The fourth potential fate of self-reactive immature B cells is that nothing happens to them; they remain in a state of immunological ignorance of their self antigen (see Fig. 8.9). Immunologically ignorant cells have affinity for a self antigen but for various reasons do not sense and respond to it. The antigen may not be accessible to developing B cells in the bone marrow or spleen, or may be in low concentration, or may bind so weakly to the B-cell receptor that it does not generate an activating signal. Because some ignorant cells can be (and in fact are) activated under certain conditions such as inflammation or when the self antigen becomes available or reaches an unusually high concentration, they should not be considered inert, and they are fundamentally different from cells with non-autoreactive receptors that could never be activated by self antigens.
The fact that central tolerance is not perfect and some self-reactive B cells are allowed to mature reflects the balance that the immune system strikes between purging all self-reactivity and maintaining the ability to respond to pathogens. If the elimination of self-reactive cells were too efficient, the receptor repertoire might become too limited and thus unable to recognize a wide variety of pathogens. Some autoimmune disease is the price of this balance: we shall see in Chapter 15 that ignorant self-reactive lymphocytes can be activated and cause disease under certain circumstances. Normally, however, ignorant B cells are held in check by a lack of T-cell help, the continued inaccessibility of the self antigen, or the tolerance that can be induced in mature B cells following their emigration from the bone marrow, which is described below.
8-7 Lymphocytes that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated.
While large numbers of autoreactive B cells are purged from the population of new lymphocytes in the bone marrow, only lymphocytes specific for autoantigens that are expressed in or can reach this organ are affected. Some antigens, like the thyroid product thyroglobulin, are highly tissue specific, or are compartmentalized so that little if any is available in the circulation. Therefore, newly emigrated self-reactive B cells that encounter their specific autoantigen for the first time in the periphery must be eliminated or inactivated also. This tolerance mechanism, which acts on newly emigrated B cells that are still immature, is known as peripheral tolerance. Like self-reactive lymphocytes in the central lymphoid organs, lymphocytes that encounter self antigens de novo in the periphery can have several fates: deletion, anergy, or survival (Fig. 8.11).
In the absence of an infection, newly emigrated B cells that encounter a strongly cross-linking antigen in the periphery will undergo clonal deletion. This was elegantly shown in studies of B cells expressing B-cell receptors specific for H-2Kb MHC class I molecules. These B cells are deleted even when, in transgenic animals, the expression of the H-2Kb molecule is restricted to the liver by the use of a liver-specific gene promoter. There is no receptor editing: B cells that encounter strongly cross-linking antigens in the periphery undergo apoptosis directly, unlike their counterparts in the bone marrow, which attempt further receptor rearrangements. This difference may be due to the fact that the B cells in the periphery are somewhat more mature and can no longer rearrange their light-chain loci.
As with immature B cells in the bone marrow, newly developed peripheral B cells that encounter and bind an abundant soluble antigen become unresponsive. This was demonstrated in mice by placing the HEL transgene under the control of an inducible promoter that can be regulated by changes in the diet. It is thus possible to induce the production of lysozyme at any time and thereby study its effects on HEL-specific B cells at different stages of maturation. These experiments have shown that both peripheral and immature bone marrow B cells are inactivated when they are chronically exposed to soluble antigen.