Receptor editing, immune diversification, and self-tolerance

Over the last few years, our knowledge of the mechanisms that control the development of B cells and shape their repertoire has expanded rapidly, with description of a number of novel cellular and molecular pathways. Among these, receptor editing is unique because it enables B cells to alter their immunoglobulin variable (V) region genes and, consequently, change the specificity of the B cell receptor (BCR) expressed at their surface. This remarkable property provides clues to long-standing questions pertaining to the fate of cells developing in the bone marrow, The majority of B lymphocytes that arise in the bone marrow do not migrate to peripheral organs to participate in an immune response but, instead, undergo apoptosis and are disposed of by resident macrophages (Osmond et al., 1994), Two reasons for the death of immature B cells are the nonproductive assembly of the heavy (H) or light (L) chain gene segments and the generation of BCR that react against self, A third, related reason is that B cells may undergo apoptosis after they have exhausted their potential for additional V gene rearrangements. The displacement of productive rearrangements by additional, productive rearrangements on the same allele may be accomplished by secondary rearrangement at the H chain locus resulting in H chain replacement, or by secondary L chain V gene rearrangements, resulting in L chain editing. Thus, receptor editing depends on the capacity of variable light (VL) and heavy (VH) genes to undergo successive rearrangements. It may provide an alternative to apoptosis of immature B lymphocytes in the bone marrow if it occurs during the 16-18 hr period after cross-linking of the BCR, but before irreversible commitment to apoptosis (Rothstein, 1996), As will be discussed here, secondary rearrangements have now been described in a number of systems. Although formal proof that they are triggered by antigen encounter is lacking, mounting evidence suggests that some secondary rearrangements are a result of receptor engagement. Receptor editing not only diversifies the repertoire, but also may allow B cells to avoid high affinity autorecognition. Hence, receptor editing has implications with regard to maintenance of B cell tolerance and, possibly, to the induction of pathogenic autoimmunity.