Cells that remain autoreactive when receptor editing efforts fail to generate a non-autoreactive receptor undergo a process known as clonal deletion, in which they are subjected to cell death by apoptosis to eliminate their specific autoreactivity from the repertoire. Early experiments using transgenic mice expressing both chains of an immunoglobulin specific for H-2Kb MHC class I molecules, in which nearly all developing B cells expressed the anti-MHC immunoglobulin as sIgM, suggested that clonal deletion was a predominant mechanism of B-cell tolerance. These studies found that transgenic mice not expressing H-2Kb had normal numbers of B cells, all bearing the transgene-encoded anti-H-2Kb receptors. However, in mice expressing both H-2Kb and the immunoglobulin transgenes, B-cell development was blocked. Normal numbers of pre-B cells and immature B cells were found, but B cells expressing the anti-H-2Kb immunoglobulin as sIgM never matured to populate the spleen and lymph nodes; instead, most of these immature B cells died in the bone marrow by apoptosis. However, more recent studies, using
Strong ligation of IgM by self antigen Arrest of B-cell development and continued light-chain rearrangement: low cell-surface IgM If the new receptor is still self-reactive, the B cell undergoes apoptosis If the new receptor is no longer self-reactive, the immature B cell migrates to the periphery and matures A new receptor speciÿcity is now expressed IgM mice bearing transgenes for autoantibody heavy and light chains that have been placed within the immunoglobulin loci by homologous recombination (see Appendix I, Section A-35, for details of this method), indicate that receptor editing, rather than clonal deletion, is the more likely outcome for immature autoreactive B cells.
We have so far discussed the fate of newly formed B cells that undergo multivalent cross-linking of their sIgM. Immature B cells that encounter more weakly cross-linking self antigens of low valence, such as small soluble proteins, respond differently. In this situation, some self-reactive B cells are inactivated and enter a state of permanent unresponsiveness, or anergy, but do not immediately die (see Fig. 8.9). Anergic B cells cannot be activated by their specific antigen even with help from antigen-specific T cells. Again, this phenomenon was elucidated using transgenic mice. Hen egg-white lysozyme (HEL) was expressed in soluble form from a transgene in mice that were also transgenic for high-affinity anti-HEL immunoglobulin. The HEL-specific B cells matured and emigrated from the bone marrow, but could not respond to antigen. Furthermore, the migration of anergic B cells is impaired, as the cells are detained in the T-cell areas of peripheral lymphoid tissues and are excluded from lymphoid follicles, thereby reducing their life-span and their ability to compete with immunocompetent B cells (described further in Section 8-8). Under normal circumstances, where few self-reactive anergic B cells successfully mature, these cells die relatively quickly. This mechanism ensures that the long-lived pool of peripheral B cells is purged of potentially self-reactive cells.