DNA Shuffle

A friend who suffers from a different auto-immune disorder was wondering how we can have both too much and too little immunity at the same time. I said something handwavy about lymphocytes gone bad. I learned in the November 2008 issue of Science Matters @ Berkeley that everyone makes bad lymphocytes, but healthy people destroy the bad ones before they can leave the bone marrow.

We rely on antibodies to recognize and sound the alarm on potential invaders. Yet our cells come programmed with less than 30,000 genes, far fewer than the billions of foreign structures we might encounter.

Even so, says Mark Schlissel, a Berkeley professor of immunology and pathogenesis, "the immune system is capable of recognizing literally hundreds of millions of foreign chemical structures."

This phenomenal flexibility comes courtesy of a remarkable DNA shuffling system called V(D)J recombination. Just as riffling a deck of cards can produce an endless variety of poker hands, shuffling specialized DNA segments in developing immune cells can produce a different antibody structure nearly every time. During the reaction, enzymes select one of many available genetic versions for each variable antibody segment, snip out the unused portions, and stitch the chosen pieces back together. The resulting antibody travels to the surface of the immune cell, or lymphocyte, where it can recognize bacteria, viruses and toxins in the bloodstream.

"All of us have developing lymphocytes in our bone marrow shuffling these antibody genes around continuously, from the time we are in the womb," Schlissel says. Schlissel studies V(D)J recombination and its place in lymphocyte development. Understanding when this reaction occurs and how it is regulated will help scientists learn to treat leukemia, lymphoma, immune deficiencies and a wide array of autoimmune diseases.
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Every shuffle of DNA segments also carries the danger of producing an antibody that recognizes the body's own tissues. To avoid such potential autoimmune reactions, every new antibody undergoes self-tolerance testing in the bone marrow. If the antibody flunks, the recombinase returns to the nucleus for another round of gene rearrangement.

Read the rest of Doing the DNA Shuffle.