The “Clonal Selection Hypothesis” and Current Concepts of B Cell Tolerance

The fundamental precepts of the clonal selection hypothesis have stood well the test of four decades of subsequent research. Thus, self–nonself-discrimination does, as predicted, rely on the unipotentiality of B cells and the elimination of self-reactive B cells as they mature via signals induced through the sIg receptors of the cells. Furthermore, many of the logical extensions of this theory have been confirmed. For example, if tolerance were to apply to the spectrum of self-antigens, tolerance induction of immature B cells should ideally be applicable to an array of self-antigenic structures over a broad concentration range. Indeed, tolerance induction of immature B cells can be induced even by extremely low concentrations of antigen and appears to be independent of the form of the antigen (58xMetcalf, E.S and Klinman, N.R. J. Exp. Med. 1976; 143: 1327–1340Crossref | PubMedSee all References, 61xMetcalf, E.S, Schrater, A.F, and Klinman, N.R. Immunol. Rev. 1979; 43: 143–183CrossrefSee all References).However, because much of the details of immune responsiveness had not yet been defined, the reality of self–nonself-discrimination by B cells is far more complex than anticipated by the clonal selection hypothesis. Interestingly, most of the exceptions to the clonal selection hypothesis result in a higher frequency of self-reactive B cells. Thus, for example, neither B cells whose sIg receptors bind soluble self-antigens with low affinity nor those that recognize antigens that present determinants monovalently are eliminated. Additionally, T cell help can circumvent B cell tolerance. Even though T cell help would rarely be available in the adult bone marrow or neonatal spleen, in some instances B cells might escape tolerance by receiving T cell or mitogenic signals. This would not be trivial during the generation of memory B cells wherein T cell help would likely be available. Thus, for newly generating memory B cells whose V region mutations create anti-self reactivity, the fate of the cells could depend on a competition for receptors by self-antigen, for which Th would not be available, and the immunizing antigen, wherein Th and positive selection would be available (Linton et al. 1991xLinton, P.J, Rudie, A, and Klinman, N. J. Immunol. 1991; 146: 4099–4104PubMedSee all ReferencesLinton et al. 1991).As a result of these exceptions to clonal selection expectations, and the absence of some self-antigens from the bone marrow, many self-reactive B cells are present in the peripheral B cell pool (62xMoller, G, Gronowicz, U, Persson, A, Coutinho, A, Moller, Hammerstron, L, and Smith, E. J. Exp. Med. 1976; 143: 1429–1438Crossref | PubMed | Scopus (24)See all References, 33xHarris, D.E, Cairns, L, Rosen, F.S, and Borel, Y. J. Exp. Med. 1982; 156: 567–584Crossref | PubMedSee all References, 18xCooper, H.M, Klinman, N.R, and Paterson, Y. Eur. J. Immunol. 1988; 19: 315–322CrossrefSee all References, 85xStockinger, B and Hausmann, B. Eur. J. Immunol. 1988; 18: 249–253Crossref | PubMedSee all References). Although, in some instances, the presence of such B cells may enable auto-antibody production, the systemic immune system has several safeguards. Most important, stimulation by most antigens requires Th, and Th specific for self-antigens are rare. Additionally, several safeguards appear to be built into the B cell tolerance mechanism per se. First, as described above, many anti-self antibodies would exhibit low affinity for self-antigens whether the B cells were stimulated by a cross-reactive foreign antigen or the self-antigen. Second, there is a second window of tolerance susceptibility that prohibits the generation of anti-self memory B cells. This eliminates the possibility of either expanded clones of anti-self B cells or the generation of high affinity anti-self B cells. Indeed, it appears that a breakdown in this mechanism may be responsible for much of autoimmune disease (Radic et al. 1989xCold Spring Harbor Symp. Radic, M.Z, Mascelli, M.A, Erikson, J, Shan, H, Shlomchik, M, and Weigert, M. Quant. Biol. 1989; 54: 933–946Crossref | PubMedSee all ReferencesRadic et al. 1989). Third, there are modes of B cell innactivation, such as anergy, that may be applicable to more mature B cells that may disfavor B cell longevity or stimulation and thus may supplement the tolerance mechanisms that eliminate newly generating anti-self cells. Finally, certain antigenic determinants, such as those present on cell surfaces, may lead to the elimination of even mature B cells, thus ensuring a lack of reactivity to certain crucial self-components. Therefore, although the mechanisms that are available to ensure the absence of auto-antibody production are far more complex than anticipated by the clonal selection hypothesis, the absence from the repertoire of mature B cells with the capacity to respond to self-constituents and generate high affinity auto-antibodies is precisely the predicted outcome of the theory.