Research suggests interrupting immune response improves multiple
sclerosis outcomes

Date:
March 22, 2022
Source:
West Virginia University
Summary:
Multiple sclerosis is a chronic disease that damages neurons. New
research looks at the role that a protein, STAT5, plays in the
development of MS.



FULL STORY ==========================================================================
A human immune system is a lot like the board game Mouse Trap: it's a
Rube Goldberg system of interacting parts. Only instead of a falling ball causing a tiny diver to leap into a tub -- which, in turn, springs a trap
on some plastic mice -- proteins trigger other proteins to activate immune cells and direct them toward germs. But if those proteins mistakenly
direct immune cells toward healthy tissue, autoimmune diseases like
multiple sclerosis -- which attacks neurons -- can arise.


==========================================================================
A new study led by Kelly Monaghan -- a researcher with the West Virginia University School of Medicine -- suggests that part of the "Rube Goldberg" immune system shows promise as a potential target for MS therapies.

"Anytime you have any kind of central nervous system issues, you have
to go through a series of steps to have cells get into the brain or
spinal cord," said Monaghan, a doctoral candidate in the Department of Microbiology, Immunology and Cell Biology. "Gaining a better understanding
of those immune mechanisms associated with MS can help to inform novel therapies." Her findings appeared in the Proceedings of the National
Academy of Science.

Her study -- funded by the National Institutes of Health -- focused
on STAT5, one of the many proteins circulating in the body that can metaphorically turn genes on or off.

"STAT5 is a transcription factor," Monaghan said. "It is a member
of the STAT protein family, and it has a lot of different roles in
cell proliferation and inflammation. Importantly, STAT5 proteins must
form dimers to regulate gene expression. The interaction of two dimers
results in the formation of tetramers, which regulate an independent set
of target genes." Monaghan and her colleagues wanted to know if STAT5 tetramers played a role in signaling white blood cells to interact and
move through the meninges. If they did play such a role, the researchers
wanted to learn more about it.



==========================================================================
"The meninges, if you don't know, are a series of three membranes that
surround the central nervous system," she said. "They act as a sort of checkpoint, if you will, to regulate the migration of cells into the
actual brain or spinal cord." The infiltration of immune cells into
the meninges is a hallmark of multiple sclerosis.

In particular, Monaghan wanted to investigate the molecular chain of
events that might cause STAT5 tetramers to command another protein --
called CCL17-to tell T cells, a type of white blood cell, to attack
the central nervous system through "friendly fire." Monaghan and her
team used two groups of mice to explore this topic. The first group had
been genetically modified so that its STAT5 tetramer proteins could not rearrange themselves in ways that would trigger the problematic CCL17
response. The second group was genetically normal.

The researchers injected both groups of mice with myelin-reactive T
cells to induce an experimental form of MS called experimental autoimmune encephalomyelitis, or EAE.



==========================================================================
In response, the genetically-normal mice developed EAE in the conventional
way, but the genetically modified mice didn't. Interrupting their STAT5 tetramer "chain reaction" protected them against the disease.

"It wasn't completely ablated, but it was significantly reduced in
severity," Monaghan said. "It was quite convincing that they developed
less severe disease, suggesting that CCL17 is the pathogenic protein
acting downstream of STAT5 tetramers." Not only did the genetically
modified mice display milder and delayed paralysis, but a later
examination of their spinal cords revealed healthier nerves that were
better at transducing signals.

"MS is very complicated," Monaghan said. "We found that the complex
immune interactions between the cells is really what contributes to the difficulty in understanding this disease." Insights like the ones gleaned
from this study can point to future treatments for MS, a condition that
more than 2.3 million people have worldwide, according to the National
Multiple Sclerosis Society.

"Patients diagnosed with MS suffer for a lifetime, and unfortunately,
their clinical symptoms get worst when the disease progresses,"
said Edwin Wan, Monaghan's mentor and an assistant professor in the
Department of Microbiology, Immunology and Cell Biology. "Current drugs
for MS treatments are quite effective at reducing the rate of relapse
but cannot stop disease progression.

The bottleneck of developing more effective drugs is that we do not have
a complete picture about how the disease is initiated and progresses."
The study's findings help to fill in that picture, bringing hypothetical
MS treatments closer to reality.

"I think these findings may also have broader implications to other
autoimmune diseases, too," Monaghan said, "because there may be several
other autoimmune diseases that are regulated by STAT5 tetramers and the downstream signaling pathway, which is quite exciting." Research reported
in this publication was supported by National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award
Number P20GM109098. The content is solely the responsibility of the
authors and does not necessarily represent the official views of NIH.


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


========================================================================== Journal Reference:
1. Kelly L. Monaghan, Drake Aesoph, Amanda G. Ammer, Wen Zheng,
Shokofeh
Rahimpour, Breanne Y. Farris, Camille A. Spinner, Peng Li, Jian-Xin
Lin, Zu-Xi Yu, Vanja Lazarevic, Gangqing Hu, Warren J. Leonard,
Edwin C. K.

Wan. Tetramerization of STAT5 promotes autoimmune-mediated
neuroinflammation. Proceedings of the National Academy of Sciences,
2021; 118 (52) DOI: 10.1073/pnas.2116256118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220322151022.htm

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