Summary: Yale-led researchers have identified two related cytokines that may help explain why some people develop progressive multiple sclerosis (MS). Their work suggests a straightforward genetic test could identify patients at higher risk of progressing to the severe form of the disease.
Source: Yale University
Researchers from Yale University, Oregon Health & Science University, and the University of California have identified two closely related cytokines — macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) — that appear to drive disease progression in some people with multiple sclerosis. These molecules, which influence immune cell signaling and movement, are linked to increased inflammation in the central nervous system and to the transition from relapsing-remitting MS to progressive MS.
The study was published in the Proceedings of the National Academy of Sciences.
Investigators found elevated levels of MIF and D-DT in men with progressive MS compared with men who have relapsing-remitting MS and with female MS patients. They also observed that higher MIF expression correlated with specific genetic variants in the MIF promoter region — notably a −794CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism — that were more common among males with progressive disease. In addition, the research detected sex-related differences in the immune receptor CD74, which may further influence disease severity.
These discoveries indicate that a simple genetic test for MIF high-expression variants could help identify MS patients at elevated risk of progression. As therapies that target the MIF pathway advance in development, selecting patients with that genetic susceptibility could make treatment more precise and effective. Such a precision-medicine approach could spare patients unlikely to benefit from unnecessary exposure, reduce development costs, and accelerate clinical trials.
“The value of this discovery to patients is that there are now approved therapies, as well as new ones in development in the Oregon and Yale labs, which target the MIF pathway and could be directed toward progressive MS,” said co-senior author Richard Bucala, M.D., professor of medicine, pathology, and epidemiology and public health at Yale. He added that using a genetic test to select patients who may benefit most from MIF inhibitors would streamline drug development by reducing cost and toxicity while providing a genetically tailored treatment.
“If you start a therapy before the disease has progressed very far, you have a much better opportunity to slow it or stop it,” said co-senior author Arthur Vandenbark, professor of neurology and molecular microbiology and immunology at the OHSU School of Medicine. “We now have a rational, molecular target for slowing or preventing the transition from relapsing-remitting to progressive MS, a stage of MS that is much more severe.”
The team combined clinical patient observations, immune profiling, and DNA analysis with laboratory models. In experimental autoimmune encephalomyelitis, a commonly used mouse model of MS, animals lacking MIF or D-DT developed milder disease. Complementing those genetic studies, researchers showed that a therapeutic agent previously developed to treat MS-like disease in rodents can block the pathological actions of both MIF and D-DT at their immune receptor — representing the first demonstration of a molecular intervention that neutralizes both homologs.
Multiple sclerosis is a chronic neurological disease affecting roughly 2.3 million people worldwide. In MS, damage to the protective sheath (myelin) around nerve fibers in the brain and spinal cord disrupts electrical signaling, causing symptoms that can include vision problems, muscle weakness, coordination and balance difficulties, and cognitive impairment. Progressive MS is characterized by gradual worsening of neurological function and fewer inflammatory attacks, and it remains the most disabling form of the disease.
Other authors on the study include 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 Caillier, Halina Offner, Jorge R. Oksenberg, Vijayshree Yadav, and Dennis Bourdette.
Funding: The research received support from the National Institutes of Health, the National Multiple Sclerosis Society, the Rocky Mountain MS Center Tissue Bank, and the Department of Veterans Affairs. Several authors and Oregon Health & Science University have a financial interest in Artielle ImmunoTherapeutics, Inc., a company that may benefit commercially from these findings and technologies.
Source: Ziba Kashef, Yale University
Original research: The peer-reviewed study is titled “MIF and D-DT are potential disease severity modifiers in male MS subjects,” published in Proceedings of the National Academy of Sciences (PNAS), September 2017, by 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 Bucala, and Arthur A. Vandenbark.
MIF and D-DT are potential disease severity modifiers in male MS subjects
Mechanisms that drive progression from relapsing-remitting to progressive MS are not well understood. In this study, investigators measured MIF and D-DT levels and examined their genetic regulation and functional roles. They found higher MIF and D-DT concentrations in males with progressive MS compared with males with relapsing-remitting MS and with female MS patients. Increased MIF and D-DT in progressive males correlated with two promoter polymorphisms that raise MIF expression. Conversely, mice genetically deficient in MIF or D-DT showed milder experimental autoimmune encephalomyelitis, implicating both proteins as co-pathogenic contributors. The authors propose that genetically determined high MIF expression promotes MS progression in males and that early, targeted anti-MIF treatment for males with high-expresser genotypes might delay or prevent progression. Targeting MIF:CD74 signaling could also offer a measurable therapeutic strategy for MS patients of both sexes.