Challenging one of the fundamental tenets of immunology, researchers at the University of Maryland School of Medicine say that mature B cells - among the body's front-line troops in the immune system's battle against invaders - can rearrange their own genetic material when confronted by unfamiliar antigens. The rearrangement permits B cells faced with a new intruder to produce different antibodies in response, something immunologists have thought that mature B cells could not do.
Their discovery also may explain the origin of follicular lymphomas, which are germinal center B cells transformed by genetic recombination in a way that leads to uncontrolled proliferation and a rare form of cancer. Shedding light on the mechanism by which the process of genetic re-arrangement is turned back on, the findings ultimately could help scientists gain more control of immune system response to infections and other challenges.
Dr. Garnett Kelsoe, professor of microbiology and immunology at the University of Maryland School of Medicine in Baltimore, and collaborators report on their findings in the December 20, 1996, issue of the journal Science.
Up to now, immunologists have believed that B cells develop the antibodies that coat their surfaces only while they are maturing in the bone marrow where they are born. Special enzymes controlled by genes known as recombination activating genes (Rag-1 and Rag-2) determine the antibodies each B cell will carry by driving the rearrangement and fusion of variable (V), diversity (D) and joining (J) gene segments into functional antibody genes. Immunologists thought that once B cells left their bone-marrow crib, Rag-1 and Rag-2 were finished with their work. Conventional wisdom in immunology says that mature B cells are capable of reproducing nothing but more B cells exactly like themselves.
"We have discovered a rejuvenating mechanism," said Kelsoe. "For the first time, we have shown that V(D)J recombination - the process by which B cells produce antibody genes - is reactivated outside bone marrow, in mature B cells. You might say they undergo a second childhood."
This second childhood occurs in germinal centers, which are rapidly proliferating clusters of B and T cells, the foot soldiers of the immune system. When antigen, the protein product of a foreign microbe, appears in the body - after infection or immunization, for example - it causes the formation of germinal centers, specialized micro-environments where large numbers of antigen-specific B and T cells proliferate to do battle with the intruder.
In previous publications in the journal Nature, Kelsoe and colleagues have reported the first direct evidence that the germinal center is a Darwinian microcosm where T cells carrying the best receptors for antigen are selected, and B cells begin to mutate their antibody genes, enabling them to adapt to the new antigen challenge.
Now the researchers have identified a novel mechanism that may generate abrupt changes in their antibody genes.
"When B cells begin to mutate in the germinal center, that is a remarkable event," said Kelsoe. "This is a second remarkable event - a renewed ability to express the V(D)J recombinase and potentially, to change receptors. The possibility that antigen may induce a novel antibody on the surface of a mature, germinal center B cell forces us to rethink fundamental immunological processes."
Now the researchers would like to determine the environmental signals that cause B and T cells to enter germinal centers in the first place. "We're looking for the DNA-signature of Rag-1 and Rag-2 activity," Kelsoe said. "We want to know how and why the recombinase is reactivated."
Coauthors on the Science article are Drs. Shuhua Han and Biao Zheng, colleagues at the University of Maryland School of Medicine; Dr. David G. Schatz, Yale University School of Medicine; and Dr. Eugenia Spanopoulou, Mount Sinai Cancer Center, New York.
Their work was funded by the National Institutes of Health National Institute of Allergy and Infectious Diseases and the National Institute on Aging.