The activation of B lymphocytes results in their proliferation, leading to expansion of antigen-specific clones, and their differentiation into plasma cells, which secrete antibodies (Fig.1). Naive B lymphocytes express two classes of membrane-bound anti bodies, immunoglobulins M and D (IgM and IgD), that function as receptors for antigens. These naive B cells are activated by antigen binding to membrane immunoglobulin (Ig) and by other signals discussed later in the chapter. The antibodies secreted in response to an antigen have the same specificity as the surface receptors on naive B cells that recognize that antigen in order to initiate the response. One activated B cell may generate a few thousand plasma cells, each of which can produce copious amounts of antibody, in the range of several thousand molecules per hour. In this way, humoral immunity can keep pace with rapidly proliferating microbes. During their differentiation, some B cells may begin to produce antibodies of different heavy-chain isotypes (or classes) that mediate different effector functions and are specialized to combat different types of microbes. This process is called heavy chain isotype (or class) switching. During the course of a B cell response to an infection, the affinity of antibodies specific for microbial proteins increases over time. This process is called affinity maturation, and it leads to the production of antibodies with improved capacity to bind to and neutralize microbes and their toxins.

Fig1. Phases of humoral immune responses. Naive B lymphocytes recognize antigens, and under the influence of helper T cells and other stimuli (not shown), the B cells are activated to proliferate, giving rise to clonal expansion, and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain isotype switching and affinity maturation, and some become long-lived memory cells.

Antibody responses to different antigens are classified as T-dependent or T-independent, based on the requirement for T cell help (Fig. 2). B lymphocytes recognize and are activated by a wide variety of chemically distinct antigens, including proteins, polysaccharides, lipids, nucleic acids, and small chemicals. Helper T lymphocytes play an important role in B cell activation by protein antigens. (The designation helper came from the discovery that some T cells stimulate, or help, B lymphocytes to produce antibodies.) T cells help B cells respond to only protein antigens because T cells can only recognize peptides derived from proteins presented as peptide–major histocompatibility complex (MHC) complexes. In the absence of T cell help, most protein antigens elicit weak or no antibody responses. Therefore, protein antigens and the antibody responses to these antigens are called T-dependent. Polysaccharides, nucleic acids, lipids, and other multivalent antigens (which contain the same structural unit repeated multiple times in tandem) can stimulate antibody production without the involvement of helper T cells. Therefore, these multivalent nonprotein antigens and the antibody responses to them are called T-independent. The antibodies produced in response to proteins exhibit more isotype switching and affinity maturation than antibodies against T-independent antigens because helper T cells stimulate these processes. Furthermore, T-dependent antigens stimulate the generation of long-lived plasma cells and memory B cells. Thus, the most specialized and long-lived antibody responses involve protein antigens and are generated under the influence of helper T cells, whereas T-independent responses are relatively simple and transient, and involve only the direct activation of B cells by antigens.

Fig2. T-dependent and T-independent antibody responses. Antibody responses to protein antigens require T cell help, and the antibodies produced typically show isotype switching and are of high affinity. Nonprotein (e.g., polysaccharide) antigens are able to activate B cells without T cell help. Most T-dependent responses are made by follicular B cells, whereas marginal zone B cells and B-1 cells play greater roles in T-independent responses. Ig, Immunoglobulin.

Different subsets of B cells respond preferentially to T-dependent and T-independent antigens (see Fig. 2). The majority of B cells are called follicular B cells because they reside in and circulate through the follicles of lymphoid organs. These follicular B cells make the bulk of T-dependent, class-switched, and high- affinity antibody responses to protein antigens and give rise to long-lived plasma cells. Marginal-zone B cells, which are located in the peripheral region of the splenic white pulp and also in the outer rim of follicles in lymph nodes, respond largely to blood-borne polysaccharide and lipid antigens; B-1 cells respond to multivalent antigens in the mucosal tissues and peritoneum. Marginal-zone B cells and B-1 cells express antigen receptors of limited diversity and make predominantly T-independent IgM responses. IgM antibodies may be produced spontaneously by B-1 cells, without overt immunization. These antibodies, called natural antibodies, may help to clear some cells that die by apoptosis during normal cell turnover and may also provide protection against some bacterial pathogens.

Antibody responses generated during the first expo sure to an antigen, called primary responses, differ quantitatively and qualitatively from responses to subsequent exposures, called secondary responses (Fig. 3). The amounts of antibody produced in the primary immune response are smaller than the amounts produced in secondary responses. In secondary responses to protein anti gens, there is increased heavy-chain isotype switching and affinity maturation, because repeated stimulation by a protein antigen leads to an increase in the number and activity of helper T lymphocytes.

Fig3. Features of primary and secondary antibody responses. Primary and secondary antibody responses differ in several respects, illustrated schematically in (A) and summarized in (B). In a primary response, naive B cells in peripheral lymphoid tissues are activated to proliferate and differentiate into anti body-secreting plasma cells and memory cells. Some plasma cells may migrate to and survive in the bone marrow for long periods. In a secondary response, memory B cells are activated to produce larger amounts of antibodies, often with more heavy-chain class switching and affinity maturation. These features of secondary responses are seen mainly in responses to protein antigens, because these changes in B cells are stimulated by helper T cells, and only proteins activate T cells (not shown). The kinetics of the responses may vary with different antigens and types of immunization. Ig, Immunoglobulin.