Immunology. Richard Coico
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 (polysaccharides). Polysaccharides are only immunogenic when associated with protein carriers. For example, polysaccharides that form part of more complex molecules—glycoproteins—will elicit an immune response, part of which is directed specifically against the polysaccharide moiety of the molecule. An immune response, consisting primarily of antibodies, can be induced against many kinds of polysaccharide molecules, such as components of microorganisms and of eukaryotic cells. An excellent example of antigenicity of polysaccharides is the immune response associated with the ABO blood groups, which are polysaccharides on the surface of the red blood cells.Figure 5.6. Some possible antigenic structures containing single and multiple epitopes.
2 Lipids. Lipids are rarely immunogenic, but an immune response to lipids may be induced if the lipids are conjugated to protein carriers. Thus, in a sense, lipids may be regarded as haptens. Immune responses to glycolipids and to sphingolipids have also been demonstrated.Nucleic acids. Nucleic acids are poor immunogens by themselves, but they become immunogenic when they are conjugated to protein carriers. DNA, in its native helical state, is usually nonimmunogenic in normal animals. However, immune responses to nucleic acids have been reported in many instances. One important example in clinical medicine is the appearance of anti‐DNA antibodies in patients with systemic lupus erythematosus (discussed in detail in Chapter 12).Read the related case: Hereditary AngioedemaIn Immunology: Clinical Case Studies and Disease Pathophysiology
3 Proteins. Virtually all proteins are immunogenic. Thus, the most common immune responses are those to proteins. Furthermore, the greater the degree of complexity of the protein, the more vigorous will be the immune response to that protein. Because of their size and complexity, proteins contain multiple epitopes.
BINDING OF ANTIGEN WITH ANTIGEN‐SPECIFIC ANTIBODIES OR T CELLS
The binding between antigen and antibodies is discussed in detail in Chapter