Lymphocytes talk about modelling immunity

Victor Apanius

Department of Biological Sciences
Florida International University
University Park Miami 33199 USA

There are a number of phenomenological aspects of vertebrate immunity that provide challenges for modelling host resistance:

1. Host resistance is multifactorial and shows compensatory behavior.

Host resistance refers to the ability of an individual to mitigate the fitness costs of infectious agents through natural (non-induced) and acquired (induced) immunity. There are many mechanisms within each of these modes that have overlapping functions to prevent and control infections. A methodological difficulty in assigning a phenotypic score for immunocompetence is that multiple effector mechanisms confer immunity and cross- regulation between mechanisms allows one mechanism to compensate for deficiencies in another mechanism. Therefore, single measures of immunity, e.g. antibody titers, may be inadequate for assessing immunocompetence. Challenging individual animals with defined infectious agents provides a better measure of immunocomptence has ethical and technical costs. More importantly, individual hosts harbor multiple parasitic infections in interactive communities which forces immunocompetence to be an operational term based on relavant experimental conditions. It is proposed that:
1. "immunocompetence" be reserved for conceptual discussions, like the terms "niche" or "stress";
2. "anti-agent acquired immunity" be used for discussion of induced and temporally varible responses against the particular agent;
3. "anti-agent natural resistance" be used for discussion of phenotypic resistance against the particular agent;
4. "anti-agent genetic resistance" be used for discussion of the genetic (additive genetic variance) component of resistance against the particular agent.

The logical relationship between these components of immunocompetence is:
- genetic resistance is a subset of natural resistance
- natural and acquired resistance are additive or, more realistically, interactive
- immunocompetence is the sum of these components across all infectious agents

For discussion

2. Host resistance is based on single-gene as well as complex epistatic inheritance.

The sickle-cell hemoglobin allele is the archetypical example of a single-gene variant that confers genetic resistance to a specific parasite. Artificial selection of domestic animals for parasite resistance or for antigen-specific acquired immunity has revealed numerous contributing loci scattered throughout the genome. The Major Histocompatibility Complex (MHC) is a 4 MB region that consistently contributes to parasite resistance also controls acquired immunity to specific antigens. The genetic features of the MHC may provide insight into host-parasite coevolution:
1. Loci within the MHC are in strong linkage disequilibirum consistent with natural selection on certain members of the complex.
2. The distinctive pattern of nucleotide substitutions indicates that selection is diversifying the antigen binding region of the expressed protein.
3. The diversified alleles retain sequence identity across speciation events. In one example, immunological function was preserved in a cross-species in vitro assay suggesting that alleles are retained for their immunlogical function.
4. Resistance conferred by MHC alleles is specific for parasite genotypes and a particular MHC-genotype does not confer resistance in all host sub-populations, presumably because of MHC-background gene interactions.
5. Trade-offs in resistance to multiple parasites are common suggesting that one particular MHC-genotype is universally advantageous.
6. Allelic frequencies in human and animal populations show a uniform distribution, i.e. no single genotype predominates.
7. MHC-heterozygotes do not show enhanced parasite resistance.

In summary, these features are consistent with frequency dependent parasite-driven selection operating on MHC genes. Despite the wealth of empirical and theoretical work on this model system, many questions remain to be answered.

For discussion

3. Antigen-specific responses show rapid somatic evolution.

For most acute and chronic infections, antigen-specific acquired immunity is the most important mode of resistance. These lymphocyte-mediated responses are initiated when parasite- derived peptides bind to MHC-encoded proteins and are presented to T or B lymphocytes with receptors that specifically bind to the antigenic peptide. These lymphocytes become metabolically activated and undergo rapid mitotic proliferation to expand the pool of lymphocytes that can recognize and destroy parasites based on their antigenic identity. This expansion of antigen- specific lymphocytes during the immune response is termed clonal expansion to underscore the role of a small population of precursor cells. These cells have re-arranged their germline antigen receptor genes and those that have binding sites that are specific for parasite antigens proliferate without additional DNA re-arrangements. However, there is a fine-tuning mechanism (affinity maturation) for increasing the binding affinity of these antigens receptors, at least for B-lymphocyte receptors or antibodies. The germinal center reaction refers to a proliferating swarm of lymphocytes that are competing for antigen in the spleen and lymph nodes. There is an increased mutation rate in these lymphocytes such that a small proportion of them have mutated antigen-receptor binding sites. Those mutants that have binding sites with a higher affinity have a selective advantage for binding antigen and proliferating further. In this way, the acquired immune response can somatically evolve to increase the effectiveness of immunity during chronic infections.

The key feature is that low-grade, chronic ("trickle") infections provide the optimal conditions for affinity maturation and the somatic evolution of acquired immunity. Although this process has been modeled to explore the consequences of alternative mutation rates, I am not aware that this dynamic increase in acquired immunity has been incoporated into demographic models.

For discussion: 1. Is somatic evolution of immunity powerful enough to be detected in epdemiological processes?
2. Does somatic evolution drive the intrahost diversification of microparasites in chronic infections?
3. Have parasites evolved "smokescreen" antigens that drive germinal center reactions but lead to ineffective antibodies?
4. What is the relationship between the number of antigenic targets, affinity maturation and the effectiveness of acquired immunity

4. Antigen-specific responses are constrained by self- reactivity (autoimmunity) and molecular mimicry by pathogens.

During the ontogeny of an individual, newly generated lymphocytes are destroyed if they express antigen-receptors that bind to self-molecules. An analogous process occurs during adulthood but has a different basis. These processes, labeled tolerance induction, affect the development of the antigen- receptor repertoire. Heuristically, one can talk about antigen- receptors that are sampling the antigenic universe but that this receptor repertoire has holes where autoreactive receptors have been deleted. Autoimmunity refers to the breakdown of tolernace and self-destruction of host tissue by the host's immune response. This can be distinguished from immunopathology because this process results from destruction of host tissue by overzealous immune mechanisms. Immunopathology can be viewed as a spillover phenomenon while autoimmunity is a permanent misindentification of self-tissue. The origins of autoimmune disease are actively being investigated and among the intriguing hypotheses is the role of infectious agents and molecular mimicry. Parasites that have antigens which resemble host molcules will be favored because will, at first principles, be invisible to acquired immunity based on lymphocyte receptors. In fact, it is believed that these infectious agents precipitate a breakdown of tolerance and induce autoimmune disease as a consequence of induced anti-parasite immunity. Down-regulation of host immunity will spare the host of autoimmune disease but will also limit the host's ability to control the infectious agent. One can envision an equilibrial condition whereby the fitness cost of parasitism is balanced by the cost of autoimmunity and parasite persistance is maintained by molecular mimicry.

Although the occurence of molecular mimicry and its role in autoimmune disease is currently controversial, the possibility that parasite antigens evolve to resemble host tissue in order to avoid acquired immunity is intuitively appealing.

For discussion

5. Antigen-specific immune responses can be categorized into two broad classes which are predictive of host resistance or susceptibility.

Generally, acquired immune responses follow a sterotyped progression of cellular and molecular events. These events are regulated by neuro-endocrine hormones and immuoregulatory molecules called cytokines. Two different cytokine profiles are often observed during an anti-parasite immune response in diferent individual hosts. These are referred to as TH1- or TH2-mediated responses and are typically associated with cell-mediated cytotoxicity and antibody-mediated cytotoxicity, respectively. It is now widely recognized that polarization and progression of the immune responses along one of these avenues is associated with resistance and susceptibility, depending on the identity of the parasite and the host's MHC- genotype and genetic background. The factors that predispose an individual to mount a TH1- or TH2-mediated immune response in one category or another is are currently being investigated.

Although, the adaptive significance of this dichotomy in immune function is poorly understood, it is clear that a significant proportion of heterogeneity in outcome of infectious disease can be attributed to deviation of the immune response in one direction or the other.

For discussion

6. Antigen-specific responses are constrained by nutritional resources.

One of the least understood aspects of vertebrate immunity is the metabolic demand that immunity places on the host nutrient budget. It is known that lymphocyte-mediated responses are sensitive to protein and calorie malnutrition, while other immune functions, e.g. natural iimunity is more resilient to nutritional stress. It is known that proliferating lymphocytes have an rapid cell cycle (14 hrs) and require a high level of nitrogen-rich substrates, e.g. glutamine, to satify the demands of nucleic acid synthesis. It is known that the first cytokine produced during an acquired immune response has profound physiological and behavioral effects: increased body temperature, increased sleep, depressed apetite and lethargy, increased release of glucose from glycogen stores, increased breakdown of skeletal muscle and an increased turnover of amino acids in the circulation. All of these features point toward elevated nutrient mobilization coupled with organismal inactivity during acquired immune responses. Finally, it is known that high levels of antigenic stimulation can depress the growth rate of animals, suggesting that nutrients are re-allocated away from growth in order to sustain immunological activity. These diverse sources of circumstantial evidence indicate that immune function competes other physiological processes for nutrients.

It is widely believed that nutrition is one factor that determines the level of immunity within and between host populations. It is proposed that the metabolic cost of different immune functions leads to qualitative, and simply quantitative, changes in immune function under various nutritional regimes

For discussion

7. Immunological memory is selective.

It seems paradoxical that a short-term viral infection can confer life-long immunological memory yet a lifetime of exposure to intestinal nematodes is associated with waning immunological memory. The mechanistic basis of immunological memory is an active field of investigation but few organizing principles. The development of memory depends rapid expansion of lymphocyte pool during the initial infection. Certain members of this pool are destined to become long-lived, quiescent memory cells. It is controversial whether or not these cells require exposure to antigens sequestered within host tissue. Nonetheless, it appears that the interaction of lymphocyte proliferation and antigenic exposure is critical for the generation of long-term immunological memory. The old concept of premunition, i.e. resistance generated by low-grade,chronic infections, may serve as an alternative mechanism to immunological memory.

In summary, the dynamics of antigenic exposure is crucial for the generation and longevity of immunological memory.

For discussion:

1. Is the development of memory related to the predictability of the host re-encountering specific infectious agents?
2. What is the role of memory in resistance to parasite that evolving within the individual host?
3. How does the variation in exposure to infectious agents relate to heterogeneity in host immunological memory?
4. What is the functional relationship between premunition and immunological memory?