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 A.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank the University of California, San Francisco MS Tissue Bank for contributing samples to this study. This work was supported by National Multiple Sclerosis Society Grant RG3794-B-6 (to A.A.V.); the Rocky Mountain MS Center Tissue Bank, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Grant BX000226 (to A.A.V.); NIH Grants R01NS080890 (to H.O.), AR049610, and AR050498 (to R.B.); and the Alliance for Lupus Research Grant 24735 (to R.B.). The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government.
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
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 -