It has long been recognized (at least in evolutionarily informed circles) that the immune system faces a dire tradeoff: too little or too specific a immune response and pathogens triumph, too much or too nonspecific and the system attacks host tissues. A new paper in Nature Ecology and Evolution analyzes the problem systematically using tools from signal detection theory. This is likely to become a landmark paper. Alas, it is not open access, but the abstract is below.
Metcalf, C. J. E., Tate, A. T., & Graham, A. L. (2017). Demographically framing trade-offs between sensitivity and specificity illuminates selection on immunity. Nature Ecology & Evolution, 1(11), 1766–1772. https://doi.org/10.1038/s41559-017-0315-3
Abstract: A fundamental challenge faced by the immune system is to discriminate contexts meriting activation from contexts in which activation would be harmful. Selection pressures on this ability are likely to be acute: the penalty of mis-identification of pathogens (therefore failure to attack them) is mortality or morbidity linked to infectious disease, which could reduce fitness by reducing lifespan or fertility; the penalty associated with mis-identification of host (therefore self-attack) is immunopathology, whose fitness costs can also be extreme. Here we use classic epidemiological tools to frame this trade-off between sensitivity and specificity of immune activation, exploring implications for evolution of immune discrimination. We capture the expected increase in the evolutionarily optimal sensitivity under higher pathogen mortality risk, and a decrease in sensitivity with increased immunopathology mortality risk; but a number of non-intuitive predictions also emerge. All else being equal, optimal sensitivity decreases with increasing lifespan; and, where sensitivity can vary over age, decreases at late ages not solely attributable to immunosenescence are predicted. These results both enrich and challenge previous predictions concerning the relationship between life expectancy and optimal evolved defenses, highlighting the need to account for epidemiological setting, lifestage-specific immune priorities, and immune discrimination in future investigations.
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RADAR, SCINTILLATION COUNTING AND POSITIVE SELECTION
The invocation by Metcalf and her colleagues (2017) of the evolution of immunological self/not-self discrimination in terms of a known physical system (receiver-operator curves) that would detect foreign aircraft (WWII radar), recalls a similar analogy with a system designed to detect radioactive emissions (liquid scintillation counter; Morton & Robinson 1949). Here there is a requirement for two photocells to simultaneously detect a light signal triggered by a radioactive emission. Thus, not-self is registered, whereas the random discharge of each individual photocell (self) is largely eliminated (Forsdyke 1968). The latter analogy (two signal hypothesis) led to the postulate that a distinct lymphocyte subpopulation that was specific for “near-self,” would have been positively selected to occupy the territory between the overlaps described by Metcalf. However, while recognizing negative selection (i.e. “selection of T cells in the thymus to avoid recognition of self can help to optimize both specificity and sensitivity”), positive selection does not have a place in the Metcalf model.
As noted by Vrisikoop et al. (2014), “selection for T cells which are anti-‘near-self’ can act as an effective barrier to prevent evolution of pathogens toward the holes in the T cell repertoire caused by deletion of self-reactive T cells through negative selection.” In other words, a host does not spread its resources too widely in trying to develop the potential to respond to a universe of possible non-self antigens, formidable in range. Rather, it anticipates viral strategy and focuses appropriately. Thus, the generation of immunological repertoires is best examined from the perspective of pathogens.
As elaborated elsewhere (Forsdyke 2015), “a microbe that could, in one step, mutate one of its antigens from a form that was non-self with respect to its host to a form that was self with respect to its host would have largely overcome the host’s immune defenses with respect to that antigen. The ‘holes’ in the repertoire that had been created by the host’s prior elimination of self-reacting lymphocytes could then be exploited. However, mutation is usually stepwise. If a microbe (non-self), by mutating a step toward self along the path from non-self to self, secured a selective advantage, then the mutant form would come to dominate the microbe population. If a member of this mutant population, by mutating a further step along the path, secured a further advantage, then this new mutant form would, in turn, come to dominate the population. Thus, an average member of the microbe population would progressively become better adapted, to the detriment of the host. Progressive mutation along the non-self-to-self path would be increasingly advantageous to the microbe. However, the advantage would be lost if, as it mutated closer to host-self, the microbe encountered progressively stiffer host defenses. Thus, positive selection of lymphocytes for specificities that were very close to, but not quite, anti-self — that is anti-‘near-self’ specificities — could be an important host adaptation.”
References for the above:
Forsdyke DR (1968) The liquid scintillation counter as an analogy for the distinction between “self” and “not-self” in immunological systems. Lancet, l: 28l-283.
Forsdyke DR (2015) Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview. Immun Cell Biol 93: 297-304.
Metcalf CJE, Tate AT, Graham AL (2017) Demographically framing trade-offs between
sensitivity and specificity illuminates selection on immunity. Nat Ecol Evol 1: 1766-1772.
Morton, G. A., Robinson, K. W. A coincidence scintillation counter. (1949) Nucleonics 4, 25-29.
Vrisekoop N, Monteiro JP, Mandl JN, Germain RN (2014) Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity 41: 181-190.