors: R
authors: Bucala
mesh_terms: D000328:Adult; D001741:Black or African American / Q000208:ethnology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D044465:White People / Q000208:ethnology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha