Studies of molecular events during peripheral B cell differentiation

Abstract: This thesis focuses on molecular changes occuring during terminal B cell differentiation as well as on somatic hypermutation and the generation and maintenance of B cell memory. During T cell dependent immune responses the average affinity for the eliciting antigen increases with time. This affinity maturation is generated by somatic hypermutation and selection for B cells carrying a high-affinty BCR. A secondary immune response is characterised by rapid differentiation of memory B cells into plasma cells producing high affinty antibodies. However, the V gene repertoire of a secondary response differs from that used in the primary response, called repertoire shift. Analysis of the repertoire shift accuring during the immune response to phOx-OVA showed that the repertoire shift occured already during the memory maintenance phase of the response. While systemic immune responses are abolished in CD28 deficient mice they mount normal IgA responses to oral immunisation with KLH-CT. We have shown that the IgA plasma cells present in the lamina propria have undergone somatic hypermutation and functional experiments indicate that they have also undergone affinity selection. This is in spite of the total absence of germinal center structures both in the PP and in the MLN. Two proteins that is differentially expressed in plasma cells were identified by cDNA subtraction. One of the proteins is Ly6C, a surface protein previously shown to be expressed on T cell subsets. We show that within the B cell lineage it is expressed only on plasma cells. Also, crosslinking of the Ly6C protein might positively modulate Ig secretion. The other protein that was identified is a novel thioredoxin-like protein, PC-TRP, expressed specifically in plasma cells. A functional analysis of the properties of this protein might yield some interesting insight into plasma cell biology.