has investigated the role of EBV in ME and CFS in subgroups of
patients.
Epstein-Barr to MS Brain Lesions & Potentially Other Disorders Involving th=
e CNS
ProHealth.com
January 6, 2012
Study demonstrates how EBV sequestered in the brain causes the nerve
cell damage of MS =96 suggests it may play a role in other disorders,
and may respond to rituximab, or antiviral therapies the researchers
are now preparing for trial
A new study by researchers at Queen Mary, University of London shows
how the Epstein-Barr virus tricks the immune system into triggering an
acute inflammatory process and nerve cell damage in the brain, which
is known to cause MS.
Previous research has suggested a link between the Epstein-Barr virus
(EBV) and multiple sclerosis, but until now the research has remained
controversial, since scientists had failed to substantiate the link.
The new study proves the virus is involved in a manner more
sophisticated and subtle than previously imagined, and may offer new
ways to treat or prevent the disease.
MS is a neurological condition that affects around 100,000 people in
the UK. It can cause vision problems and difficulties with walking and
fatigue, and tends to strike mainly young and middle-aged women.
Its root causes are not completely understood, but both genes and
environment are known to play a role. Some previous research has
suggested that EBV triggers MS, but subsequent studies had failed to
find the connection.
The new research, published Jan 3 by the journal Neurology, looked at
post mortem brains of MS patients, examining areas where neurological
damage had recently occurred. (See =93Association of innate immune
activation with latent Epstein-Barr virus in active MS lesions.=94)
Dr. Ute-Christiane Meier from Barts and the London Medical School,
part of Queen Mary, led the research. She explained:
=93EBV is quite a clever virus; when it=92s not growing and spreading it
can hide away in our immune cells... In this study we used a different
technique which allowed us to detect the virus in the brains of some
people affected by MS, even when it was hiding away in the cells.=94
Dr Meier and her team of collaborators found that, although the virus
was not actively spreading, it was releasing a chemical message into
areas of the brain nearby.
This chemical message - made up of small RNA molecules - was
activating the body=92s immune system, causing inflammation. This
damages nerve cells in the brain and causes MS symptoms.
Dr Meier continued:
=93We have to be careful and have to study more MS brains, but this is
potentially very exciting research. Now we understand how EBV gets
smuggled into the brain by cells of the immune system and that it is
found at the crime scene, right where the attack on our nervous system
occurs. Now we know this, we may have a number of new ways of treating
or even preventing the disease.=94
Possible Target for Rituximab or Anti-Virals
One possibility is the widely-used cancer treatment Rituximab; a drug
which is known to kill the cells of the immune system in which the
virus hides. It is now being trialed as a treatment for MS - as well
as myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).
Another possible approach, using anti-viral treatment, will be tested
in clinical trials currently in preparation by Professor Gavin
Giovannoni and colleagues, also at Queen Mary.
Dr. Meier adds:
=93If we can pinpoint EBV as a trigger, it=92s possible that we could
alter the course of MS or potentially even prevent the condition by
treating the virus. MS so often strikes young women, and its
unpredictable nature makes it an incredibly difficult disease to live
with. We desperately need better ways to tackle the condition.=94
Interestingly, the research also hinted that infection with EBV and
its action on the immune system could also be playing a role in other
brain diseases such as cancer (e.g., lymphoma) and stroke.
This research was supported by the Medical Research Council and MS
charities, Roan Charitable Trust and Aims2Cure.
Source: Based on Queen Mary University of London press release, Jan 4, 2012
A previous MedPage Today article stated:
Epstein-Barr virus may play a role in multiple sclerosis (MS) by
activating innate immune responses, researchers found.
Examination of postmortem brain tissue turned up RNA segments of the
virus specifically in areas of active MS lesions overexpressing an
inflammatory cytokine involved in innate immunity, according to a
study by Ute C. Meier, DPhil, of Queen Mary University of London, and
colleagues.
That cytokine, interferon-alpha, was overexpressed in active areas of
white matter MS lesions but not in inactive lesions, normal-appearing
white matter, or normal brain tissue from controls, the group reported
online in Neurology.
Significantly higher densities of cells labeling for interferon-alpha
were present in acute MS lesions (130 =B1 9.4 cells/mm2) and active
borders of chronic active MS lesions (114.8 =B1 9.7 cells/mm2) compared
with inactive MS lesions (18.22 =B1 2.8 cells/mm2), normal-appearing
white matter (4.4 =B1 1.2 cells/mm2), and control tissue (12.25 =B1 2
cells/mm2, P<0.0001).
"Perhaps [the subtle role] is not too surprising as Epstein-Barr virus
is a persistent virus with the aim to coexist rather than eradicate
the host," the authors wrote.
The virus has a strong epidemiologic link to MS, they pointed out.
Individuals who have had a symptomatic case of infectious
mononucleosis from Epstein-Barr virus are twice as likely to later
develop MS, with risk appearing higher for smokers.
Determining the mechanism for the link to Epstein-Barr virus could aid
in developing better treatments for the neurodegenerative disease,
Meier's group suggested, and there could be broader implications as
well.
"Our study casts new light on mechanistic interactions of viral RNAs
and innate immune activation in the [central nervous system], and may
highlight the propensity of latent viral infections to contribute to
neuroinflammation in the CNS, not only in multiple sclerosis but also
in other neuroinflammatory diseases," they wrote.
Their study revitalizes debate over how common Epstein-Barr
virus-infected B cells are in MS brains and whether they are a driving
factor, Jan D. L=FCnemann, of the University of Zurich, Switzerland,
noted in an accompanying editorial.
But even if the accumulation of Epstein-Barr virus-infected B cells in
such lesions represent merely bystanders, that doesn't necessarily
make them silent and innocent, he wrote.
Rather than requiring active infection, the latent infection in these
immune cells appeared to stimulate or maintain innate immune responses
contributing to the inflammatory milieu in MS lesions.
In the seven MS patients' postmortem brain tissue studied, active MS
lesions (defined by the presence of dense lymphocytic infiltrates with
numerous B cells) all contained Epstein-Barr virus infected cells.
But few of those infected cells expressed a viral protein indicating
active replication, suggesting "that viral gene expression is limited
to a few proteins that are expressed during latent infection,"
L=FCnemann explained.
Such cells weren't unique to MS, but were also detected in CNS tissue
from two control patients with stroke, which the researchers pointed
out is also a disease in which inflammation plays an important role.
Notably, Epstein-Barr virus-positive cells were present in much higher
numbers in active MS lesions than expected in peripheral blood B
cells, "which suggests that these cells are recruited to or accumulate
in CNS infiltrates," L=FCnemann noted.
Meier's group also tested the process by infecting human embryonic
kidney cells with Epstein-Barr virus-encoded RNA and found that this
significantly stimulated interferon-alpha production.
Interferon-alpha showed up in macrophages and microglia suggesting
local production as part of an acute inflammatory process.
"Thus even latent Epstein-Barr virus infection can trigger
interferon-alpha production observed in active multiple sclerosis
lesions, and therefore contribute to the neuroinflammation," the
investigators concluded.
The study was supported by AIMS2CURE, the Roan Charitable Trust, and
grants from the Medical Research Council, UAEU FMHS Project, and the
Wellcome Trust.
Meier reported receiving research support from British Technology
Group, ABN/MS Society, Aims2Cure, and the Roan Charitable Trust.
L=FCnemann reported receiving research support from Baxter
International, the Swiss National Science Foundation, the
Gemeinnutzige Hertie-Stiftung, the Swiss Multiple Sclerosis
Foundation, the Betty and David Koetser Foundation, and the Ernst
Schering Foundation.
Primary source: Neurology
Source reference:
Tzartos JS, et al "Association of innate immune activation with latent
Epstein-Barr virus in active MS lesions" Neurology 2012; 78: 15-23.
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