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.

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.