In this chapter, I describe the attributes of host and parasite molecules that determine immune recognition. Two terms frequently arise in discussions of recognition. Specificity measures the degree to which the immune system differentiates between different antigens. Cross-reactivity measures the extent to which different antigens appear similar to the immune system. The molecular determinants of specificity and cross-reactivity define the nature of antigenic variation and the selective processes that shape the distribution of variants in populations.
The first section discusses antibody recognition. The surfaces of parasite molecules contain many overlapping antibody-binding sites (epitopes). An antibody bound to an epitope covers about 15 amino acids on the surface of a parasite molecule. However, only about 5 of the parasite’s amino acids contribute to the binding energy. A change in any of those 5 key amino acids can greatly reduce the strength of antibody binding.
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The second section focuses on the paratope, the part of the antibody molecule that binds to an epitope. Antibodies have a variable region of about 50 amino acids that contains many overlapping paratopes. Each paratope has about 15 amino acids, of which about 5 contribute most of the binding energy for epitopes. Paratopes and epitopes define complementary regions of shape and charge rather than particular amino acid compositions. A single paratope can bind to unrelated epitopes, and a single epitope can bind to unrelated paratopes.
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The third section introduces the different stages in the maturation of antibody specificity. Naive B cells make IgM antibodies that typically bind with low affinity to epitopes. A particular epitope stimulates division of B cells with relatively higher-affinity IgM antibodies for the epitope. As the stimulated B cell clones divide rapidly, they also mutate their antibody-binding regions at a high rate. Mutant lineages that bind with higher affinity to the target antigen divide more rapidly and outcompete weaker-binding lineages. This mutation and selection produces high-affinity antibodies, typically of type IgA or IgG.
The fourth section describes “natural” antibodies, a class of naive IgM antibodies. Each natural antibody can bind with low affinity to many different epitopes. Natural antibodies from different B cell lineages form a diverse set that binds with low affinity to almost any antigen. One in vitro study of HIV suggested that these background antibodies bind to the viruses with such low affinity that they do not interfere with infection. By contrast, in vivo inoculations with several different pathogens showed that the initial binding by natural antibodies lowered the concentrations of pathogens early in infection by one or two orders of magnitude.
The fifth section contrasts affinity and specificity. Poor binding conditions cause low-affinity binding to be highly specific because detectable bonds form only between the strongest complementary partners. By contrast, favorable binding conditions cause low-affinity binding to develop a relatively broad set of complementary partners, causing relatively low specificity. The appropriate measure of affinity varies with the particular immune process. Early stimulation of B cells appears to depend on the equilibrium binding affinity for antigens. By contrast, competition between B cell clones for producing affinity-matured antibodies appears to depend on the dynamic rates of association between B cell receptors and antigens.
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The sixth section compares the cross-reactivity of an in vivo, polyclonal immune response with the cross-reactivity of a purified, monoclonal antibody. Polyclonal immune responses raise antibodies against many epitopes on the surface of an antigen. Cross-reactivity declines linearly with the number of amino acid substitutions between variant antigens because each exposed amino acid contributes only a small amount to the total binding between all antibodies and all epitopes. By contrast, a monoclonal antibody usually binds to a single epitope on the antigen surface. Cross-reactivity declines rapidly and nonlinearly with the number of amino acid substitutions in the target epitope because a small number of amino acids control most of the binding energy.
The seventh section discusses the specificity and cross-reactivity of T cell responses. Four steps determine the interaction between parasite proteins and T cells: the cellular digestion of parasite proteins, the transport of the resulting peptides to the endoplasmic reticulum, the binding of peptides to MHC molecules, and the binding of peptide-MHC complexes to the T cell receptor (TCR). Mason (1999) estimates that each TCR cross-reacts with ~105 different peptides. If a TCR reacts with a specific peptide, then the probability that it will react with a second, randomly chosen peptide is only ~10−4. Thus, the TCR can be thought of as highly cross-reactive or highly specific depending on the point of view.
The eighth section lists the ways in which hosts vary genetically in their responses to antigens. MHC alleles are highly polymorphic. The germline genes that contribute to the T cell receptor have some polymorphisms that influence recognition, but the germline B cell receptor genes do not carry any known polymorphisms.
The final section takes up promising lines of study for future research.
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