NIH scientists build a cellular blueprint of MS lesions

September 14, 2021
Chronic lesions with inflamed rims, or “smoldering” plaques, in the brains of people with multiple sclerosis have been linked to more aggressive and disabling forms of the disease. Using brain tissue from humans, researchers built a detailed cellular map of chronic MS lesions, identifying genes that play a critical role in lesion repair and revealing potential new therapeutic targets for progressive MS.

Chronic active lesions are characterized by a slow, expanding rim of immune cells called microglia. Microglia normally help protect the brain, but in MS they can become overactive and secrete toxic molecules that damage nerve cells. Other cells found at the edge of the lesions, such as astrocytes and lymphocytes, may also contribute to ongoing tissue damage. Prior studies suggest microglia are the main culprits behind lesion expansion, but the exact types of cells found near lesions and their biological mechanisms are elusive.

To better understand MS lesions, researchers at the National Institutes of Health’s National Institute of Neurological Disorders and Stroke used single-cell RNA sequencing – a powerful technique which enables researchers to catalog gene activity patterns in individual cells – to examine postmortem brain tissue of five MS patients and three healthy controls. By analyzing the gene activity profiles of more than 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.

The team found a great diversity of cell types in the tissue surrounding chronic active lesions compared to normal tissue, and a high proportion of immune cells and astrocytes at the active edges of those lesions. Microglia comprised 25 percent of all immune cells present at the lesion edges. 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.

To determine the function of C1q, researchers knocked out the gene in the microglia of mouse models of MS and examined the brain tissue for signs of neuroinflammation. In mice lacking microglial C1q, they found significantly decreased tissue inflammation compared to control animals. Additionally, in another group of animals, blocking C1q reduced iron-containing microglia, revealing a potential new therapeutic avenue to treat chronic brain inflammation in MS and related neurodegenerative diseases.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, according to the study’s authors, it’s possible that targeting C1q in human microglia could halt MS lesions in their tracks.

The study was published in the journal Nature.

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