| The antibody repertoire can be divided into a STAGE I and a STAGE II repertoire. Antibodies of the STAGE I repertoire are expressed on naive, mature B cells. The STAGE I repertoire is shaped by the processes of V(D)J recombination and by tolerance mechanisms. Somatic modification of STAGE I receptors by processes like somatic hypermutation and receptor editing give rise to the STAGE II repertoire which can is expressed on activated and memory B cells. The research presented in this thesis is largely concerned with the transition between the STAGE I and the STAGE II repertoires. The second chapter describes our attempts to understand the phenomenon of repertoire shift in which germline-encoded (STAGE I) antibodies that dominate a primary response to a given antigen are severely depleted or absent from the set of STAGE II receptors specific for the same epitope. We present evidence that most somatic mutations are harmful to these STAGE I antibodies and thereby prevent their entry into the memory compartment, or STAGE II repertoire. The third chapter concerns itself with the need for peripheral tolerance mechanisms, a need that arises as a result of somatic diversification of STAGE I receptors. Somatic changes in antibody receptors pose the threat of creating autoreactive antibodies in addition to high affinity antibody variants. The possibility of receptor editing acting as a peripheral tolerance mechanism is explored, and the conclusion is reached that receptor editing is more likely to act as a second major somatic diversification mechanism in addition to somatic hypermutation. In Chapter Four, we consider the degree of order in rearrangement processes in an attempt to explain the observed patterns of Jkappa usage and the number of cells with only one rearranged kappa allele. Results obtained using computer modeling indicate that order in light chain rearrangement, within and between kappa alleles, is the most compatible with the experimental data. Additionally, order in rearrangements, both in the formation of STAGE I and STAGE II repertoires helps to preserve allelic exclusion. |
