The interplay of evolution and environment in B cell diversification Origins of Lymphocyte Diversity

The in vitro splenic focus technique has been used in conjuction with isoelectric focusing and antiidiotype analysis to establish that the adult murine B-cell repertoire consists of more than 10 ⁷ clonotypes, whereas at birth the repertoire contains only 10 ⁴ clonotypes. The adult repertoire and the neonatal expression and sequential acquisition of clonotypes is relatively invariant from individual to individual within experimental limits. Since the adult repertoire appears too large to be encoded in inherited genetic information, the authors have postulated that the expression of the B-cell repertoire is the result of the 'predetermined permutation' of inherited genetic information such that each individual expresses invariably each potential specificity at least once in a lifetime. Such a mechanism is predicated on evolutionary selective pressures for repertoire establishment rather than antigen-driven somatic events. Antigenic selection appears to play no significant role in the acquisition of the B-cell repertoire since (1) the pattern of expression appears independent of the presence of extrinsic antigen or T-cell recognition; (2) repertoire acquisition is similar in conventional and germ-free mice; and (3) the primary repertoire is represented by B cells that are clearly distinguishable from secondary B cells generated by antigenic stimulation. On the other hand, it can be demonstrated that developing B cells are exquisitely susceptible to tolerization. Thus, negative selective forces presumably do play an important role in repertoire expression, particularly with reference to polymorphic self antigens.