Somatic mutation, affinity maturation and the antibody repertoire: a computer model.

Somatic mutation has been implicated as a significant and possibly primary factor in the maturation of antibody affinity in the humoral immune response. B cells stimulated by antigen experience a hyper-mutation in the gene segments that code for the antigen-binding site of the antibody, creating antibody specificities that did not exist at the time of immunization. Although most of the mutations are likely to be disadvantageous, new specificities with a higher affinity for the antigen are sometimes created. These higher-affinity cells are preferentially selected for proliferation and eventual antibody secretion, resulting in a progressively higher average affinity over time. In this paper we present the results of an investigation of somatic mutation through the use of a computer model. At the basis of the model is a large repertoire of discrete antibodies and antigens, having three-dimensional structures, that exhibit properties similar to those of the real populations. The key factor is that the binding strength between any antibody/antigen pair can be calculated as a function of the complementarity of the (a) size, (b) shape and (c) functional groups that comprise the two structures. The created repertoires are imbedded in a dynamical system model of the immune response to directly evaluate the affect of somatic mutation on affinity maturation. We also present an expanded hypothesis of clonal selection and development to explain how the mutational restrictions imposed by the genetic code and the structure of the antibody repertoire, along with antigen concentration, affinity, and probabilistic factors may interact and contribute to the expansion of specific clones as the response develops over time.