Second Shot at Making Antibodies

Some sentries of the immune system--so-called B cells, which are charged with checking out the passersby of the bloodstream--undergo a type of basic training. As a B cell develops, it shuffles bits of a gene to create a receptor that will recognize one specific potential villain. If it comes up with a dud receptor, it dies during its training. Immunologists have long thought that each B cell had just one chance at shuffling its receptor gene, but a paper in today's issue of Science reports that mature B cells can rearrange the gene later in life in an effort to increase their ability to latch onto a foreigner.

Once a B cell encounters the specific antigen that its receptor recognizes, it becomes activated and migrates to a germinal center--regions in the spleen, lymph nodes, and gut. Once there, B cells that prove adept at binding to antigens become "memory" B cells that return to the bloodstream. Last year, researchers were surprised to find that the two other genes that are required for shuffling the receptor gene were active in the germinal centers .

Garnett Kelsoe, an immunologist at the University of Maryland School of Medicine in Baltimore, and his colleagues wanted to know if this genetic activation in the germinal centers indeed results in changes in the receptor. To do this, they inoculated mice with chicken gamma-globulin (CGG), which activates B cells programmed to recognize CGG. They then looked for DNA breaks associated with receptor gene rearrangement by using a version of the polymerase chain reaction that amplifies broken DNA. They found breaks in the spleen's germinal center of inoculated mice, indicating that B cells were rearranging their receptor genes. The spleens of uninoculated mice showed no such changes.

In another experiment, Kelsoe found that B cells expressing the rearrangement genes bound less tightly to an antigen than did B cells that didn't rearrange their DNA. This implies that those with low antigen affinity are probably rearranging to improve their affinity. "These are the weak and flabby antibodies doing anything they can to improve," Kelsoe says.

Yong-Jun Liu, an immunologist at DNAX in Palo Alto, California, says these papers demonstrate a "very important mechanism" for maintaining functional B cells. Liu says it has been technically difficult to study the mechanism for B cell rearrangement in the developing immune system. Now, he thinks the germinal centers could provide a good model for studying how rearrangements take place during development.