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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 A.

Proceedings of the National Academy of Sciences - PNAS, 2017-10, Vol.114 (40), p.E8421-E8429 [Revista revisada por pares]

United States: National Academy of Sciences

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MIF and D-DT are potential disease severity modifiers in male MS subjects
Autor: 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.
Materias: Adult ; Animal models ; Animals ; Antigens, Differentiation, B-Lymphocyte - genetics ; Antigens, Differentiation, B-Lymphocyte - metabolism ; Biological Sciences ; Dopachrome isomerase ; Experimental allergic encephalomyelitis ; Female ; Females ; Gene expression ; Genes ; Histocompatibility Antigens Class II - genetics ; Histocompatibility Antigens Class II - metabolism ; Homology ; Humans ; Inflammation ; Intramolecular Oxidoreductases - genetics ; Intramolecular Oxidoreductases - metabolism ; Intramolecular Oxidoreductases - physiology ; Leukocyte migration ; Macrophage migration inhibitory factor ; Macrophage Migration-Inhibitory Factors - genetics ; Macrophage Migration-Inhibitory Factors - metabolism ; Macrophage Migration-Inhibitory Factors - physiology ; Macrophages ; Male ; Males ; Mice ; Mice, Knockout ; Microsatellites ; Middle Aged ; Migration inhibitory factor ; Multiple sclerosis ; Multiple Sclerosis - genetics ; Multiple Sclerosis - metabolism ; Multiple Sclerosis - pathology ; PNAS Plus ; Polymorphism ; Polymorphism, Genetic ; Rodents ; Severity of Illness Index ; Signaling ; Single-nucleotide polymorphism
Es parte de: Proceedings of the National Academy of Sciences - PNAS, 2017-10, Vol.114 (40), p.E8421-E8429
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
1R.B. and A.A.V. contributed equally to this work.
Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved August 21, 2017 (received for review July 11, 2017)
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.
Descripción: 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.
Editor: United States: National Academy of Sciences
Idioma: Inglés

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

United States: National Academy of Sciences

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