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Latent virus sparks inflammation in MS
01-07-2012, 12:10 PM
Post: #1
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 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 ± 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 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.

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)
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