Researchers have found that patients with multiple sclerosis carry a population of immune cells that overreact to Epstein-Barr virus.
The virus, which causes mononucleosis and may contribute to some cancers, has long been suspected to play a role in multiple sclerosis. However, the mechanism linking the virus to the disease was poorly understood.

Researchers think that multiple sclerosis, which can cause vision problems, muscle weakness, and difficulty with coordination and balance, is a result of the immune system attacking the body's own nervous system. Not everyone who is infected with Epstein-Barr develops multiple sclerosis, but the results of the new study, published in the journal Brain, suggest that some individuals' unusually strong reaction to the virus may trigger the disease.
The findings could lead to new therapeutic strategies for better control of the damage caused in this autoimmune disorder.

The culprit, the researchers say, may be a population of T cells that helps boost other components of the immune system in response to the virus. " What we discovered in the peripheral blood of the multiple sclerosis patients were T cells that appeared to be primed for action against EBV," said Nancy Edwards, at the National Institutes of Health ( NIH ) and co-author of the paper.

" The susceptibility to acquire multiple sclerosis is inherited, but environmental insults such as viral infections are thought to trigger the disease, and Epstein-Barr virus is one of the leading candidate triggers," said first author Jan Lünemann, at The Rockefeller University in New York. " Epstein-Barr virus does not cause multiple sclerosis, but the immune response to this virus is different in multiple sclerosis patients, and our hypothesis is that the altered immune response contributes to the development and progression of the disease."

The people with multiple sclerosis, who are universally infected with Epstein Barr virus, showed increased antibody responses to certain EBV proteins in previous studies, Lünemann said. " Very recent investigations have shown that such enhanced responses occur years before onset of clinical symptoms of multiple sclerosis," he noted, indicating that EBV plays an important role early in the development of the disease.

" Our aim was to investigate what causes these increased antibody concentrations and if T cell responses to EBV are different in patients with multiple sclerosis," Lünemann said. He and Edwards focused on one viral protein, called Epstein-Barr virus-encoded nuclear antigen1 ( EBNA1 ).

Epstein-Barr virus usually persists life-long inside immune system B cells and is kept under control by virus-specific T cells. When B cells divide, the virus produces EBNA1 and uses it to slip its own DNA into the new cell. T cells that target EBNA1 are a crucial component of EBV-specific immune responses in individuals without multiple sclerosis.

Lünemann, Edwards, and colleagues began by collecting T cells from 20 untreated patients with multiple sclerosis and 20 volunteers who had been infected by Epstein-Barr virus but did not have the autoimmune disease. They then isolated from each patient the T cells that specifically responded to EBNA1.

A series of experiments revealed a pattern among the EBNA1 T cells in multiple sclerosis patients that was not seen in the healthy volunteers. " We saw a dual effect, not only was there an increased number of EBNA1 responsive T cells, but these T cells proliferated to a greater extent when they were stimulated by antigens," said Edwards.

" We also examined T-cell responses to influenza hemagglutinin, antigens derived from cytomegalovirus, and even EBV antigens other than EBNA1," Edwards said. " The T-cell responses to these were all normal in multiple sclerosis patients, indicating a distinct role for EBNA1 in the disorder."

The team then wanted to determine which portion of EBNA1 the T cells were recognizing. Generally, immune cells recognize one small, specific part on a protein, called an immunodominant region. Earlier evidence had pointed to one end of the protein, so the team decided to focus there. Münz supplied a series of 51 peptides, small segments of the EBNA1 protein, that the team added to T cells from multiple sclerosis patients and healthy controls.

As expected, the T cells in the healthy volunteers activated only in the presence of a specific group of peptides. But, Edwards said, " EBNA1-specific T cells from the multiple sclerosis patients not only increased in frequency, but also recognized a much broader region of the protein, compared to healthy people who carried the EBV virus."
Immunologists call this phenomenon epitope-spreading. " This was an interesting and unexpected finding, " said Edwards.

Finally, the team discovered that the hyper-reactive T cells belonged to the CD4 compartment of memory T cells and that these cells were strong producers of interferon-gamma, an anti-viral protein that shapes immune responses. " Animal research has shown that pro-inflammatory CD4 cells directed against central nervous system antigens can trigger an multiple sclerosis-like disease," said Edwards.

The next step will be to determine how these over-reactive immune cells trigger the destruction of the myelin sheathing that insulates nerve cells. " The broadened response of the T cells could lead them to recognize and attack cells they aren't supposed to, like brain cells," said Münz. This process, called molecular mimicry, is seen in other autoimmune disorders, such as lupus.

Source: Howard Hughes Medical Institute, 2006


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