Single nucleus RNA sequencing identifies inflamed brain cells likely involved in MS nerve degeneration

MS nerve degeneration

MRI scans of a patient’s brain showing the chronic active lesions (areas of localized damage marked by arrows within magnified insets) associated with multiple sclerosis (MS). Johns Hopkins Medicine and National Institute of Neurological Disorders and Stroke researchers have identified which brain cell types sustain the chronic inflammation that leads to the signature lesions and nerve degeneration. Credit: Adapted from Absinta et al, Nature, Sept. 8, 2021

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.

Researchers at Johns Hopkins Medicine and NINDS 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  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.

SourceJohns Hopkins Medicine

Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD, Jin J, Fitzgerald KC, Song A, Liu P, Lin JP, Wu T, Johnson KR, McGavern DB, Schafer DP, Calabresi PA, Reich DS. (2021) A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature [Epub ahead of print]. [abstract]

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