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 at the National Institutes of Health’s National
Institute of Neurological Disorders and Stroke (NINDS) built a detailed
cellular map of chronic multiple sclerosis lesions, identifying genes that play a
critical role in lesion repair and revealing potential new therapeutic
targets for progressive multiple sclerosis. 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 multiple sclerosis,” said Daniel Reich MD
PhD, 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 multiple sclerosis 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 multiple sclerosis lesions, Dr. Reich and his colleagues used
single-cell RNA sequencing, a powerful technique that enables
researchers to catalog gene activity patterns in individual cells, to
examine post-mortem brain tissue of five multiple sclerosis 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 multiple sclerosis 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
“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 MD
PhD 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 multiple sclerosis 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 multiple sclerosis and related neurodegenerative
According to the authors, it’s possible that targeting C1q in human microglia could halt multiple sclerosis lesions in their tracks.
In multiple sclerosis, 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 multiple sclerosis, 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 multiple sclerosis,
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
multiple sclerosis. The current study identifies microglia and C1q as promising targets
for progressive multiple sclerosis and supports the use of chronically inflamed rim
lesions as an MRI biomarker for disease progression.
There is no cure for multiple sclerosis, 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.
Source: News Release
September 10, 2021