Study Links MIF, D-DT Molecules to Progressive Multiple Sclerosis Development

Two molecules known to regulate cellular signaling contribute to the underlying mechanism of progressive multiple sclerosis (MS), found a recent study conducted by investigators at Oregon Health & Science University (OHSU) and Yale University School of Medicine.

The study, “MIF and D-DT are potential disease severity modifiers in male MS subjects,” appeared in the journal Proceedings of the National Academy of Sciences. The two molecules are macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT).

“If you start a therapy before the disease has progressed very far, you have a much better opportunity to slow it or stop it,” the study’s co-senior author, Arthur Vandenbark, said in a university news release.

“We now have a rational, molecular target for slowing or preventing the transition from relapsing-remitting to progressive MS, a stage of MS which is much more severe,” added Vandenbark, a professor of neurology, molecular microbiology,and immunology at OHSU.

These two proteins are related to each other, as they participate in the same cellular signaling process that regulate the immune system’s response. Previous studies have blamed them for the worsening of several autoimmune and inflammatory disorders including rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus.

The research team found that patients with progressive MS had higher levels of MIF and D-DT proteins than those with the relapsing-remitting form of the disease. In addition, these proteins inflamed the central nervous system, making patients sicker.

An analysis of the genes that encode the proteins revealed that higher levels of MIF were linked to the presence of two genetic variants that are more frequent in patients — particularly males — with progressive disease. Researchers confirmed their findings with animal models of MS-like disease that were genetically engineered to lack MIF and D-DT proteins.

Taken together, this finding suggests that a simple genetic test could identify patients carrying the MIF genetic susceptibility — and therefore more likely to develop a severe form of MS.

“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 and Yale medical professor Richard Bucala.

This study was partially funded by the National Institutes of Health, the National Multiple Sclerosis Society, the Rocky Mountain MS Center Tissue Bank and the U.S Department of Veterans Affairs.