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

Gil Benedek, Roberto Meza-Romero, Kelley Jordan, Ying Zhang, Ha Nguyen, Gail Kent, Jia Li, Edwin Siu, Jenny Frazer, Marta Piecychna, Xin Du, Antoine Sreih, Lin Leng, Jack Wiedrick, Stacy J. Caillier, Halina Offner, Jorge R. Oksenberg, Vijayshree Yadav, Dennis Bourdette, Richard BucalaArthur A. Vandenbark

Research output: Contribution to journalArticle

40 Scopus citations

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 −794CATT58 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.

Original languageEnglish (US)
Pages (from-to)E8421-E8429
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number40
DOIs
StatePublished - Oct 3 2017

Keywords

  • Disease modifier
  • Multiple sclerosis
  • Sex differences

ASJC Scopus subject areas

  • General

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