September 28, 2021

A cellular map of brain lesions in multiple sclerosis

At a Glance

  • Researchers created a detailed map of cells in the expanding lesions involved in more disabling forms of multiple sclerosis.
  • The findings reveal potential new therapeutic targets for progressive disease.
MRI scan of a human brain with multiple sclerosis Researchers used single-cell RNA sequencing to map the cells found at the edges of chronic MS lesions. Reich lab, NIH/NINDS

Multiple sclerosis (MS) is a long-lasting condition that affects the brain and spinal cord. It occurs when the body’s immune system attacks the protective layer that forms around nerve cells, called myelin. This can lead to vision loss, muscle weakness, problems with balance and coordination, fatigue, numbness, and other debilitating symptoms. A subset of people will develop progressive MS, resulting in extensive brain tissue damage and disability.

There is no cure for MS. Anti-inflammatory medications that quiet the immune system can help MS patients manage their symptoms. But treatments are not as effective for patients with chronic active lesions—areas of damage or scarring that slowly expand. These “smoldering” MS lesions are visible on MRI scans as dark-rimmed spots on the brain.

A previous study found that chronic active lesions are linked to more aggressive and disabling forms of MS. The research team, led by Dr. Daniel Reich of NIH’s National Institute of Neurological Disorders and Stroke (NINDS), set out to learn more about the cells that drive these chronic active lesions. Results appeared in Nature on September 8, 2021.

The team used single-cell RNA sequencing to map the cells found at the edges of chronic MS lesions. Single-cell RNA sequencing is a powerful technique that enables researchers to catalog gene activity patterns in individual cells. The researchers analyzed the gene activity profiles of over 66,000 cells from post-mortem human brain tissue. The samples were taken from five MS patients and three healthy controls.  

The scientists were able to create the first comprehensive map of cell types involved in chronic lesions, as well as their gene activity patterns and interactions. They found a great diversity of cell types in the tissue surrounding chronic active lesions compared to healthy brain tissue. These included elevated numbers of immune cells and astrocytes at the active edges of lesions. Astrocytes are a type of glial cell—a class of cells that support neurons in the nervous system.

The team also found that microglia made up 25% of all immune cells at the lesion edges. Microglia normally help protect the brain, but in MS and other neurodegenerative diseases, they can become overactive and secrete toxic molecules that damage nerve cells. 

Further work revealed that the gene for complement component 1q (C1q), an important and evolutionarily ancient protein of the immune system, was activated mainly in a subgroup of microglia responsible for driving inflammation. This suggests that C1q may contribute to lesion progression.

To test this idea, the researchers removed the gene in the microglia of a mouse model of MS. The mice lacking microglial C1q had significantly less brain tissue inflammation than control animals. Blocking C1q in mice also reduced the number of microglia involved in damage in the lesions.

These results suggest that targeting C1q in human microglia might halt MS lesions. The findings could help in the development of new treatments for progressive MS.

“We identified a set of cells that appear to be driving some of the chronic inflammation seen in progressive MS,” Reich says. “These results also give us a way to test new therapies that might speed up the brain’s healing process and prevent brain damage that occurs over time.”

Related Links

References: A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. 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. Nature. 2021 Sep 8. doi: 10.1038/s41586-021-03892-7. Online ahead of print. PMID: 34497421.

Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS); Adelson Medical Research Foundation; Conrad N. Hilton Foundation; Cariplo Foundation.