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 Vandenbark

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

Fingerprint

Multiple Sclerosis
Macrophage Migration-Inhibitory Factors
Sex Factors
Autoimmune Experimental Encephalomyelitis
dopachrome isomerase
Microsatellite Repeats
Single Nucleotide Polymorphism
Genotype
Therapeutics
Genes

Keywords

  • Disease modifier
  • Multiple sclerosis
  • Sex differences

ASJC Scopus subject areas

  • General

Cite this

MIF and D-DT are potential disease severity modifiers in male MS subjects. / Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley; Zhang, Ying; Nguyen, Ha; Kent, Gail; Li, Jia; Siu, Edwin; Frazer, Jenny; Piecychna, Marta; Du, Xin; Sreih, Antoine; Leng, Lin; Wiedrick, Jack; Caillier, Stacy J.; Offner, Halina; Oksenberg, Jorge R.; Yadav, Vijayshree; Bourdette, Dennis; Bucala, Richard; Vandenbark, Arthur.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 40, 03.10.2017, p. E8421-E8429.

Research output: Contribution to journalArticle

Benedek, G, Meza-Romero, R, Jordan, K, Zhang, Y, Nguyen, H, Kent, G, Li, J, Siu, E, Frazer, J, Piecychna, M, Du, X, Sreih, A, Leng, L, Wiedrick, J, Caillier, SJ, Offner, H, Oksenberg, JR, Yadav, V, Bourdette, D, Bucala, R & Vandenbark, A 2017, 'MIF and D-DT are potential disease severity modifiers in male MS subjects', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 40, pp. E8421-E8429. https://doi.org/10.1073/pnas.1712288114
Benedek, Gil ; Meza-Romero, Roberto ; Jordan, Kelley ; Zhang, Ying ; Nguyen, Ha ; Kent, Gail ; Li, Jia ; Siu, Edwin ; Frazer, Jenny ; Piecychna, Marta ; Du, Xin ; Sreih, Antoine ; Leng, Lin ; Wiedrick, Jack ; Caillier, Stacy J. ; Offner, Halina ; Oksenberg, Jorge R. ; Yadav, Vijayshree ; Bourdette, Dennis ; Bucala, Richard ; Vandenbark, Arthur. / MIF and D-DT are potential disease severity modifiers in male MS subjects. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 40. pp. E8421-E8429.
@article{365325c2fa9d4fe3ac84520ee3053f45,
title = "MIF and D-DT are potential disease severity modifiers in male MS subjects",
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.",
keywords = "Disease modifier, Multiple sclerosis, Sex differences",
author = "Gil Benedek and Roberto Meza-Romero and Kelley Jordan and Ying Zhang and Ha Nguyen and Gail Kent and Jia Li and Edwin Siu and Jenny Frazer and Marta Piecychna and Xin Du and Antoine Sreih and Lin Leng and Jack Wiedrick and Caillier, {Stacy J.} and Halina Offner and Oksenberg, {Jorge R.} and Vijayshree Yadav and Dennis Bourdette and Richard Bucala and Arthur Vandenbark",
year = "2017",
month = "10",
day = "3",
doi = "10.1073/pnas.1712288114",
language = "English (US)",
volume = "114",
pages = "E8421--E8429",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "40",

}

TY - JOUR

T1 - MIF and D-DT are potential disease severity modifiers in male MS subjects

AU - Benedek, Gil

AU - Meza-Romero, Roberto

AU - Jordan, Kelley

AU - Zhang, Ying

AU - Nguyen, Ha

AU - Kent, Gail

AU - Li, Jia

AU - Siu, Edwin

AU - Frazer, Jenny

AU - Piecychna, Marta

AU - Du, Xin

AU - Sreih, Antoine

AU - Leng, Lin

AU - Wiedrick, Jack

AU - Caillier, Stacy J.

AU - Offner, Halina

AU - Oksenberg, Jorge R.

AU - Yadav, Vijayshree

AU - Bourdette, Dennis

AU - Bucala, Richard

AU - Vandenbark, Arthur

PY - 2017/10/3

Y1 - 2017/10/3

N2 - 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.

AB - 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.

KW - Disease modifier

KW - Multiple sclerosis

KW - Sex differences

UR - http://www.scopus.com/inward/record.url?scp=85030219641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030219641&partnerID=8YFLogxK

U2 - 10.1073/pnas.1712288114

DO - 10.1073/pnas.1712288114

M3 - Article

C2 - 28923927

AN - SCOPUS:85030219641

VL - 114

SP - E8421-E8429

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 40

ER -