Epstein-Barr virus (EBV) has long been a prime suspect in the genesis of multiple sclerosis (MS), but like T.S. Eliot’s Mystery Cat, Macavity, it is just not there when the crime scene – in this case the central nervous system (CNS) - is searched. Yes, one or two viral sightings around MS lesions have been reported, but these findings have never been reproduced by other scientists.
However, the circumstantial evidence for an EBV trigger in MS is compelling. A number of studies, for example, have shown that the risk of developing MS is about 15 times higher in people who are EBV positive and two to three fold higher in those who develop infectious mononucleosis than in their asymptomatic counterparts. “Indeed,” says Richard Ransohoff, MD from the Cleveland Clinic in Ohio, “it has become clear that multiple sclerosis is almost never dissociated from prior EBV infection.”
Destruction of Myelin Sheaths in the CNS Appears to Be Collateral Damage
Why disease-initiating EBV is rarely if ever found in the vicinity of neuronal destruction may just have been explained by Joan M. Goverman and her colleagues at the University of Washington in Seattle. Using a specialized mouse model of MS, Dr. Goverman has identified a subset of warrior white blood cells known as CD8+ T cells* with dual antigen receptors; one specific for a virus and another that recognizes brain-specific myelin. Notably, T cells expressing dual antigen receptors exist in humans as well as mice.
When these particular T cells meet up with an EBV it alerts them to a possible viral invasion and they circulate throughout the body searching for and destroying any EBV-infected host cells they find. But they also attack the axon-protecting myelin sheaths in the CNS recognized by their second antigen receptors. Thus, an initial viral infection can trigger a CD8+ T cell-induced autoimmunity; an ongoing active viral infection is not needed – that one viral encounter is enough to drive a sustained autoimmune response.
Looking at a Different Set of T Cells Pays Off
Few scientists have studied CD8+ T cells, preferring to investigate CD4+ T cell instead because of their strong connection with MS susceptibility. Moreover, CD4+ T cells play a major role in experimental MS-like disease in mice, making them easier to investigate than CD8+ T cells.
But, says Goverman, “we decided to investigate CD8+ T cells because they typically outnumber CD4+ T cells in both acute and chronic lesions of MS patients and they also appear [to be] more antigen-driven than CD4+ T cells in the blood and central nervous system of individuals with this disease.” To do this, Goverman and her team of scientists had to invent a whole new kind of mouse, a TCR-transgenic one that generates CD8+ T cells which recognize myelin basic protein (MBP).
When these mice were infected with a wild-type vaccinia virus which does not encode MBP they unexpectedly became ill with a virulent type of autoimmune encephalomyelitis demonstrating that CD8+ T cell tolerance can be broken by an activating virus. Importantly, T-cell tolerance was broken only in the cells with dual antigen receptors.
“This [work] is highly relevant,” says Dr. Ransohoff, “as CD8+ T cells are the predominant subtype found in lesions of multiple sclerosis….”
A Few Words About MS and EBV
MS, an inflammatory, demyelinating autoimmune disease of the CNS, affects more than a million people worldwide. The expert consensus is that MS occurs when genetically predisposed people are exposed to environmental factors that trigger a breakdown in T-cell tolerance to myelin antigens. Once activated, these T cells attack the myelin sheaths surrounding axons in the brain and spinal cord causing nerve cells to fray and eventually break altogether.
EBV is a notoriously bad virus, generally hiding in B lymphocytes between bouts of biological ill will. In addition to its association with MS, EBV is known to cause a broad spectrum of human malignancies including Burkitt’s lymphoma, Hodgkin’s lymphoma, AIDS-associated lymphoma and nasopharyngeal carcinoma. Classified as a human herpesvirus 4 (HHV-4), EBV infects more than 95% of the adult human population worldwide. Like other herpesviruses, EBV can remain latent for a lifetime and sometimes reactivate.
*CD stands for ‘cluster of differentiation’- a marker used to differentiate one cell type from another.
Research details and other information can be found in:
Ji Q, Perchellet A, Goverman JM. "Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs." Nature Immunology. July 2010; 11: pp.628-634. (Posted online June 6th; doi:10.1038/ni.1888)
Ransohoff RM. "Turning over the ^Chance card on MS susceptibility." Nature Immunology. July 2010; 11: pp. 570-572.
Kumar P, Abhik S, Robertson ES. "Epstein-Barr Virus Hijacks Cell-Cycle Machinery." Microbe. June 2010; 5 (6): pp. 251-256.
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