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This article is part of the supplement: Lupus 2012: New targets, new approaches

Meeting abstract

Role of MIF gene polymorphisms in systemic lupus erythematosus and prospects for therapeutic intervention

R Bucala

  • Correspondence: R Bucala

Author affiliations

Yale School of Medicine, New Haven, CT, USA

Citation and License

Arthritis Research & Therapy 2012, 14(Suppl 3):A33  doi:10.1186/ar3967

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S3/A33


Published:27 September 2012

© 2012 Bucala; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Meeting abstract

The cytokine macrophage migration inhibitory factor (MIF) counter-regulates the immunosuppressive action of glucocorticoids and inhibits activation-induced apoptosis. MIF is encoded in a polymorphic locus with a variant allele frequency >5% and high-expression alleles are associated with clinical severity of rheumatoid arthritis, scleroderma, and asthma but improved outcome from pneumonia.

We completed a candidate gene association study in SLE (3195 patients and controls) to examine the relationship between two promoter polymorphisms in MIF: a -794 CATT5-8 microsatellite repeat (rs5844572), where increased repeat number leads to greater MIF expression; and a -173 G/C SNP (rs755622) that is in linkage disequilibrium with CATT7. Patients with the high-expression CATT7 allele had lower SLE incidence: OR = 0.63, P = 0.001 in Caucasians and OR = 0.46, P = 0.012 in African-Americans. Among patients with established SLE, those with serositis, nephritis, and cerebritis had reduced frequencies of low-expression MIF genotypes (CATT5) when compared with patients without end-organ involvement (P = 0.005 for serositis, P = 0.023 for nephritis, and P = 0.04 for cerebritis). Plasma MIF levels and TLR4, TLR7, and TLR9 stimulated MIF production reflected the underlying MIF genotype of the studied groups. These data suggest that MIF exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE, perhaps by contributing to enhanced clearance of infectious agents. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage [1].

We also examined the therapeutic impact of MIF antagonism in two mouse models of spontaneous SLE. In both the NZB/NZW F1 and the MRL/lpr mouse strains, anti-MIF or small molecule MIF receptor antagonism reduced functional and histological indices of glomerulonephritis, MIF-R+ leukocyte recruitment, and proinflammatory cytokine and chemokine expression [2]. A humanized anti-MIF developed from our studies has recently entered phase I clinical testing [3].

These data highlight the importance of MIF in the development of autoimmunity and support the potential clinical feasibility of pharmacologic MIF antagonism. We anticipate that MIF antagonists may be most effectively applied in those individuals who, on the basis of their genotype, manifest a MIF-dependent form of autoimmunity.

References

  1. Sreih A, et al.: Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus.

    Arthritis Rheum 2011, 63:3942-3951. PubMed Abstract | Publisher Full Text OpenURL

  2. Leng L, et al.: A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice.

    J Immunol 2011, 186:527-538. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  3. ClinicalTrials.gov Identifier: NCT01541670