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Affinity Maturation and Somatic Cell Hypermutation: Intricately Controlled Processes that are Unlike Mutation and Selection

[Editor's Note: This is part three of a six-part response from microbiologist Don Ewert to Kathryn Applegate's arguments that the vertebrate adaptive immune system is an example of Darwinian evolution in action. Part one can be found here, and part two is here.]

The second stage of B cell receptor development is initiated when a foreign protein enters our body and is detected by a circulating B cell using its cell surface antigen receptor (BCR). The BCRs that recognize these antigens improve their affinity (binding capacity) for the antigen by entering into a fine-tuning process called affinity maturation. This process ensures that highly effective antibody receptors are produced and released as cell-free antibodies into the circulation as the B cell completes its development. This increase in the strength of binding between a single antigenic determinant and an individual antibody combining site does not affect the specificity of the antibody, i.e. its ability to distinguish between small regions (epitopes) on the same antigen. Rather it allows for antibodies to remain bound to the foreign antigen for longer periods of time, thus giving the body a greater chance to clear the antigen-antibody complexes. The changes in the affinity of the receptor for an antigen results from the accumulation of nucleotide replacements that change the attractive and repulsive forces, mainly electrostatic forces, of the antigen combining site. The molecular mechanism for improving the affinity of the BCR is called somatic cell hypermutation (SHM), since the changes that are introduced in the DNA of the B cell (a somatic cell) cannot be passed on to the offspring of the animal.

Once the B cell begins to proliferate, each of the progeny cells undergoes a process which introduces mutations in the variable (V) (antigen binding) region of the immunoglobulin gene at a rate that is six orders of magnitude greater than the average spontaneous mutation rate. These mutations are designed to produce slight changes in the regions of the antigen combining site of the antibody, called the complementarity-determining region (CDR). As a result, the clonal progeny of the activated B cells each have slightly different affinity for the antigen. Each of the clonally derived B cells then pass through a gauntlet of cells presenting the antigen in the lymph nodes and spleen. B cells with receptors that bind weakly or not at all are programmed to die by apoptosis, and those that can bind will continue to proliferate antigen.

As the level of antigen decreases during the immune response, B cells with high affinity receptors are able to out-compete low-affinity receptor B cells for the scarce antigen and will continue to proliferate and differentiate to become plasma cells that secrete high affinity circulating antibodies, and also to become memory B cells that stay around waiting for another encounter with the antigen. This process of positive selection ensures that the most effective antibody and the cells that produce them (memory cells) are retained, such that the second encounter with the pathogen will be met rapidly with "tailored bullets" specific to the foreign invader.

On the surface, affinity maturation may appear to resemble a neo-Darwinian mechanism: random mutations produce an altered phenotype that causes the more "fit" to survive and the less fit to die. But that is where the similarity ends. Research during the past decade has revealed that SHM is an intricately controlled process that targets genetic changes to specific sites within the variable region of the rearranged immunoglobulin gene while protecting the rest of the genome. It is anything but an undirected process like Darwinian evolution.