Investigators at the Howard Hughes Medical Institute (HHMI) have identified a mechanism that might account for how a viral infection starts a vicious cycle of autoimmune disease. The researchers have found that the Epstein-Barr Virus, a mononucleosis culprit, triggers the body’s production of immune T cells displaying Epstein-Barr virus-encoded nuclear antigen1 (EBNA1), and these cells in turn seem to attack central nervous system auto-antigens, through a process called molecular mimicry.
HHMI explains:
Lünemann, Edwards, and colleagues [Nancy Edwards, an HHMI-NIH research scholar at the National Institutes of Health; Jan Lünemann, a neurologist and immunologist at The Rockefeller University in New York -ed.] began by collecting T cells from 20 untreated patients with MS 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 MS 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 MS 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 MS 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 MS 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. “At this point, I really believed we had a story.”
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 MS-like disease,” said Edwards. “So we knew we were looking at the right population of T cells.”
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.
Picture caption: Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) thought to be mediated by T cells attacking the insulating myelin sheath of nerve cells. EBNA1-specific T cells (1) or antibodies (2) could falsely recognize and attack CNS auto-antigens, a process called molecular mimicry. Or EBNA1-specific T cells could ramp up the action of auto-aggressive myelin-specific T cells with soluble pro-inflammatory molecules such as interferon-gamma, a mechanism termed bystander activation (3). In addition, latent EBV antigens could sustain the survival of auto-reactive B cells (4), or they could be triggered by auto-antigens that initiate viral replication (5), in turn elevating EBV-specific T cell responses (6).
The press release…
