EMBARGOED by the Journal of Experimental Medicine for 9 am EST April 28, 2003

Staph Infection Process Leading to B Cell Suicide Described by UCSD Researchers

The method that Staphylococcus aureus (staph) infection uses to inactivate the body's immune response and cause previously healthy B cells to commit suicide, is described for the first time by researchers at the University of California, San Diego (UCSD) School of Medicine in the May 5, 2003 issue of the Journal of Experimental Medicine. The paper was selected for early online publication on April 28.

Normally, B cells mount an early defense against invading bacteria. From this immunologic experience, memory B cells are developed with the ability to quickly recognize these antigens and destroy the bacteria if they return in the future. When staph infections occur, however, this important process for immune defense can be corrupted.

In studies with mice, the researchers found that a staph protein, called SpA, acts like a B cell toxin because it mounts a pre-emptive attack to target a specific region on the antigen receptors of B cells, which ultimately causes their death. Although the B cells begin to respond, they are quickly shut down, as the SpA de-activates these B cell antigen receptors, and there is also loss of other surface molecules such as CD19 and CD21, which are important for amplifying immune responses. Then, within a few hours, the SpA toxin induces B cells to turn on themselves in a programmed suicide process called apoptosis. As a direct consequence, the B cells never get a chance to develop the memory cells necessary to recognize and fight future staph infections.

"This mechanism may explain why staph infections are so common and why many people get them recurrently," said Gregg Silverman, M.D., UCSD professor of medicine and senior author of the paper.

He noted that apoptosis usually takes place on a regular basis in a small proportion of cells to control the size of lymphocyte populations and maintain homeostasis, to keep a balance in the internal equilibrium of body. However, SpA co-opts the normal apoptosis process, in effect killing the B cells too early, before they've had a chance to do their job.

"Inappropriate mechanisms of induced apoptosis are not unique to many infections," Silverman said. "However, we should be able to use the same process induced by SpA, to treat the disease-causing B cells in autoimmune diseases and cancers like leukemia and lymphoma. These studies may also help us to make protective vaccines against staph."

In follow up studies, the Silverman team will examine people with staph infections to verify that the same process takes place and that it prevents individuals from defending against staph infections. In addition, the investigators are planning a clinical trial in one to two years to treat patients that have autoimmune diseases such as lupus, that occur due to faulty B cells.

The study was supported by grants from the National Institutes of Health and the Alliance for Lupus Research. In addition to Silverman, the study was conducted by the paper's co-author Carl S. Goodyear, Ph.D., a UCSD postdoctoral researcher.

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For additional information about Dr. Silverman's work, see:

http://health.ucsd.edu/news/2002/04_23_Silverman.html

http://medicine.ucsd.edu/rdcc/silverman.shtml

http://health.ucsd.edu/news/2001/05_15_Faculty.html

http://cancer.ucsd.edu/summaries/gsilverman.htm

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