"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 t
Source:Howard Hughes Medical Institute