Overlap Stimulation of Primary and Secondary B Cells

The humoral immune response to antigenic stimulation is usually typified by the elaboration of a heterogeneous, yet highly specific population of antibody molecules. In light of recent studies showing that a homogeneous antibody product is released by the progeny of a single antibody-forming cell precursor (B cell) (1, 2), the heterogeneity of serum antibody is probably a consequence of the composite antibody products of several stimulated clonal precursor cells whose individual potential antibody specificity" is restricted (2, 3). Thus, the specificity inherent in the humoral immune response may be envisaged as a function of both the extensiveness of the individual's B-cell repertoire, and the selective stimulation of those precursor cells within the repertoire whose potential antibody product interacts best with the given antigen (2). Several observations suggest, however, that the specificity of stimulation of precursor cells from previously immunized mice is less rigorous. An animal immunized initially with one antigenic determinant and exposed later to a different, but structurally similar, determinant responds to this second determinant by producing antibody with a higher affinity for the original antigen, a phenomenon referred to as "original antigenic sin" (4, 5). Similarly, when tolerance to one antigen is broken using a closely related immunogen, subsequent stimulation with the tolerogen results in the production of antibody that reacts better with the immunogen used to break tolerance (6). Such examples of anomalous stimulation by one immunogen of cells whose antibody product reacts better with a different immunogen may be a reflection of differences in the requirements for stimulation of primary and secondary precursor cells. Differences in the parameters of stimulation of primary and secondary precursor cells have been previously reported by this laboratory (2). The response of primary B cells to hapten-protein conjugates is inhibited by a concentration of free hapten 20-100 times lower than that required for equivalent inhibition of the response of secondary B cells (2). Furthermore, the affinity of antibodies released by the clonal