Typical Antibody Response

The most fundamental property of the immune system is the ability to distinguish self from nonself. An incoming substance will be regarded as antigenic if it differs from self. We will explore the question of what is self in Section 2.4, but for now, let us consider the case of the first encounter of a bacterial infection, where the bacterium may be safely assumed to be nonself.

Upon entry into the body, at least a few of the bacteria will die, or be killed by lysozyme or pre-existing antibody and complement, or killed intra-cellularly following phagocytosis. Whatever the means of death of the bacteria, the fragments will ultimately be phagocytosed. Some phagocytic cells are specialized to present foreign proteins to T and B lymphocytes.

Within 2-3 days, the first specific IgM antibody from the primary response will be detectable. IgM is a large pentameric or hexameric polymer of the basic H2L2 structure referred to above. Many bacterial antigens are polymeric, with multiple repeating motifs. The polymeric nature of IgM allows it to bind tightly to polymeric antigens, because even if one antigen-combining site lets go, the others will stay attached (Fig. 2.4). Thus, even if the affinity of the individual sites is low (as is often the case for primary responses), the overall strength of binding, which is known as avidity, will be very high (see Metzger, 1970 for further discussion). IgM is also particularly efficient at activating complement, and thus acts as an excellent primary defence.

Three or four days after the primary antigenic challenge, the immune response starts to switch to IgG, a process which requires T cells (Fig. 2.5). Like IgM, IgG antibodies interact with complement and kill bacteria. In addition, IgG greatly facilitates phagocytosis of any remaining bacteria by binding

Fig. 2.4. Effect of valency on strength of binding of antibody to antigen. For a multivalent antigen, the pentameric structure oflgM will allow strong binding, even if the affinity of each individual binding site is low. The divalent binding of antigen to IgG also strengthens binding, because if one site releases antigen, the other may still retain it. Divalent F(ab')2 fragments of IgG will also bind strongly for the same reason, while binding to monovalent Fab fragments is much weaker. The fragmentation of antibodies and its effect on strength of binding of antigen will be discussed in more detail in Chapters 5 and 9 (see especially Section 9.5.1).

Fig. 2.4. Effect of valency on strength of binding of antibody to antigen. For a multivalent antigen, the pentameric structure oflgM will allow strong binding, even if the affinity of each individual binding site is low. The divalent binding of antigen to IgG also strengthens binding, because if one site releases antigen, the other may still retain it. Divalent F(ab')2 fragments of IgG will also bind strongly for the same reason, while binding to monovalent Fab fragments is much weaker. The fragmentation of antibodies and its effect on strength of binding of antigen will be discussed in more detail in Chapters 5 and 9 (see especially Section 9.5.1).

to specific receptors for IgG (Fc receptors) that are present on the surface of many phagocytic cells. Specific IgG antibodies also neutralize bacterial toxins by binding to them. The antibody response will, if successful, neutralize toxins and kill bacteria, and thus defend the body.

As early as 3-4 days after the injection of antigen in a primary response, the affinity of the IgG starts to increase (reviewed by Nossal, 1992a, Gray, 1993; Kiippers et al., 1993; MacLennan, 1994). Affinity maturation is a kind of Darwinian selection at the somatic cell level. Hypermutation of the variable portions of antibody genes and selective survival of those B cells with membrane immunoglobulin of sufficient affinity to bind the steadily diminishing amount of antigen results in a progressively improved 'fit' between antigen and antibody (Fig. 2.6; see Kiippers et al., 1993).

If there is no additional input of antigen, the antibody response usually declines gradually over a period of weeks. However, antigenic stimulation is often sustained over very long periods by the persistence of very small amounts of antigen that remain attached to the surface of follicular dendritic cells in the lymphoid follicles (B cell areas) of spleen and lymph nodes, via specific antibody attached to Fc receptors (reviewed by Nossal, 1992a, Gray, 1993 and MacLennan, 1994). The decline in antibody may be greatly retarded if the antigen is given in a 'depot' form where it is very gradually released, as is the case when Freund's adjuvant is used. If, some time after the initial dose of antigen, a further dose is given, the 'secondary response' is usually much greater than the primary response and occurs more rapidly

Antigen Antigen

(primary (boost)

immunization)

Fig. 2.5. A typical antibody response.

Antigen Antigen

(primary (boost)

immunization)

Fig. 2.5. A typical antibody response.

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