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.

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.

Both Caucasians and African Americans with the high‐expression MIF haplotype −794 CATT₇/−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 CATT₅) 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.

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.