The evolution of powerful yet perilous immune systems

Abstract

The mammalian immune system packs serious punch against infection but can also cause harm: for example, coronavirus disease 2019 (COVID-19) made headline news of the simultaneous power and peril of human immune responses. In principle, natural selection leads to exquisite adaptation and therefore cytokine responsiveness that optimally balances the benefits of defense against its costs (e.g., immunopathology suffered and resources expended). Here, we illustrate how evolutionary biology can predict such optima and also help to explain when/why individuals exhibit apparently maladaptive immunopathological responses. Ultimately, we argue that the evolutionary legacies of multicellularity and life-history strategy, in addition to our coevolution with symbionts and our demographic history, together explain human susceptibility to overzealous, pathology-inducing cytokine responses. Evolutionary insight thereby complements molecular/cellular mechanistic insights into immunopathology.

Evolutionary gain and loss of a pathological immune response to parasitism

“…For example, adult Soay sheep with higher self-reactive antibody titers had lower reproductive rates ( 5 ), although immune costs have not been found in some other systems, perhaps because costs are condition dependent ( 6 ). Evolutionary optimization theory suggests that the marginal benefit of evolving increased parasite resistance must be balanced against the marginal costs imposed by the immune response ( 7 ). As a result, populations may evolve toward an intermediate optimum with partial resistance and some autoimmune costs.…”

Revising immune cell coordination: Origins and importance of single‐cell variation

“…Besides, immune cells must weigh the costs and benefits of each possible outcome given that future and must decide in the presence of other, potentially competitive decision‐makers [i.e., other (immune) cells able of producing soluble signaling molecules] [ 16 ]. Likewise, in practice, the optimal immune response balances out the tradeoffs posed by infection (harm caused by the infectious agent) and immunopathology (harm caused by the immune system) [ 7 , 17 ]. For example, fighting a pathogen favors a rapid and potent immune response, however, proinflammatory cytokines can be harmful to uninfected cells.…”

“…Besides, and importantly, immune signaling systems need to be carefully controlled, as every unit of power to kill pathogens (e.g., pro‐inflammatory cytokines, such as type I IFN (IFN‐I), etc.) also possesses power to kill its own cells [ 7 ].…”

One hand washes the other: cooperation and conflict in hygiene and immunity

“…Strong resistance responses, which generally seek to inhibit parasite replication and reduce burden, can be extremely costly (Sheldon & Verhulst 1996;Viney et al 2005;Graham et al 2011aGraham et al , 2021. If resistance reduces the number of parasites shed to the rest of the population, investing in this cost can be construed as an altruistic act.…”

“…As such, animals have evolved a wide range of behavioural and immunological methods for avoiding infection or reducing its impact. Because these traits themselves are often costly to the infected individual while benefitting its conspecifics (Graham et al 2005(Graham et al , 2021Buck et al 2018;Hart & Hart 2018), investment in such traits (i.e., "immune cooperation") will depend on social context and patterns of relatedness. Reciprocally, failing to invest in such traits is analogous to "immune cheating", foisting the burden of infection on conspecifics while protecting one's own health.…”