Self-Tolerance Checkpoints in B Lymphocyte Development

Abstract

The chapter discusses humoral self-tolerance as the cumulative action of a series of separate checkpoints placed along the B cell lineage. The strategy of employing multiple and distinct checkpoints presumably minimizes the risk that one or two inherited or somatically acquired mutations leads to uncontrolled autoantibody production, analogous to the role of checkpoints in the cell cycle that minimize neoplasia. Each checkpoint may depend on distinct sets of genes and molecules. From a genetic perspective, the use of broad terms such as “deletion” or “anergy” can be used to describe several distinct checkpoint mechanisms that likely involve discrete molecular pathways. The chapter discusses self-tolerance checkpoints acting (1) during formation of the pre-immune B cell repertoire and (2) during subsequent formation of an immune repertoire. A series of cellular phenomena potentially censor and remove autoantibody-bearing B cells from the pathway to antibody secretion. Each of these checkpoints has triggering thresholds that depend on the local auto-antigen concentration, auto-antigen valency, and the B cell's binding affinity for elimination of auto-reactive B cells in the bone marrow. These thresholds impose limits on the extent of tolerance.