The human immune system is a brilliantly adaptable weapon against foreign invaders. But it all depends on the work of specialized cells called lymphocytes that have made a risky evolutionary gambit to mutate their own DNA.
New research to be published this week in Nature shows for the first time that a molecule devoted to DNA repair plays a broader role in this genetic reshuffling - called recombination - than scientists had thought. Because mistakes in recombination can have catastrophic consequences, the new research could help explain processes that lead to some of the most aggressive types of cancer, such as leukemia and B cell lymphomas.
Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology, his brother André Nussenzweig, a senior investigator at the National Institutes of Health Experimental Immunology Branch in the National Cancer Institute, and colleagues used genetically altered "knockout" mice that were missing the DNA repair molecule, known as 53BP1, to study how its absence would affect a specific type of genetic reshuffling called V(D)J recombination.
They found that the knockout mice had 50 percent fewer lymphocytes in their bone marrow and 80 percent fewer in their thymus, a collection of glands that helps produce specialized immune cells. The mice also had problems with the lymphocytes that remained. To combat infection, these cells must have receptors that can recognize a foreign substance when they encounter it, beginning the process of producing an antibody to fight it. In mice lacking 53BP1, however, the sections of DNA, or loci, that must recombine to build these receptors are farther apart than normal, making their recombination much less likely, the researchers found.