Novel immune cell population may trigger inflammation in multiple
sclerosis and other brain disorders

Date:
December 1, 2021
Source:
Weill Cornell Medicine
Summary:
A group of immune cells that normally protect against inflammation
in the gastrointestinal tract may have the opposite effect in
multiple sclerosis (MS) and other brain inflammation-related
conditions, according to a new study. The results suggest that
countering the activity of these cells could be a new therapeutic
approach for such conditions.



FULL STORY ==========================================================================
A group of immune cells that normally protect against inflammation in the gastrointestinal tract may have the opposite effect in multiple sclerosis
(MS) and other brain inflammation-related conditions, according to a new
study by Weill Cornell Medicine and NewYork-Presbyterian researchers. The results suggest that countering the activity of these cells could be a
new therapeutic approach for such conditions.


==========================================================================
The researchers, who reported their finding Dec. 1 in Nature, were
studying a set of immune cells called group 3 innate lymphoid cells
(ILC3s), which help the immune system tolerate beneficial microbes and
suppress inflammation in the intestines and other organs throughout the
body. They discovered a unique subset of these ILC3s that circulate in
the bloodstream and can infiltrate the brain -- and, to their surprise,
do not quench inflammation but instead ignite it.

The scientists called this subset inflammatory ILC3s, and found them in
the central nervous system of mice with a condition modeling MS. Instead
of constraining the immune response, this subset of ILC3s spurred another
group of immune cells called T cells to attack myelinated nerve fibers,
leading to MS- like disease symptoms. The researchers detected similar inflammatory ILC3s in the peripheral blood and cerebrospinal fluid of
MS patients.

"This work has the potential to inform our understanding of, and
potential treatments for, a broad variety of conditions involving T-cell infiltration of the brain," said senior author Dr. Gregory Sonnenberg, associate professor of microbiology and immunology in medicine in the
Division of Gastroenterology and Hepatology and a member of the Jill
Roberts Institute for Research in Inflammatory Bowel Disease at Weill
Cornell Medicine.

MS affects more than two million people worldwide. Other conditions that feature chronic brain inflammation afflict tens of millions more and
include Alzheimer's and Parkinson's diseases. There is also evidence
that neuroinflammation develops naturally with aging and is a major
factor in age- related cognitive decline, and more recently inflammatory
T-cell responses in the brain have been linked to neurological symptoms associated with SARS-CoV- 2 infection.

The researchers have shown in recent work that ILC3s residing in the
gut act as sentinels and immune regulators, suppressing inflammation -- including inflammatory T-cell activity -- and warding off cancer. In the
new study, they examined the roles of ILC3s in the brain, and found,
contrary to their expectation, that ILC3s are not normally present in
the brain under healthy conditions but can infiltrate the brain from
the bloodstream during inflammation. When they do infiltrate the central nervous system, they have pro-inflammatory rather than anti-inflammatory effects.



==========================================================================
The researchers showed with a mouse model of MS that these inflammatory
ILC3s in the brain function as antigen-presenting cells: They display
bits of myelin protein, the main ingredient in the insulating layer
around nerve fibers, to T cells -- prompting them to attack myelin,
causing the nerve damage that gives rise to disease signs. They found
the inflammatory ILC3s in close association with T cells in regions of
active inflammation and nerve damage in the mouse brains.

"The infiltration of these inflammatory ILC3s to the brains and spinal
cords of mice coincides with the onset and peak of disease," said first
author John Benji Grigg, a Weill Cornell Graduate School of Medical
Sciences doctoral candidate in the Sonnenberg laboratory. "Further, our experimental data in mice demonstrate these immune cells play a key role
in driving the pathogenesis of neuro-inflammation." The researchers
discovered that they could prevent MS-like disease in the animals by
removing from the ILC3s a key molecule called MHCII, which normally is
used in the antigen-presenting process -- the removal essentially blocks
the cells' ability to activate myelin-attacking T cells.

"Despite our very best disease-modifying therapies for MS, patients
continue to progress, and since disease onset is early in life, they
face the prospect of permanent physical and cognitive disability,"
said co-author Dr. Tim Vartanian, professor of neuroscience in the Feil
Family Brain and Mind Institute at Weill Cornell Medicine, chief of the division of multiple sclerosis and neuro- immunology and a professor of neurology in the Department of Neurology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.

"Identification of inflammatory ILC3s with antigen presentation
capabilities in the central nervous system of people with MS offers a
new strategic target to prevent nervous system injury." Finally, the researchers discovered that ILC3s that reside in other tissues in the
body can be programmed, in effect, to counter the activity of brain- infiltrating T cells, preventing the MS-like condition disease in mice.

This work was completed in close collaboration with Dr. Ari Waisman,
director of the Institute for Molecular Medicine at the University Medical Center of Johannes Gutenberg University Mainz, where the researchers
built on prior research demonstrating that there are gut-resident ILC3s
that display antigens to T cells in a slightly different way to promote
T-cell inactivity, or "tolerance." The researchers demonstrated that
by experimentally exposing these tolerance-inducing intestinal ILC3s
to myelin, they could block neuroinflammatory T-cell activity and the development of MS-like disease in the mice.

The work therefore points to the possibility that MS and potentially
many other inflammatory conditions could someday be treated either by
directly inhibiting the activity of inflammatory ILC3s that infiltrate
the brain, or by targeting self-antigens to the intestinal ILC3s that
promote tolerance in other tissues, Dr. Sonnenberg said.

========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. John B. Grigg, Arthi Shanmugavadivu, Tommy Regen, Christopher N.

Parkhurst, Anees Ahmed, Ann M. Joseph, Michael Mazzucco, Konrad
Gronke, Andreas Diefenbach, Gerard Eberl, Timothy Vartanian,
Ari Waisman, Gregory F. Sonnenberg. Antigen-presenting innate
lymphoid cells orchestrate neuroinflammation. Nature, 2021; DOI:
10.1038/s41586-021-04136-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211201203919.htm

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