NIH scientists build a cellular blueprint of multiple sclerosis lesions

Chronic lesions with inflamed rims, or "smoldering" plaques, in the brains of people with multiple sclerosis (MS) have been linked to more aggressive and disabling forms of the disease. Using brain tissue from humans, researchers at the National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS) 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. 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 Daniel Reich, M.D., Ph.D., senior investigator at NINDS. "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. 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. Other cells found at the edge of the lesions, such as astrocytes and lymphocytes, may also contribute to ongoing tissue damage. Prior studies suggest that 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, Dr. Reich and his colleagues used single-cell RNA sequencing, a powerful technique which enables researchers to catalog gene activity patterns in individual cells, to examine post-mortem brain tissue of five MS patients and three healthy controls. Samples were provided by the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands, and the NINDS Neuroimmunology Clinic.

"Single-cell RNA sequencing technology allows us to do a much deeper dive into the types of cells present in MS lesions," said Dr. Reich.

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.

Dr. Reich's 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% of all immune cells present at the lesion edges.

"Our dataset is very rich. The beauty of having such a detailed map is that now we have a better understanding of the entire network of cells involved in smoldering inflammation," said Martina Absinta, M.D., Ph.D., a former post-doctoral fellow in Dr. Reich’s lab and current adjunct assistant professor at Johns Hopkins University, Baltimore, who led the study.

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.

According to the authors, it’s possible that targeting C1q in human microglia could halt MS lesions in their tracks.

In MS, the immune system attacks myelin, a protective layer that forms around nerve cells in the brain and spinal cord, leading to vision loss, muscle weakness, problems with balance and coordination, fatigue, numbness, and other debilitating symptoms. A subset of people develop progressive MS, resulting in extensive brain tissue damage and disability. Anti-inflammatory medications help patients manage their symptoms by dampening the responses of immune cells in the blood and lymph nodes. But treatments are not as effective for patients with chronic lesions who experience ongoing brain tissue inflammation.

"We have terrific therapies that block new inflammation but nothing to stop the inflammation that's already there," said Dr. Reich. "In order to make strides in developing new therapies for progressive MS, we’re going to need to pick apart the cellular and molecular mechanisms one by one."

In 2019, Dr. Reich and his team reported that damaging, chronic active lesions may be a hallmark of progressive MS. The current study identifies microglia and C1q as promising targets for progressive MS and supports the use of chronically inflamed rim lesions as an MRI biomarker for disease progression.

There is no cure for MS, and no therapies that directly treat chronic active lesions. 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.

This study was supported in part by the Intramural Research Program at the NINDS.

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.
A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis.
Nature, September 8, 2021. doi: 10.1038/s41586-021-03892-7

Most Popular Now

Primary endpoint met in COMET-TAIL Phase III trial…

GlaxoSmithKline plc (LSE/NYSE: GSK) and Vir Biotechnology, Inc. (Vir) (Nasdaq: VIR) announced headline data from the randomised, multi-centre, open-label COMET-TAIL Phase...

Merck and Ridgeback's molnupiravir, an oral COVID-…

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Ridgeback Biotherapeutics announced that the United Kingdom Medicines and Healthcare products Re...

Two billion doses of AstraZeneca’s COVID-19 vaccin…

AstraZeneca and its partners have released for supply two billion doses of their COVID-19 vaccine to more than 170 countries across every continent on the planet in the l...

Johnson & Johnson COVID-19 vaccine named one o…

The editors of Time announced that the Johnson & Johnson COVID-19 vaccine has been selected as one of Time's Best Inventions of 2021. The vaccine, for which Johnson & ...

New target for COVID-19 vaccines identified

Next generation vaccines for COVID-19 should aim to induce an immune response against 'replication proteins', essential for the very earliest stages of the viral cycle, c...

Safety concerns raised for neuroblastoma candidate…

St. Jude Children's Research Hospital scientists looking for drugs to improve survival of children with high-risk neuroblastoma found a promising candidate in CX-5461. Th...

Pfizer's novel COVID-19 oral antiviral treatment c…

Pfizer Inc. (NYSE: PFE) today announced its investigational novel COVID-19 oral antiviral candidate,PAXLOVID™, significantly reduced hospitalization and death, based on a...

Repurposing a familiar drug for COVID-19

For the past year and a half, the COVID-19 pandemic has continued to engulf the globe, fueled in part by novel variants and the uneven distribution of vaccines. Every day...

'Dancing molecules' successfully repair severe spi…

Northwestern University researchers have developed a new injectable therapy that harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal ...

Researchers reveal a strategy for next-generation …

A study led by the Garvan Institute of Medical Research has revealed a guide to developing COVID-19 vaccines that both prevent the coronavirus from infecting human cells ...

A target for potential cancer drugs may, in fact, …

In recent years, much scientific effort and funding has focused on developing drugs that target an enzyme with the unwieldy name of Src homology 2-containing protein tyro...

Pfizer to provide U.S. government with 10 million …

Pfizer Inc. (NYSE: PFE) today announced an agreement with the U.S. government to supply 10 million treatment courses of its investigational COVID-19 oral antiviral candid...