Epstein-Barr virus tricks the immune system into triggering inflammation and nerve cell damage which is known to cause MS and ? ME

healthcanal.com, 05/01/2012 :

A new study from researchers at Queen Mary, University of London shows how a particular virus tricks the immune system into triggering inflammation 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 the research has remained controversial since scientists have so far 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, difficulties with walking and fatigue, and tends to strike mainly young and middle-aged women.

Its 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 have failed to find the connection.

The new research, which is published in the journal Neurology, looked at post mortem brains of MS patients, examining areas where neurological damage had recently occurred.

Lead researcher, Dr Ute-Christiane Meier explained: “EBV is quite a clever virus; when it’s 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.”

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’s immune system, causing inflammation. This damages nerve cells in the brain and causes MS symptoms.

Dr Meier continued: “We 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.”

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.

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.

“If we can pinpoint EBV as a trigger, it’s possible that we could alter the course of MS or potentially even prevent the condition by treating the virus,” Dr Meier added.

“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.”

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 and stroke.

This research was supported by the Medical Research Council and MS charities, Roan Charitable Trust and Aims2Cure.
For media information, contact: Alex Fernandes Deputy Head of Communications Queen Mary,
University of London
email: a.fernandes@qmul.ac.uk

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neurology.org/content/78/1/15.abstract:

• Articles

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

1. J.S. Tzartos, DPhil, 
2. G. Khan, PhD, 
3. A. Vossenkamper, MD, 
4. M. Cruz-Sadaba, PhD, 
5. S. Lonardi, MSc, 
6. E. Sefia, MSc, 
7. A. Meager, PhD, 
8. A. Elia, PhD,
9. J.M. Middeldorp, PhD, 
10. M. Clemens, PhD, 
11. P.J. Farrell, PhD, 
12. G. Giovannoni, PhD and 
13. U.-C. Meier, DPhil

+Author Affiliations

1. From the Department of Neuropathology (J.S.T.), John Radcliffe Hospital, University of Oxford, UK; Department of Biochemistry (J.S.T.), Hellenic Pasteur Institute, Athens, Greece; Faculty of Medicine and Health Sciences (G.K.), Department of Microbiology and Immunology, United Arab Emirates University, Al-Ain, UAE; Institute of Cell and Molecular Sciences, Neuroimmunology Group, Neuroscience Centre (U.C.M., G.G., E.S.), and Centre for Infectious Disease (A.V.), Queen Mary University of London, UK; Biotherapeutics (A.M.), National Institute for Biological Standards and Control, Health Protection Agency, South Mimms, Potters Bar, UK; St George's (A.E.), University of London, Basic Medical Sciences, of London, UK; Department of Biochemistry (J.S.T.), Hellenic Pasteur Institute, Athens, Greece; VU University Medical Centre (J.M.), Amsterdam, the Netherlands; Department of Chemistry & Biochemistry (M.C.), School of Life Sciences, University of Sussex, Brighton, UK; Section of Virology (P.F.), Imperial College Faculty of Medicine, London, UK; Department of Surgical Pathology (S.L.), University of Brescia, Italy; and Instituto de Medicina Molecular Aplicada (M.C.S.), University San Pablo, Madrid, Spain.

1. Correspondence & reprint requests to Dr. Meier: u.meier@qmul.ac.uk

ABSTRACT

Objective: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain.

Methods: White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization.

Results: We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro.

Conclusion: These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.

FOOTNOTES

• Study funding: AIMS2CURE (G.G., U.M.), Roan Charitable Trust (U.M., G.G.), MRC grant (G.G.), UAEU FMHS Project Grant (G.K.), Wellcome Trust grant no. WT082609MA (M.C.)