The immune system uses many strategies to generate its enormous repertoire of diverse antibodies, but their relative importance is not understood. Here we address the contribution of antibody gene libraries to the antibody repertoire. We introduce a general framework, in which we can study many antibody-pathogen matching rules, including the widely-used shape-space model (Perelson and Oster, 1979). We use the genetic algorithm as a model of evolution to investigate the type of antibody repertoires that might evolve in relation to a given pathogenic environment. For the antibody/pathogen matching rules that we studied, the scaling relation between fitness and the size of the evolved antibody library is only a shifted variant of the scaling relation that we obtain with random libraries of the same size. We discuss how our results compare to the antibodies that are expressed in newborns, and we discuss the implications of our results for recent experiments with phage a...

This dissertation is approved, and it is acceptable in quality and form for publication on microfilm: Approved by the Dissertation Committee: Accepted:

Flow cytometric analysis of antigen-specific, idiotype-positive (id+), B cell development in transgenic mice expressing a rearranged M167-/ ~ gene shows that large numbers of phosphocholine (PC)-specific, M167-id + B cells develop in the spleen and bone marrow of these mice. Random rearrangement of endogenous Vx genes, in the absence of a subsequent receptor-driven selection, should give rise to equal numbers of T15- and M167-id + B cells. The observed 100-500-fold amplification of M167-id + B cells expressing an endogenous encoded Vx24J.5 light chain in association with the M167 V.l-id transgene product appears to be an antigen driven, receptormediated process, since no amplification of non-PC-binding M167 V.1/V~22, T15-id + B cells occurs in these/~-only transgenic mice. The selection and amplification of antigen-specific, M167id + B cells requires surface expression of the ~ transgene product; thus, no enhancement of M167-id + B cells occurs in the M167 /~Amem-transgenic mice, which cannot insert the/~ transgene product into the B cell membrane. Surprisingly, no selection of PC-specific B cells occurs in M167-g-transgenic mice although large numbers of B cells expressing a crossreactive M167-id are present in the spleen and bone marrow of these mice. The failure to develop detectable numbers of M167-id +, PC-specific B cells in M167-K-transgenic mice may be due to a very low