Epitopes

The molecular fragment recognized by antibodies or effector cells is called an epitope or antigenic determinant. Generally, these are low-molecular-weight hydrophilic fragments (Fig. 1) processed by phagocytic cells. In any molecule, there may be several different epitopes creating multivalent antigens. However, one epitope will be dominant over the other epitopes. The immune response is usually generated toward the dominant epitope (Table 1). However, as the immune response evolves, the predominant epitope will change by a mechanism known as epitope spreading.

There are several types of epitopes. Sperm whale myoglobin has five linear, sequential epitopes containing six to eight hydrophilic amino acids in the bends of the normal a-helix conformation (Fig. 3). Most of these epitopes are recognized in the native, fragmented, and extended conformations of the molecule. More frequently, linear epitopes are not accessible to antibody in the native configuration and react only with denatured forms of the molecule.

Globular proteins have different conformational epitopes created when sequential or nonsequential epitopes are brought together in close proximity by folding (Smerdou et al., 1996). The nonsequential conformational epitopes of hen egg-white lysozyme are well characterized (Fig. 2). The conformational determinant shown consists of a closed loop structure formed by disulfide bonds at amino acids 64 and 80. The immune system recognizes the tertiary loop

Figure 1. The relationship between epitopes and internal peptides. CD4 Th cells recognize internal peptides exposed during antigen processing by macrophages. The amino acids of hen egg-white lysozyme are plotted against the protrusion in the tertiary protein structure. The T-cell epitopes are composed of amino acids with a minimum of protrusion. Modified from Modern Trends in Human Leukemia, Rothbard, 1987, 7:44-66.

Figure 1. The relationship between epitopes and internal peptides. CD4 Th cells recognize internal peptides exposed during antigen processing by macrophages. The amino acids of hen egg-white lysozyme are plotted against the protrusion in the tertiary protein structure. The T-cell epitopes are composed of amino acids with a minimum of protrusion. Modified from Modern Trends in Human Leukemia, Rothbard, 1987, 7:44-66.

structure (Benjamin et al., 1984) . Reduction of the disulfide bonds with mercap-toethanol disrupts the tertiary structure and the antigenicity is lost.

New epitopes can be created by proteolysis, phosphorylation, or other modifications of proteins. The alterations in the secondary or tertiary structure create a neoantigen. For example, amino acids are often added to recombinant proteins that are subsequently refolded in the laboratory. Both manipulations of native proteins can create immunogenic neoantigens.

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