into T lymphocytes with specialized function; T lymphocytes also interact with B lymphocytes, inducing them to synthesize and secrete antibodies.
A second exposure to the same immunogen results in a secondary response. This may occur after the response to the first immune event has leveled off or has totally subsided (within weeks or even years). The secondary response differs from the primary response in many respects. Most notably and biologically relevant is the much quicker onset and the much higher magnitude of the response. In a sense, this secondary (and subsequent) exposure behaves as if the body remembered that it had been previously exposed to that same immunogen. In fact, secondary and subsequent responses exploit the expanded number of antigen‐specific lymphocytes generated in response to the primary immune response. Thus the increased arsenal of responding lymphocytes accounts, in part, for the magnitude of the response observed. The secondary response is also called the memory or anamnestic response, and the B and T lymphocytes that participate in the memory response are termed memory cells.
ANTIGENICITY AND ANTIGEN‐BINDING SITE
An immune response induced by an antigen generates antibodies or lymphocytes that react specifically with the antigen. The antigen‐binding site of an antibody or a receptor on a lymphocyte has a unique structure that allows a complementary fit to some structural aspect of the specific antigen. The portion of the immunoglobulin that specifically binds to the antigenic determinant or epitope is concentrated in several hypervariable regions of the molecule, which form the complementarity‐determining region (CDR). Additional structural features of the immunoglobulin molecule are described in Chapter 6.
Various studies indicate that the size of an epitope that combines with the CDR on a given antibody is approximately equivalent to 5–7 amino acids. These dimensions were calculated from experiments that involved the binding of antibodies to polysaccharides and to peptide epitopes. Such dimensions would also be expected to correspond roughly to the size of the complementary antibody‐combining site (termed paratope), and indeed this expectation has been confirmed by X‐ray crystallography. The small size of an epitope (peptide) that binds to a specific T‐cell receptor (TCR) (peptides with 8–12 amino acids) is made functionally larger, since it is noncovalently associated with MHC proteins of the antigen‐presenting cell. This bimolecular epitope–MHC complex then binds to the TCR, forming a trimolecular complex (TCR–epitope–MHC).
EPITOPES RECOGNIZED BY B CELLS AND T CELLS
There is a large body of evidence indicating that the properties of many epitopes recognized by B cells differ from those recognized by T cells (Table 5.1). In general, membrane‐bound antibody present on B cells recognizes and binds free antigen in solution. Thus, these epitopes are typically on the outside of the molecule, accessible for interaction with the B‐cell receptor. Terminal side chains of polysaccharides and hydrophilic portions on protein molecules generally constitute B‐cell epitopes. An example of an antigen with five linear B‐cell epitopes located on the exposed surface of myoglobulin is shown in Figure 5.3. B‐cell epitopes may also form as a result of the folded conformation of molecules as shown in Figure 5.4. Such epitopes are called conformational or discontinuous epitopes, where noncontiguous residues along a polypeptide chain are brought together by the folded conformation of the protein, as shown in Figure 5.3. In contrast to B cells, T cells are unable to bind soluble antigen. The interaction of an epitope with the TCR requires APC processing of the antigen in which enzymatic degradation takes place to yield small peptides, which then associate with the MHC. Thus, T‐cell epitopes can only be continuous or linear because they are composed of a single segment of a polypeptide chain.
Figure 5.3. Example of antigen (sperm whale myoglobin) containing five linear B‐cell epitopes (red), one of which is bound to the antibody‐binding site of antibody specific for amino acid residues 56–62.
Figure 5.5 illustrates the structural organization of a class I MHC with an antigenic peptide bound to it. Generally, such processed epitopes are internal denatured linear hydrophobic areas of proteins. Polysaccharides do not yield such areas and indeed are not known to bind or activate T cells. Thus, polysaccharides contain solely B‐cell recognizable epitopes, whereas proteins contain both B‐ and T‐cell recognizable epitopes (see Table 5.1). Antigenic epitopes may have the characteristics shown schematically in Figure 5.6. Thus, they may consist of a single epitope (hapten) or have varying numbers of the same epitope on the same molecule (e.g., polysaccharides). The most common antigens (proteins) have varying numbers of different epitopes on the same molecule.
TABLE 5.1. Antigen Recognition by B and T Cells
| Characteristic | B cells | T cells |
|---|---|---|
| Antigen interaction | B‐cell receptor (BCR) binds antigen (Ag) | T‐cell receptor (TCR) binds antigenic peptides bound to MHC |
| Nature of antigens | Protein, polysaccharide, lipid | Peptide |
| Binding soluble antigens | Yes | No |
| Epitopes recognized | Accessible, sequential, or nonsequential | Internal linear peptides produced by antigen processing (proteolytic degradation) |
Figure 5.4. Antigen showing amino acid residues (circles), which form a nonsequential epitope “loop” (blue) resulting from the disulfide bond between residues 64 and 80. Note the binding of an epitope‐specific antibody to the nonsequential amino acids that constitute the epitope.
Figure 5.5. Structure of a MHC class I molecule (ribbon diagram) with antigenic peptide (ball‐and‐stick model).
MAJOR CLASSES OF ANTIGENS
The following major chemical families may be antigenic.
1 Carbohydrates
