*MS Article* CNS can send out signals to invite auto-immune attacks

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CNS can send out signals to invite autoimmune attacks

Jun 16, 2006, 23:49, Reviewed by: Dr. Priya Saxena

" Experiments by others suggested that natalizumab prevented immune cells

from crossing the blood-brain barrier — it was thought to prevent the

cells from leaving the blood stream, "

By Washington University School of Medicine in St. Louis, It may sound

like a case of blame the victim, but researchers at Washington

University School of Medicine in St. Louis have shown that cells in the

central nervous system can sometimes send out signals that invite

hostile immune system attacks. In mice the researchers studied, this

invitation resulted in damage to the protective covering of nerves,

causing a disease resembling multiple sclerosis.

" It's been clear for quite a while that our own lymphocytes (white blood

cells) have the ability to enter the central nervous system and react

with the cells there, " says , Ph.D., professor of molecular

biology and pharmacology. " Under normal circumstances, the brain and the

immune system cooperate to keep out those cells that might harm the

brain. But in people with multiple sclerosis, they get in. "

The researchers found that they could prevent destructive immune cells

from entering nervous system tissue by eliminating a molecular switch

that sends " come here " messages to immune cells. Ordinarily, flipping

that switch would cause immune cells to rush to the vicinity of the

cells that sent the signals and destroy whatever they consider a danger

— including nerve cell coatings.

But in the mice in which the switch was removed, the researchers saw

that immune cells previously primed by the scientists to attack the

central nervous system (CNS) did not enter the CNS, and the mice stayed

healthy.

In contrast, normal mice treated with the same hostile immune cells had

numerous immune cells in their CNS tissue and developed symptoms similar

to multiple sclerosis.

" What allows the primed lymphocytes into the CNS are signals from the

CNS asking them in, " says. " We determined that the astrocytes,

the specialized cells that provide nutrients to neurons, are among the

cells most active in sending signals to attract lymphocytes. "

The molecular switch that sends the call to immune cells is termed the

tumor necrosis factor receptor (TNFR). When TNFR is activated, it causes

cells to send out signal molecules called chemokines that direct immune

cells to the site of damage or infection. The researchers found that

astrocytes in mice were producing chemokines in response to activation

of their TNFR molecules.

TNFR activation also makes the astrocytes bristle with specific adhesion

molecules that act like Velcro to bind to similar molecules on the

surface of the immune cells. That allows the immune cells that are

attracted by the chemokines to stick around and do more harm.

One of the most promising new drugs for treating multiple sclerosis,

natalizumab (tradename Tysabri), works by blocking the ability of the

immune cells to stick in the CNS through this Velcro mechanism,

notes. Natalizumab is being tested in clinical trials and appears to be

much better at preventing the nerve cell destruction associated with

multiple sclerosis than previous therapies.

" Experiments by others suggested that natalizumab prevented immune cells

from crossing the blood-brain barrier — it was thought to prevent the

cells from leaving the blood stream, " says. " We are working on

that question, and we think that it doesn't necessarily prevent them

from getting out of the blood, but it does keep them from getting

further into the brain. The immune cells pile up in the space around the

blood vessels. This space, the perivascular space, serves as a

gatekeeper to determine what gets in and what doesn't. "

Next, the research team will study various regions of the brain to

determine the types of signals sent to and from different areas of the

CNS to the immune system.

- Gimenez MA, Sim J, Archambault AS, Klein RS, JH. A tumor

necrosis factor dependent receptor 1-dependent conversation between

central nervous system-specific T cells and the central nervous system

is required for inflammatory infiltration of the spinal cord. American

Journal of Pathology 2006;168(4):1200-1209.

medicine.wustl.edu

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Written By Gwen son

Funding from the National Institutes of Health, the National Multiple

Sclerosis Society and Pfizer Inc. supported this research.

Washington University School of Medicine's full-time and volunteer

faculty physicians also are the medical staff of -Jewish and St.

Louis Children's hospitals. The School of Medicine is one of the leading

medical research, teaching and patient care institutions in the nation,

currently ranked fourth in the nation by U.S. News & World Report.

Through its affiliations with -Jewish and St. Louis Children's

hospitals, the School of Medicine is linked to BJC HealthCare.

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