Latent virus sparks inflammation in MS

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Latent virus sparks inflammation in MS: 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 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 ± 9.4 cells/mm2) and active

borders of chronic active MS lesions (114.8 ± 9.7 cells/mm2) compared

with inactive MS lesions (18.22 ± 2.8 cells/mm2), normal-appearing

white matter (4.4 ± 1.2 cells/mm2), and control tissue (12.25 ± 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. Lünemann, 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, "

Lünemann 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, " Lünemann 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.

Lünemann reported receiving research support from Baxter

International, the Swiss National Science Foundation, the

Gemeinnutzige Hertie-Stiftung, the Swiss Multiple Sclerosis

Foundation, the Betty and 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.

Additional source: Neurology

Source reference:

Lünemann JD " Epstein-Barr virus in multiple sclerosis: A continuing

conundrum " Neurology 2012; 78: 11-12.

Source: Medpage Today © 2012 Everyday Health, Inc. (04/01/12)