Experiments using genetically modified mice that enforce the expression of self-reactive B-cell receptors have shown that there are four possible fates for self-reactive immature B cells (see Fig. 8.9, last three panels). These fates are the production of a new receptor by a process known as receptor editing; cell death by apoptosis, resulting in clonal deletion; the induction of a permanent state of unresponsiveness to antigen, or anergy; and a state of immunological ignorance in which antigen concentrations are too low to stimulate B-cell receptor signaling. The outcome for each self-reactive B cell is dependent on the interaction of the B-cell receptor with the self antigen.
Fig. 8.10 Replacement of light chains by receptor editing can rescue some self-reactive B cells by changing their antigen specificity. When a developing B cell expresses antigen receptors that are strongly cross-linked by multivalent self antigens such as MHC molecules on cell surfaces (top panel), its development is arrested. The cell decreases surface expression of IgM and does not turn off the RAG genes (second panel). Continued synthesis of RAG proteins allows the cell to continue light-chain gene rearrangement. This usually leads to a new productive rearrangement and the expression of a new light chain, which combines with the previous heavy chain to form a new receptor; the process is called receptor editing (third panel). If this new receptor is not self-reactive, the cell is ‘rescued’ and continues normal development, much like a cell that had never reacted with self antigen (bottom right panel). If the cell remains self-reactive, it may be rescued by another cycle of rearrangement; however, if it continues to react strongly with self antigen, it will undergo apoptosis, resulting in clonal deletion from the repertoire of B cells (bottom left panel).
Immature B cells that express an autoreactive receptor recognizing a multivalent self antigen can be rescued by further gene rearrangements that replace the autoreactive receptor with a new receptor that is not self-reactive. This mechanism is termed receptor editing (Fig. 8.10). When an immature B cell first produces sIgM, RAG proteins are still being made. If the receptor is not self-reactive, the absence of sIgM cross-linking allows gene rearrangement to cease and B-cell development continues, with RAG proteins eventually disappearing. For an autoreactive receptor, however, an encounter with the self antigen results in strong cross-linking of sIgM; RAG expression continues, and light-chain gene rearrangement can continue, as described in Fig. 8.8. These secondary rearrangements can rescue immature self-reactive B cells by deleting the self-reactive light-chain gene and replacing it with another sequence. If the new light chain is not autoreactive, the B cell continues normal development. If the receptor remains autoreactive, rearrangement continues until a non-autoreactive receptor is produced or until no additional light-chain V and J gene segments are available for recombination. The importance of receptor editing as a mechanism of tolerance is well established, as defects in this process contribute to the human autoimmune diseases systemic lupus erythematosus and rheumatoid arthritis, two diseases characterized by high levels of autoreactive antibodies (see Chapter 15).
It was originally thought that the successful production of a heavy chain and a light chain caused the almost instantaneous shutdown of light-chain locus rearrangement and that this ensured both allelic and isotypic exclusion. The unexpected ability of self-reactive B cells to continue to rearrange their light-chain genes, even after having made a productive rearrangement, suggests an alternative mechanism of allelic exclusion, where the fall in the level of RAG proteins that follows a successful non-autoreactive rearrangement could be the principal means by which light-chain rearrangement is terminated. It is now apparent that allelic exclusion is not absolute, as there are rare B cells that express two different light chains.