Affinity Maturation

It was observed long ago that the affinities of antibodies increase with time during immunization with a T-dependent antigen. When such an antigen is injected for the first time, it induces the occurrence of low-affinity IgM antibodies, which are rapidly replaced by IgG. This takes place in the first two weeks of the primary response. At the same time, an increase of the average affinity is usually observed. If the same antigen is given a second time, IgG antibodies are subsequently produced at a higher yield, and with an average affinity that is still increasing. This is characteristic of the secondary response, a phenomenon that may be repeated and amplified by multiple administrations of the antigen. This is why long-term immunization schedules are used whenever both high titers and high affinity are wanted. Affinity maturation, which is a unique property of B cells stimulated by T-dependent antigens, is the consequence of (1) the clonal organization of lymphocytes, (2) the expansion of clones that have been stimulated specifically by the antigen, and (3) the presence of a very peculiar mechanism that generates somatic mutations at each cellular division of stimulated B cells.

1. Antibody specificities are spread randomly in the huge collection of clones that represent at any given time the repertoire expressed by B lymphocytes that have rearranged their immunoglobulin genes and thus have IgM at their surface. Clones that are potentially reactive to the antigen proliferate, as the result of the cooperation between T cells and B cells and the phenomenon of antigen processing and presentation. This ensures that the first wave of antibodies are generally of low or moderate affinity.

 2. As the immunization proceeds, expansion of the B-reactive cell population takes place, giving rapidly growing colonies, termed germinal centers, in secondary lymphoid organs (lymph nodes, tonsils, spleen). Germinal centers are highly organized structures that favor cell–cell interactions that will amplify local B-cell division and expansion.

 3. At the same time, somatic mutations will be triggered by a mechanism that is probably enzyme-driven, but still not completely elucidated. The rate of the mutations that are introduced is of the order of 1 × 10³ per base pair and per generation, which is excessively high. As a result of these mutations, some clones will gain affinity, whereas others will lose. One therefore needs mechanisms to select clones of high affinity and eliminate those of lower affinity; otherwise the system would expand indefinitely and explode. Stimulation by antigen will favor the saving and expansion of clones with the highest affinity, whereas apoptosis will operate on cells that did not receive stimuli as they lost recognition ability.

PCR and DNA sequencing at the level of single cells allowed the group of Rajewsky to trace the successive mutations that occurred at each cell division, so that it was possible to reconstruct a genealogical tree of these mutations within the germinal center. Interestingly, hypermutated cells can ultimately follow two types of differentiation: One leads to the terminal plasma cells, which will secrete circulating antibodies, and the other leads to the so-called memory cells that may persist for long periods of time and may be restimulated with great efficiency in the course of another run of immunization.

 The extraordinary plasticity and adaptability of the immune system are thus quite remarkable and allow it to respond efficiently to pathogens. Raising memory cells endowed with the ability to produce rapidly high-affinity antibodies is an obvious goal of vaccination.