Epstein-Barr deaths tied to faulty protein.

Most people don't even know when they've got Epstein-Barr virus. Usually, it strikes in early childhood, when the symptoms are a mild fever or nothing at all. A few people dodge the Epstein-Barr virus when young, contracting it in adolescence or later as mononucleosis, a manageable disease.

In about one in a million cases, however, Epstein-Barr virus sets off a chain reaction that causes immune cells to multiply recklessly, leading to fatal cases of mononucleosis, lymph cancer, or a shortage of disease-fighting antibodies. This syndrome--called X-linked lympho-proliferative disease, or Duncan disease--strikes boys almost exclusively and kills 70 percent of its victims before age 10. No one with Duncan disease has been known to reach age 40.

Two teams of scientists in Europe and the United States have now pinpointed a genetic mutation that causes this fatal sensitivity to Epstein-Barr virus.

Analyzing data from Britain, France, Germany, Italy, and the United States, researchers report in the October NATURE GENETICS that 9 of 16 unrelated patients with Duncan disease had mutations in the SH2D1A gene, which encodes a protein that plays an instrumental role in the immune system. Without a gene to provide the blueprint for a usable SH2D1A protein, Duncan disease appears inevitable, they find. No significant mutation appeared in 50 healthy men.

Another group of researchers from the United States, Austria, and Italy unveils the function of SH2D1A protein in the Oct. 1 Nature. After studying defective signaling between immune cells in Duncan disease patients, they traced the problem back to the mutated SH2DIA gene. The researchers report that normal SH2D1A protein halts runaway proliferation of immune cells.

Viruses need to invade a living cell in order to replicate, and the host cell of choice for the Epstein-Barr virus is the immune system's own B lymphocyte, a white blood cell. The fever and fatigue that mononucleosis patients feel "is really the immune system bringing the B cells under control," says David N. Liebowitz, a virologist and oncologist at the University of Chicago. "The body recognizes they are infected and not normal and tries to kill them and prevent them from killing the host."

It is at this stage that Duncan disease goes beyond mononucleosis and poses a deadly paradox: The body puts up a massive immune response, but to no avail. Instead of killing rogue B cells, immune system T cells coexist peacefully with them, apparently because of the defective SH2D1A protein, says Juan Sayos, an immunologist at Beth Israel Deaconess Medical Center in Boston and a coauthor of the Nature paper. Other immune cells also fail to kill off the infected cells.

T and B cells both have surface proteins called SLAM (for signaling lymphocyte-activation molecule) that hook up to each other like jigsaw puzzle pieces. This SHA3V1 docking site enables the immune cells to communicate, wade into battle together, and reproduce indefinitely. Unfortunately, SLAM doesn't always know when to quit. Working SH2D1A protein on T cells normally modulates this immune process by limiting the SLAM protein's activity.

Tragically, people with a mutated SH2D1A lose this blocking capability, and their T and B cells keep signaling each other to multiply. "They proliferate out of control," says geneticist Alison J. Coffey of the Sanger Centre in Hinxton, England, a coauthor of the Nature Genetics paper. In the process, the T cells encourage reproduction of the virus-infected B cells, aggravating the disease, Sayos says.

The research may provide some basis for synthesizing the SH2D1A protein as a potential treatment for Duncan disease, although that possibility is still far off, Coffey says. Meanwhile, she and other researchers will look for this mutated gene in other diseases.