Author:
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 A.
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.
Funder
National Multiple Sclerosis Society
U.S. Department of Veterans Affairs
HHS | NIH | National Institute of Neurological Disorders and Stroke
HHS | National Institutes of Health
Alliance for Lupus Research
Publisher
Proceedings of the National Academy of Sciences
Cited by
81 articles.
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