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

1996; Cell Press; Volume: 5; Issue: 3 Linguagem: Inglês

10.1016/s1074-7613(00)80314-3

1097-4180

Norman R. Klinman,

Immune Response and Inflammation

The "clonal selection hypothesis" evolved largely as a means to account for "the absence of immunological response to self constituents and the related phenomena of immunological tolerance" (Burnet 1957). Thus, the presence of a cell surface molecule that reflected the unique specificity of each cell provided a convenient means, not only for selective antigenic stimulation, but also for the selective elimination of cells by self-antigen (Burnet 1957; Burnet 1959; Talmage 1957). The initial formulation of the hypothesis assumed that the so-called randomization of specificities, and thus, tolerance susceptibility, would be limited to the perinatal period. However, contemporaneous refinements of the theory appreciated the need to account for the lifelong generation of novel specificities and that "susceptibility to the induction and maintenance of tolerance by the timely introduction of the antigen may have only a coincidental relationship to the immunological incompetence of the newborn animal" (Lederberg 1959). The clonal selection hypothesis has endured as a unifying framework for understanding self–nonself-discrimination in spite of the relative paucity of information concerning both the cellular and molecular basis of the immune response available at the time it was formulated. Not surprisingly, subsequent research has identified layers of complexity in immune responsiveness, including the participation of two very different cell types, T and B cells. Furthermore, the parameters of tolerance induction of T versus B cells were shown to be quite distinct, which shattered any possibility of a unifying hypothesis for tolerance induction (Taylor 1969; Weigle et al. 1974; Howard and Mitchison 1975).