Scientists Build Cellular Blueprint of MS Lesions

A new study lays the groundwork for potential new therapies for progressive multiple sclerosis. Chronic lesions with inflamed rims, or “smoldering” plaques, in the brains of people with MS have been linked to more aggressive and disabling forms of the disease. Using brain tissue from humans, NINDS researchers built a detailed cellular map of chronic MS lesions, identifying genes that play a critical role in lesion repair. The study was published in Nature.

“We identified a set of cells that appear to be driving some of the chronic inflammation seen in progressive MS,” said NINDS senior investigator Dr. Daniel Reich. “These results 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.”

Chronic active lesions are characterized by a slow, expanding rim of immune cells called microglia. Normally, microglia help protect the brain. But in MS and other neurodegenerative diseases, microglia can become overactive and secrete toxic molecules that damage nerve cells.

To better understand MS lesions, Reich and colleagues used single-cell RNA sequencing to examine post-mortem brain tissue of 5 MS patients and 3 healthy controls. Samples were provided by the Netherlands Brain Bank and the NINDS Neuroimmunology Clinic.

By analyzing the gene activity profiles of over 66,000 cells from human brain tissue, researchers created the first comprehensive map of cell types involved in chronic lesions, as well as their gene expression patterns and interactions.

More detailed analyses revealed that the gene for complement component 1q (C1q), an important and evolutionarily ancient protein of the immune system, was expressed mainly by a subgroup of microglia responsible for driving inflammation, suggesting that it may contribute to lesion progression.

In mouse models, knocking out the C1q gene led to significantly decreased tissue inflammation. Study authors contend it’s possible that targeting C1q in human microglia could halt MS lesions in their tracks.

For progressive MS, anti-inflammatory medications help patients manage their symptoms, but treatments are not as effective for patients with chronic lesions who experience ongoing brain tissue inflammation. By gaining a deeper understanding of lesion features, this study may help pave the way toward early clinical trials to test new therapies for this aspect of the disease.