How is tolerance generated?

There are three major, overlapping theories that account for immunological tolerance. The first is that the repertoires of T and B lymphocytes are somehow purged, actually or functionally, of potentially self-reactive immunocytes. There are three subvariants of this theory, namely clonal deletion, clonal abortion and clonal anergy. Clonal anergy, an antigen-driven down-regulation of immunocyte responsiveness, is preferred on experimental grounds. The second theory is that self-reactive lymphocytes exist but are constantly held in check by suppressor cells. The suppressor cells have not been shown to possess the capacity to discriminate between self and not self. The third theory is that self antigens, through reasons of accessibility and processing, never enter the afferent limb of immune induction effectively. The contributions which each postulated mechanism make are different and all three may enter the picture in some tolerance models. Repertoire purging, if it exists, must be incomplete, because self-reactive B and T cells can readily be detected and stimulated in vitro. For repertoire purging to survive as a concept it must be redefined in terms of the type of antigen to which it is supposed to apply (e.g. ubiquitous cell-surface antigens) and the affinity cut-off point below which it is not reasonable to expect purging. Some of the technical issues impeding speedy experimental solutions centre on the permissive character of the antibody-mediated or cell-mediated lysis assays in current use.