Immune system B cells are an inventive little army. When challenged by antigens - proteins produced by invaders such as bacteria - they proliferate and secrete other proteins called immunoglobulins or antibodies. The molecular structure of these antibodies is a perfect fit, a receptor that locks onto and disarms the enemy.
Immunologists know there is genetic machinery that generates countless kinds of antibodies in immature B cells developing in the bone marrow, but up to now, they believed the design process was random and independent of antigen's presence or influence. And they thought that once B cells matured, they lost their ability to recombine their genetic material and produce new and different antibodies.
Not so, says Dr. Garnett Kelsoe, professor of microbiology and immunology at the University of Maryland School of Medicine. Mature B cells can reactivate the molecular machinery that makes new genes, which in turn design novel antibody molecules. What's more, they can do it outside the bone marrow, in peripheral lymphoid tissues such as the spleen and lymph nodes. Even more significant is the fact that their renewed recombination of the B cells' genetic material is antigen-driven. "The antigen in effect instructs failing B cell to make a new, antigen-specific receptor," Kelsoe said. In other words, the intruder itself hands the defending army a blueprint for repairing ineffective weapons against it.
"At least in theory, this means we could expand lymphocyte repertoires to meet a patient's needs," he said. For example, it should be possible to reconstitute more quickly the damaged immune system of a cancer patient whose bone marrow has been irradiated.
Kelsoe and colleagues report on their findings in the October 10 issue of the journal Science.
The University of Maryland School of Medicine researchers, including Kelsoe, Shuhua Han, Biao Zheng, and Michiko Shimoda, and collaborators Stacey R. Dillon and Mark S. Schlissel at Johns Hopkins University School of Medicine, immunized mice with antigen, jumpstarting an immune reaction. Lymphocytes began proliferating in the spleen, growing into collections of active B and T cells known as germinal centers. In the germinal centers, where rapid mutation produces many B cells destined to fail and die, the recombination enzymes were turned back on in failing B cells, enzymes were turned back on, causing the cells' genetic material to recombine, generating new antibodies that were a perfect fit for the antigen threatening them.
"We now know that the recombination enzymes are being expressed again in mature B cells; we know that the genes are being rearranged, and we know that this mechanism actually is responding to antigen exposure," Kelsoe said.
"This appears to be a rescue mechanism for cells that have been damaged by mutation," he suggested. "The germinal center is a Darwinian microcosm, and every potential soldier is an investment worth protecting."
Kelsoe and colleagues' research was funded in part by the National Institutes of Health, the Leukemia Society of America, the Arthritis Society, the Jeanne M. and Joseph P. Sullivan Foundation and the Santa Fe Institute.
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Science