Fig. 11.24 The generation of secondary antibody responses from memory B cells is distinct from the generation of the primary antibody response. These responses can be studied and compared by isolating B cells from immunized and unimmunized donor mice, and stimulating them in culture in the presence of antigen-specific effector T cells. The primary response usually consists of antibody molecules made by plasma cells derived from a quite diverse population of precursor B cells specific for different epitopes of the antigen and with receptors that have a range of affinities for the antigen. The antibodies are of relatively low affinity overall, with few somatic mutations. The secondary response derives from a far more limited population of high-affinity B cells, which have, however, undergone significant clonal expansion. Their receptors and antibodies are of high affinity for the antigen and show extensive somatic mutation. The overall effect is that although there is usually only a 10to 100-fold increase in the frequency of activatable B cells after priming, the quality of the antibody response is radically altered, in that these precursors induce a far more intense and effective response.
10,000 100 10 1 0.1 0.01
Fig. 11.25 Both the affinity and the amount of antibody increase with repeated immunization. The upper panel shows the increase in antibody concentration with time after a primary (1°), followed by a secondary (2°) and a tertiary (3°), immunization; the lower panel shows the increase in the affinity of the antibodies (affinity maturation). Affinity maturation is seen largely in IgG antibody (as well as in IgA and IgE, which are not shown) coming from mature B cells that have undergone isotype switching and somatic hypermutation to yield higher-affinity antibodies. The blue shading represents IgM on its own, the yellow shading IgG, and the green shading the presence of both IgG and IgM. Although some affinity maturation occurs in the primary antibody response, most arises in later responses to repeated antigen injections. Note that these graphs are on a logarithmic scale; it would otherwise be impossible to represent the overall increase of around 1 millionfold in the concentration of specific IgG antibody from its initial level.
the expression of a switched surface immunoglobulin isotype, compared with naive B cells that express surface IgM and IgD. In contrast, plasma cells have very low surface immunoglobulin altogether. In humans, a marker of memory B cells is CD27, a member of the TNF receptor family that is also expressed by naive T cells and binds the TNF-family ligand CD70, which is expressed by dendritic cells (see Section 9-17).
A primary antibody response is characterized by the initial rapid production of IgM and a slightly delayed IgG response due to time required for class switching (Fig. 11.25). The secondary antibody response is characterized in its first few days by the production of relatively small amounts of IgM antibody and much larger amounts of IgG antibody, with some IgA and IgE. At the beginning of the secondary response, antibodies are made by memory B cells that were generated in the primary response and have already switched from IgM to another isotype, and that express IgG, IgA, or IgE on their surface. Memory B cells express somewhat higher levels of MHC class II molecules and the co-stimulatory ligand B7.1 than do naive B cells. This helps memory B cells acquire and present antigen more efficiently to TFH cells compared with naive B cells, and to TFH cells through the B7.1 receptor CD28, so that they can in turn help in antibody production so it begins earlier after antigen exposure compared with primary responses. The secondary response is characterized by a more vigorous and earlier generation of plasma cells than in the primary response, thus accounting for the almost immediate abundant production of IgG (see Fig. 11.25).
during secondary immune responses.