Deletion of autoreactive B cells Several powerful mechanisms exist to prevent self-reactive B cells from maturing to secrete potentially destructive autoantibodies. These mechanisms act in addition to the removal of self-reactive helper T cells.

Large numbers of B cells are produced in the bonemarrow throughout life, but very few become matureB cells. Most B-cell death is the result of a normal devel-opmental process which removes the excess of immatureB cells that enter secondary lymphoid organs, such as thespleen and lymph nodes. Within the pool of immatureB cells, there will be some that bear self-reactive antigenreceptors, which can bind to molecules found in healthybody tissues. There is now considerable evidence to showthat various specific mechanisms actively remove auto-reactive B cells from the repertoire, before they have achance to mature into cells that secrete autoantibodies.During the production of B cells from haemopoietic stemcells, DNA rearrangements combine variable- and con-stant-region gene segments to create the genes thatencode the immunoglobulin heavy and light chains. Thetotal repertoire of heavy and light chains that can be gen-erated by this process is very large, but each B cell carriesonly one functional immunoglobulin light chain and onefunctional heavy chain gene rearrangement. Consequen-tly, the 105 or so immunoglobulin molecules expressed bya B cell on its surface, which are the cell's antigen-specificreceptors, have only one specificity. Activation of a B cellthrough its surface receptors can start a series of reactionsthat leads to proliferation, followed by differentiation ofthe cell's progeny into antibody-secreting cells (plasmacells) or memory B cells. The antigen-binding portion ofthe secreted antibody is encoded by the same rearrangedvariable-region gene segments as the surface receptors,and so has the same specificity.Some immunoglobulin gene rearrangements produceB cells with receptors that bind to foreign molecules suchas those associated with pathogenic bacteria or viruses.When stimulated, B cells of this type produce antibodiesthat can prevent or limit infection. But gene rearrange-ment can also lead to the production of immunoglobulinthat binds to 'self' molecules found within the healthybody. Activation of self-reactive antigen receptors resultsin the production of autoantibodies that might causedisease. In Graves disease, for example, over-activity ofthe thyroid results from the action of an autoantibodythat mimics the action of thyroid-stimulating hormoneby recognizing and binding to the hormone receptor inthe thyroid, leading to over-production of the thyroidhormone, thyroxin. Some forms of haemolytic anaemiaare also caused by autoimmune reactions in which redblood cells are destroyed following the binding of auto-antibodies to one of their surface molecules.Most of us, however, avoid producing autoantibodies.This results mainly from mechanisms that cause the deathof autoreactive T and B cells soon after they first expressantigen-specific receptors and before they can be trig-gered to become effector cells (in the case of T cells) orantibody-secreting cells. The processes that select andweed out self-reactive T cells during their development inthe thymus have been the subject of intense investigation.Less work has been directed at the study of the elimina-tion or inactivation of autoreactive B cells. It is oftenassumed that tolerance to autoantigens is due entirely tothe removal of autoreactive T cells, including those thatwould provide the help needed to stimulate autoreactiveB cells to produce antibody, but this is not the case. Thereis clear evidence that direct selection also occurs in favourof B cells that are not self-reactive (Table 1).Pre-B cells become newly produced, virgin B cells whenthey first express immunoglobulin on their surface: It haslong been realized that stimulation of the antigen receptorat this stage can cause cells to die without leaving the mar-row. This has been demonstrated experimentally by cross-linking this surface receptor with antibody against theconstant region of surface immunoglobulin (Table 1) [1].Nemazee and Biirki [2] demonstrated a similar phen-omenon in mice carrying transgenes encoding the heavyand light chains of an antibody against a normal self cell-surface antigen - a class I major histocompatibility com-plex (MHC) molecule that is expressed on almost all cellsin the body, including those in the bone marrow. Thetransgenes in these mice were expressed in most B cells,and so virtually all B cells carried antigen receptors specificfor the self MHC molecule. All these B cells died withoutleaving the marrow, presumably as a result of interactionwith the self antigen carried on bone marrow cells.Goodnow, Basten and colleagues [3,4] have identified anadditional mechanism that results in inactivation ofautoreactive B cells at a later stage of development. Theyused mice that carried three transgenes; two encoded theheavy and light chains of an antibody against hen egglysozyme, and the third encoded lysozyme itself. A vari-ety of results are obtained with this system, depending onthe way lysozyme is expressed by the mice (see Table 2).If lysozyme is present on the surface of cells, the newlyproduced anti-lysozyme-specific B cells die without leav-ing the marrow [4]. This is similar to the effect describedabove, in which autoreactive B cells are deleted inNemazee and Burki's mice [2], and newly producedB cells die in mice given anti-immunoglobulin.©