A B lymphocyte must feel like a student in an uncompromising boarding school. It is forced to endure a series of tests. If it passes them it gets to advance to the next grade. But if it fails, the consequences are grave. In fact, the grave. I've described a number of these high stakes trials in the last post. When a cell has overcome them, and while still in the bone marrow, it makes use of its newly rearranged antibody gene to synthesize B cell receptors, proteins that embed in the cell membrane. The cartoon at the right shows one of these. Notice that the molecule traverses the cell membrane with only a tiny portion (three amino acids) of the heavy chain sticking into the cell. Notice also that most of the receptor looks just like a typical antibody as depicted in a previous post. It bears at one end an antigen binding site and at the other a tail consisting of heavy chains specified by one of the constant segments of the heavy chain gene. Once in the membrane, it pairs with two other transmembrane proteins, Ig-alpha and Ig-beta. And there it must sit awaiting yet another trial.
Why is another hurdle placed before a B lymphocyte before it can leave the bone marrow and take up residence in sites where it can detect invaders? We've already seen that antibodies can take on millions of different configurations in its variable region, so many that it can bind to virtually any molecule. Of course, that means that molecules that are not foreign, not invading microbes, can also be detected. If that happens, the immune system may attack substances that are naturally part of the body (referred to as self molecules) resulting in potentially serious autoimmune diseases. The last step in B cell maturation helps to ensure that that doesn't occur. If a B cell carries a receptor that strongly reacts with one of the surrounding molecules in the bone marrow, it is directed to commit suicide. Only those cells that don't encounter a molecule to which it can bind pass this test. If a cell does, it exits the bone marrow, and heads toward more appropriate pastures. A summary of the checkpoints that B cell must endure is shown in the figure at the right.
Two questions. First, how does the B cell receptor get positioned on the cell surface? Second, since its binding site is outside the cell, how does it communicate to the interior that it has detected a molecule to which it can bind?
The answer to the first question is relatively simple. The role that a particular antibody plays is dependent on the constant region of the heavy chain. Recall that the heavy chain gene bears nine different constant segments. Any one can potentially join onto the rearranged variable segments but at this stage of B cell development, either a special C-mu or C-delta segment attaches (it does so via RNA splicing, not DNA rearrangement). These heavy chains are special in that they bear a short tail of amino acids. The resultant protein is directed to the cell membrane because of the chemical nature of this end piece. It binds there, sticking just three amino acids across the membrane into the interior of the cell to help hold it in place. In addition, two other proteins, Ig-alpha and Ig-beta, join the receptor at the cell surface, aiding in its attachment to the membrane.
One clarification. B cell receptors are bound to the cell membrane not like notes tacked to a billboard but like rafts on a pond. Like rafts, they cannot sink or rise. Instead they float freely on the surface. The fact that B cell receptors can move about helps to provide an answer to the next question.
How does a cell pass information from the outside to the interior? The answer involves a discussion of "signal transduction", a term defined by an anomymous Wikipedia author as follows: "Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, ... which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors..." When a B cell receptor has bound an antigen in its variable region, it utilizes the two transmembrane proteins previously described, Ig-alpha and Ig-beta, to transmit a signal to the interior. The details of signal propagation are Rube Goldbergian in complexity. They're critical to learn for those carrying on research in the field, but aren't if sufficient general interest for me to want to either learn or teach it. However, the initial events are fascinating and relatively straightforward in principle.
Most invading microorganisms are surrounded by a picket fence of sorts that consists of multiple copies of the same molecule linked together to form a protective barrier. Each B cell receptor can bind one of these molecules. And, since there are many B cell receptors on any given B lymphocyte, many receptors may bind at the same time to adjoining "pickets". Since receptors can move about on the cell surface, they may clump together as shown in the figure at the right. This cluster of receptors brings the Ig-alpha and Ig-beta proteins of adjacent molecules close together. And when they are in proximity they enzymatically alter each other, causing a chain of enzymatic reactions that end up signaling to the cell that something wicked is afoot. These signals help activate the B cell, causing it to become an antibody synthesizing powerhouse, a topic for next time.