Molecular mechanisms regulating B-cell negative selection.

The commitment of a pluripotential stem cell to the B-cell lineage and the progression of the committed B-cell precursor to a mature, immunocompetent B-cell is a highly regulated process. Extrinsic processes and internal programmes initiate and regulate the changes in gene expression that alter the phenotype and functional characteristics of the B-cell as it proceeds through its maturation. Many of these processes are only now beginning to be recognized and some have begun to be defined. This level of regulation of differentiation and cellular development is common to many if not all cellular lineages. In addition, B (and T) lymphocytes have superimposed on this developmental process another level of regulation. This level involves signals generated through the antigen receptor and exists to select for lymphocytes expressing receptors with certain characteristics and specificities. This selection process not only serves to encourage development of B-cells with functional antigen receptors (positive selection) but also provides a mechanism of elimination of clones able to respond to endogenous or self antigens (negative selection). Thus signalling through the antigen receptor at defined stages of B-cell development provides checkpoints for ordered B-cell maturation and further allows the shaping of the repertoire that will be represented among the mature, immunocompetent B-cells. Although the importance of the B-cell antigen receptor (BCR) expressed on the surface of mature B-cells has been recognized for some time, it is only relatively recently that we have begun to recognize a role for this receptor (or