New clues to multiple sclerosis triggers and progression
Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, leads to incurable progressive disability, including physical and cognitive impairment and fatigue. Existing MS treatments act broadly on the immune system. But the disease is triggered by environmental factors in genetically predisposed individuals, according to project coordinator Maja Jagodic(opens in new window), professor of Neuroinflammation, Department of Clinical Neuroscience, Karolinska Institute(opens in new window), Stockholm. Jagodic researches epigenetic regulation in people with MS. She has identified epigenetic markers of disease activity and progression based on DNA methylation, which inhibits specific gene expression. “Epigenetic mechanisms, which regulate gene expression without affecting the genetic code, mediate the processes that cause MS,” she explains. “These are the layers of regulation in cells that integrate all the signals, from environmental exposures, external signals and from genetic variants in the body. So, we can use it to understand what goes wrong.” Other groups at Karolinska have focused on the complex interactions between genetic and non-genetic factors in MS in the EU-funded MultipleMS(opens in new window) project. But Jagodic cites the importance of understanding the molecular mechanisms of these complex interactions by studying epigenetic marks. She points to the potential development of new treatments by artificially modifying aberrant epigenetic states.
A viral trigger for MS
The Epi4MS project, which was funded by the European Research Council(opens in new window), found evidence that the Epstein-Barr virus(opens in new window) (EBV), a common pathogen, acts as a trigger for MS by breaking down immune tolerance. This is the body’s ability to distinguish between foreign invaders and its own tissue. In a major breakthrough, the team found that a certain type of immune cell is cross-reactive. Such cells can recognise both EBV, implicated in triggering MS, and the brain proteins, causing harm. “The level of this cross-reactivity is higher than anybody expected,” Jagodic adds. “These cells are more aggressive and more inflammatory. And they have changed their epigenomes, so they can better migrate to the brain tissue.”
MS progression is driven by brain processes
Previously, MS was thought to have two distinct phases: early immune dysregulation, followed by neurodegeneration. Researchers found that neurodegenerative processes begin much earlier and are driven by processes taking place in the target tissue – the brain. “We observed accelerated epigenetic biological ageing in people who are affected,” Jagodic says. The project also revealed that microglia – the brain’s immune cells that maintain brain health – lose their ability to clear cellular debris leading to progressive neurodegeneration. The team used animal models to modify the brain’s ability to recover from inflammatory insult. “The aim is to boost the reparative and regenerative capacity of microglia and target the progressive stage of disease,” she remarks. “Both pharma companies and academia are trying to develop different types of EBV vaccines, potentially preventing MS. But there is truly an unmet need – for those who already have the disease and are entering the second stage of progression – related to the mechanisms taking place in the brain.”
New methodologies and tools
“Cells that are pathogenic in this type of disease are very rare. They also migrate to the brain that is not easily accessible. So we have very limited material to study,” Jagodic explains. Measuring epigenetic changes in rare clinical samples is challenging. Establishing their functional impact on gene expression and cellular phenotypes is even more difficult, she adds. It requires new methodologies to improve the mapping of epigenic marks and the different types of modifications, and tools to artificially modify them to investigate the consequences.