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Frank SA. Immunology and Evolution of Infectious Disease. Princeton (NJ): Princeton University Press; 2002.

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Immunology and Evolution of Infectious Disease.

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Chapter 16Recap of Some Interesting Problems

My Problems for Future Research span many different technical and conceptual challenges for understanding antigenic variation. These fifty-six problems arise from my synthesis of the molecular processes of recognition, the dynamics of infections within hosts, the variability of populations, and the methods for studying evolution.

There is no point in covering once again so many diverse topics. Instead, I have chosen to recap four examples, to highlight the kinds of problems that integrate different levels of analysis. I summarize each example briefly, as a reminder of the potential for integrating structure, function, biochemical kinetics, population dynamics, and evolution.

16.1. Population-Level Explanation for Low Molecular Variability

Immune memory against the measles virus provides lifelong protection because the measles virus does not evolve widespread escape variants. Measles can vary its dominant surface antigen, hemagglutinin, and limited variation does occur (Griffin 2001). So it is an interesting puzzle why antigenic variants do not spread as in many other viruses.

Perhaps the very high infectiousness of measles causes the common strain to spread so widely in the host population that little heterogeneity occurs among hosts in immune memory profiles. If memory responds against a few different epitopes, then no single-step mutational change allows a measles variant to spread between previously infected hosts. The only "nearby" susceptible class of hosts arises from the influx of naive newborns, which depends on the birthrate of the host population. Naive hosts do not impose selective pressure for antigenic change.

This explanation for the lack of antigenic variation suggests that the epidemiological properties of the parasite and the demographic structure of the hosts affect the patterns of molecular variation in antigens. These population processes do not control the possible types of variation or the molecular recognition between host and parasite, but instead shape the actual distribution of variants.

A population-level explanation for the measles virus's lack of widespread antigenic variation may be wrong. The lack of variation may simply reflect conservation of some essential viral function in a dominant antigen, such as binding to host receptors. My point here is that the lack of molecular variation does not necessarily mean that the explanation resides at the molecular level. Population processes can strongly influence the distribution of molecular variants.

16.2. Molecular-Level Explanation for Population Dynamics

The causal chain can move in the other direction, from the molecular nature of host-parasite recognition to the dynamics of populations. For example, five or so amino acids determine most of the binding energy between an antibody and an antigen. Often a single amino acid substitution in the antigen can abolish the defensive capability of a particular antibody specificity for a matching epitope. This type of recognition is qualitative, in which a single change determines whether or not recognition occurs.

Binding reactions may change in a qualitative way between molecular variants. But the dynamics of an infection within a host depend on all of the parasite's epitopes and all of the specific B and T cell lineages that recognize different epitopes. The interactions within the host between the population of parasites and the populations of different immune cells determine immunodominance, the number of different epitopes that stimulate a strong immune response.

Immunodominance sets the number of amino acid substitutions needed to avoid host recognition. This aggregate recognition at the level of individual hosts controls the spread of antigenic variants through a population of previously exposed hosts. Thus, molecular interactions affect immunodominance, and immunodominance sets the pace of evolutionary change and the distribution of variants in parasite populations.

16.3. Binding Kinetics and the Dynamics of Immunodominance

The control of immunodominance remains poorly understood. Rao's (1999) analyses suggest the kinds of studies that may generate new insight. Rao showed that initial stimulation of B cells depended on an affinity window for binding between antibodies and epitopes. Low-affinity binding did not stimulate division of B cell lineages, whereas high-affinity antibodies bound the antigen so effectively that the B cell receptors received little stimulation. Intermediate affinity provided the strongest stimulation for initial expansion of B cell clones.

After initial stimulation and production of IgM, the next phase of B cell competition occurs during affinity maturation and the shift to IgG production. The B cell receptors with the highest on-rates of binding for antigen tended to win the race to pass through affinity maturation. The limiting step may be competition for stimulation by helper T cells. This competition for T cell help apparently depends on the rate at which B cells acquire antigens rather than on the equilibrium affinity of binding to antigens.

Equilibrium affinity is the ratio of the rate at which bonds form (on-rate) to the rate at which bonds break (off-rate). The contrast between the early selection of equilibrium affinity (on:off ratio) and the later selection of on-rate may provide insight into the structural features of binding that separately control on-rates and off-rates. This is a superb opportunity to relate structure to function via the kinetic processes that regulate the immune response.

16.4. Diversity and Regulation of Archival Repertoires

Some parasites store archival libraries of antigenic variants in their genomes. Switching expression between variants may allow the parasite to escape recognition by immune responses directed at previously expressed variants. Alternatively, a sequence of variants may exploit the mechanisms of immune recognition and regulation to interfere with the ability of the host to mount new responses to variants expressed later in the sequence. Variants can potentially interfere with new host responses by exploiting original antigenic sin—the tendency of the host to enhance a cross-reactive response to a previously encountered antigen instead of generating a new and more focused response to a novel variant.

The interesting problem concerns the evolution of the archival repertoire. How do the different molecular mechanisms of escape and immune interference shape the diversity and cross-reactivity of variants stored within each parasite's genome?

The type of immune recognition may influence the pattern of diversification between antigenic variants. For example, IgM antibodies with relatively low affinity and high cross-reactivity control Borrelia hermsii, a spirochete with an archival library of variants (Barbour and Bundoc 2001). By contrast, many parasites face control by the more highly specific IgA and IgG antibodies. It would be interesting to know if B. hermsii requires a relatively greater molecular distance between variants to escape IgM cross-reactivity than parasites controlled by IgG antibodies. If so, then B. hermsii's variants may have diverged under a different pattern of specificity and cross-reactivity from that influencing the divergence of variants in other parasites.

Parasites with archival variants have particularly interesting dynamics within hosts. If the variants are produced too quickly, the host develops specific immunity against all types early in the infection, and the infection cannot persist for long. If the variants arise too slowly, the parasite risks clearance before switching to a novel type. Thus, the pacing of molecular switches in the parasite must be tuned to the dynamics of the host's immune response. This system of contained dynamics within individual hosts may be particularly amenable to experimental study, providing insight into the interactions between host immunity, antigenic escape variants, the shaping of antigenic repertoires, and the evolution of the molecular control systems that regulate antigenic switching.

16.5. Final Note

The technical advances in molecular biology have greatly accelerated the pace of discovery in immunology and parasite biology. When reviewing various topics, I found that many key articles had been published in the past eighteen months.

This book's synthesis may soon be outdated with regard to the latest details for each particular subject. But, for the first time, it has been possible to see the subject as a whole, to discuss in an informed way the interactions between different processes and different ways of study. The problems that I raised for future study will continue to provide key challenges for many years to come.

Copyright © 2002, Steven A Frank.
Bookshelf ID: NBK2407

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