Autoreactivity and the positive selection of B cells

The diversity among B-cell antigen receptor (BCR) specificities is generated by random rearrangement of gene segments during early B-cell development. While such stochastic recombination of gene segments is important for diversity, it introduces the risk of producing self-reactive BCRs which might lead to the development of autoimmune diseases. Therefore, it has been proposed that negative selection of autoreactive BCR specificities during early B-cell development are required to establish tolerance towards self. In fact, transgenic mouse models have identified a number of "tolerance mechanisms" such as receptor editing, clonal deletion and anergy, all of which prevent the development of autoreactive B cells. Recent data, however, reveal that self-recognition is crucial for the generation of B cells, and that the precursor-BCR (pre-BCR), which is essential for early B-cell development, basically plays the role of an autoreactive BCR. Moreover, although it has become clear that autoreactive B cells are present in the periphery of healthy individuals, the role of autoantigen in their development, persistence and regulation is unclear. This review outlines the important role of autoreactivity in early B-cell development and presents potential models for the regulation of the activation of peripheral B cells by different forms of self or foreign antigens.