Epstein-Barr deaths tied to faulty protein.Most people don't even know when they've got Epstein-Barr virus Epstein-Barr virus (EBV), herpesvirus that is the major cause of infectious mononucleosis and is associated with a number of cancers, particularly lymphomas in immunosuppressed persons, including persons with AIDS. . 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 mononucleosis /mono·nu·cle·o·sis/ (-noo?kle-o´sis) excess of mononuclear leukocytes (monocytes) in the blood.
chronic mononucleosis chronic fatigue syndrome. , 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 immune system
Cells, cell products, organs, and structures of the body involved in the detection and destruction of foreign invaders, such as bacteria, viruses, and cancer cells. Immunity is based on the system's ability to launch a defense against such invaders. . 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 B lymphocyte or B-lymphocyte
See B cell.
A type of lymphocyte that circulates in the blood and lymph and produces antibodies when it encounters specific antigens. , 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 virologist
microbiologist specializing in virology. 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 immune response
An integrated bodily response to an antigen, especially one mediated by lymphocytes and involving recognition of antigens by specific antibodies or previously sensitized lymphocytes. , but to no avail. Instead of killing rogue B cells, immune system T cells T cells
A type of white blood cell produced in the thymus gland. T cells are an important part of the immune system. Infants born with an underdeveloped or absent thymus do not have a normal level of T cells in their blood. coexist peacefully with them, apparently because of the defective SH2D1A protein, says Juan Sayos, an immunologist at Beth Israel Deaconess Medical Center Both an international and regional referral center, Beth Israel Deaconess Medical Center (BIDMC) in Boston, Massachusetts is a major teaching hospital of Harvard Medical School. It was formed out of the 1996 merger of Beth Israel Hospital (founded in 1916) and 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 SHA SHA - Secure Hash Algorithm 3V1 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 ge·net·i·cist
A specialist in genetics.
a specialist in genetics.
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.