MIF and D-DT are potential disease severity modifiers in male MS subjects


  1. Arthur A. Vandenbarka,b,g,h,1,2

  1. aNeuroimmunology Research, VA Portland Health Care System, Portland, OR 97239;

  2. bTykeson MS Research Laboratory, Department of Neurology UHS-46, Oregon Health & Science University, Portland, OR 97239;

  3. cDepartment of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520;

  4. dBiostatistics & Design Program, School of Public Health, Oregon Health & Science University, Portland, OR 97239;

  5. eDepartment of Neurology, University of California, San Francisco, CA 94143;

  6. fDepartment of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239;

  7. gDepartment of Neurology, Oregon Health & Science University, Portland, OR 97239;

  8. hDepartment of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239
  1. Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved August 21, 2017 (received
    for review July 11, 2017)

Significance

The biological processes that are involved in the progression of multiple sclerosis (MS) are far from complete. Macrophage
migration inhibitory factor (MIF) and its homolog, D-dopachrome tautomerase (D-DT), are immunoregulatory cytokines known to
be involved in the worsening of various autoimmune disorders. We demonstrate that genetically controlled high MIF expression
(and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers. In addition,
we show that MIF or D-DT deficiency ameliorates the disease severity of the murine model of MS. Our data suggest that targeting
CD74, the common receptor for MIF and D-DT, with therapies such as partial MHC class II constructs could be therapeutically
beneficial for inhibiting MS clinical progression in selected patients.

Abstract

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory
factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common
receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive
disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs.
males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly
correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a −794CATT5–8 microsatellite repeat and a −173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental
autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings
indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these
two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically
isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally,
selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both
sexes.

Footnotes

  • Author contributions: G.B., H.O., D.B., R.B., and A.A.V. designed research; G.B., R.M.-R., K.J., Y.Z., H.N., G.K., J.L., E.S.,
    J.F., M.P., X.D., A.S., L.L., and V.Y. performed research; L.L., S.J.C., J.R.O., and R.B. contributed new reagents/analytic
    tools; G.B., R.M.-R., J.W., J.R.O., R.B., and A.A.V. analyzed data; V.Y. and D.B. oversaw the recruitment of MS subjects and
    healthy controls at Oregon Health & Science University; and G.B., R.M.-R., H.O., J.R.O., R.B., and A.A.V. wrote the paper.

  • Conflict of interest statement: A.A.V., H.O., G.B., R.M.-R., and Oregon Health & Science University have a significant financial
    interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the results of this research
    and technology. This potential conflict of interest has been reviewed and managed by the Oregon Health & Science University
    and VA Portland Health Care System Conflict of Interest in Research Committees. R.B. and L.L. are listed as coinventors on
    patents describing migration inhibitory factor and CD74 antagonists, and migration inhibitory factor genotyping.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1712288114/-/DCSupplemental.



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