Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to focal lesions (areas of localized damage) in the brain and spinal cord. Some patients with MS have lesions with “rims” of inflammation — known as chronic active lesions — that contribute to more rapid disability accumulation (when a patient with MS experiences multiple losses of physical abilities) than in people without rim lesions.

To better understand how lesion edge inflammation causes brain cells to degenerate in MS, researchers at Johns Hopkins Medicine and the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) have identified which brain cell types sustain the chronic inflammation that leads to the signature lesions.

In a study published Sept. 8, 2021, in the journal Nature, the Johns Hopkins Medicine and NINDS team determined that microglia (tiny immune cells that specifically protect the brain) and astrocytes (special glial cells that perform numerous support functions for the central nervous system) are the specific cellular subtypes that are inflamed in MS chronic active lesions.

Using a new technique called single nucleus RNA sequencing, the researchers identified what the microglia and astrocyte cells are doing when inflamed. They determined how these inflammatory cells communicate with each other while damaging brain tissue, and used this insight to look for a means to stop the process.

The team — which included Johns Hopkins Medicine neurologists Martina Absinta, M.D., Ph.D.; Peter Calabresi, M.D., co-director of the Johns Hopkins Multiple Sclerosis Precision Medicine Center; and Daniel Reich, M.D., Ph.D., a Johns Hopkins trainee who now directs the Translational Neuroradiology Section at NINDS — focused its investigation on C1q, a molecule associated with the activation of the immune response in inflamed microglia. Using a series of experiments, the group determined that without C1q, the microglia do not activate and stay uninflamed.

“In theory, we suggest that inhibiting C1q in patients with MS could reduce the detrimental smoldering inflammation persisting in these chronic active brain lesions,” says study lead author Absinta. “The great thing is that we have imaging biomarkers [biological tags for detecting chronic inflammation with MRI scans], so we can see the hot spots and be able to identify patients who might benefit from such treatment.”

“This study highlights the power of precision medicine to not only identify patients at risk of more severe disease, but to leverage novel technologies to identify specific therapeutic targets for people with progressive MS, a form of the disease that is often resistant to treatment,” says Calabresi.

“We found commonalities in the inflamed microglia subpopulation with other neurodegenerative diseases like Alzheimer’s,” says Absinta. “We hope that this finding encourages clinicians to explore similar therapeutic approaches.”

Absinta says the next steps in this research are to design clinical trials using the MRI biomarker and potentially the precision medicine targets identified in this study.

This study was supported by the Intramural Research Program of NINDS, the Adelson Medical Research Foundation, the Conrad N. Hilton Foundation and the Cariplo Foundation.