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.

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.

Figure 1

Diagram of the human MIF gene showing its three exons, predicted transcription factor binding sites, and the −173 G/C SNP (rs 755622) and −794 CATT_5-8 (rs 5844572) polymorphisms. The numerical prefixes refer to nucleotide distance upstream from the transcription start site. The −173C allele, −794 CATT₇ and −794 CATT ₈ repeats, and −794 CATT₇/−173C haplotype are associated with higher expression of MIF.

Figure 2

A). MIF plasma levels in SLE patients and controls grouped by ethnicity. The columns depict the mean level of MIF in 116 Caucasian patients and 55 healthy controls, and 44 African-American patients and 44 healthy controls. Values are mean ± SEM. **p<0.001 by unpaired t test. B). MIF plasma levels in SLE patients grouped by MIF haplotype. The columns depict the mean level of MIF in 17 Caucasian patients and 41 African-American patients with either the high expression, 7C or the low expression, 5G MIF haplotype. Values are mean ± SEM. *p<0.001 by unpaired t test. C). TLR7 induced MIF release from PBMCs is regulated by MIF haplotype. The columns depict MIF released by Monocytes from Caucasian individuals with low expression, 5G (n=20) or high expression, 7C (n=10) MIF haplotype. Values are mean ± SEM. *p=0.046 by unpaired t test. D). Correlation between MIF and TNFα plasma levels in 160 Caucasian and African-American SLE patients. TNFα and MIF levels were positively correlated, r²=0.19, p=0.04 by Spearman correlation test.