The Anti-Self B Cell Repertoire

Abstract

A notable feature of B cells that has been observed recently in several laboratories is that a relatively small group of V_H segments predominates in the expressed V_H gene repertoire of normal humans. The results of a number of different experiments suggest that the phenomenon of repertoire restriction is due to clonal selection at the level of both mature and immature B cells. For instance, in examining sequences of the over-represented V_H genes we found examples of somatic mutations that were typical of an antigen-driven immune response, and which were manifestations of selection of mature B cell clones (Huang, et al., 1992). But we also found cases of over-represented V_H genes that had germline sequences. Each of these unmutated V_H segments was linked to a clonally unique and unmutated (D-J_H) CDR3 (Stewart, et al., 1992). These latter findings suggest a process of positive selection that is linked to the heavy chain in B cells that do not mutate their V_H genes. These and related results have led us and others to propose that clonal selection occurs not only in mature B cells but also in pre-B cells (Schwartz, 1993; Nishimoto, et al., 1991; Decker, et al., 1991). We propose that positive selection of pre-B cells differs from clonal selection of mature B cells in two ways: (a) pre-B cells lack a mechanism for V gene somatic mutation; and (b) positively selected pre-B cells have a differentiation advantage, whereas antigen-driven mature B cells gain a proliferative advantage.