Getting down to specifics: B cells match response to threat
If the immune system were to choose a motto, “Know thine enemy” would be a fitting one. With the great variety of disease-causing bacteria, viruses and parasites on the loose, the ability to identify and appropriately respond to invaders is key to keeping the body healthy. And there’s no time to waste in waffling—action must be taken before the marauders get the upper hand.
Fortunately for us, B cells are up to the challenge. Produced in our bone marrow, these white blood cells churn out antibodies at just the right time and have the remarkable ability to tailor the germ-fighting molecules to the specific intruder. “It’s a marvelous phenomenon that we can respond to any pathogen that comes along,” says Wesley Dunnick. But just how is that feat accomplished? That’s what Dunnick would like to know.
Some of the basics already are understood. We humans have eight main types of antibodies—Y-shaped molecules made up of two identical light protein chains and two identical heavy protein chains. All antibodies have this same general structure, but a small region at the tip of the molecule is extremely variable, allowing for millions of antibodies with slightly different tips to be combined with each of the eight basic types. And because it’s the tip that engages with bacteria, viruses and other foreign molecules, this diversity gives the immune system the ability to recognize a vast assortment of attackers.
But B cells don't constantly pump out a hodgepodge of antibodies that may or may not be needed. They only get busy during an infection, and even then “the only B cells that actually make antibody are those that are responding to a given pathogen at a given moment,” says Dunnick. “ That’s a very small number, maybe one in 10,000 or one in 100,000.” Those chosen few must respond quickly and efficiently when pressed into service, and Dunnick wants to know what regulatory mechanisms assure that B cells make the right antibodies at the right time, with the requisite efficiency.
He knows that one crucial step in the production of appropriate antibodies involves rearrangement of DNA such that particular genes are properly lined up—an impressive feat in itself. “These are the only cells in the body we know about that change their DNA in order to do what they do,” Dunnick says. “What we're trying to understand is how changing the DNA changes the immune response.”
In experiments with transgenic mice, Dunnick and coworkers have systematically deleted a specific set of regulatory elements—segments of DNA that control gene expression—and found that all elements in the set are needed for greatest efficiency. Another regulatory region in front of each gene dictates which antibody type is produced, the researchers have learned. “Now we want to know the mechanisms by which these regulatory elements influence genes.”
Understanding the fine points could lead to new ways of preventing and fighting not only infections but also allergies, as allergy sufferers are known to produce excessive amounts of a particular antibody. And although these applications may not come to fruition right away, continuing to delve into the details of antibody specificity is essential groundwork, Dunnick says.
“Development of medical interventions takes years, but without the foundation that this kind of work provides, it can’t happen at all.”
