In this paper we address the issue of how to think about immunity. Many immunological writings suggest a straightforward option: the view that the immune system is primarily a system of defense, which naturally invites the talk of strong immunity and strong immune response. Despite their undisputable positive role in immunology, such metaphors can also pose a risk of establishing a narrow perspective, omitting from consideration phenomena that do not neatly fit those powerful metaphors. Building on this analysis, we argue two things. First, we argue that the immune system is involved not only in defense. Second, by disentangling various possible meanings of 'strength' and 'weakness' in immunology, we also argue that such a construal of immunity generally contributes to the distortion of the overall picture of what the immune system is, what it does, and why it sometimes fails. Instead, we propose to understand the nature of the immune system in terms of contextuality, regulation, and trade-offs. We suggest that our approach provides lessons for a general understanding of the organizing principles of the immune system in health and disease. For all this to work, we discuss a wide range of immunological phenomena.

Department of Analytic Philosophy Institute of Philosophy Czech Academy of Sciences Jilská 352 1 110 00 Prague Czech Republic

Department of Philosophy University of Vienna Universitätsstraße 7 1010 Vienna Austria

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Alizadeh D, Larmonier N. Chemotherapeutic targeting of cancer-induced immunosuppressive cells. Cancer Res. 2014;74:2663–2668. doi: 10.1158/0008-5472.CAN-14-0301. PubMed DOI PMC

Alizon S, Hurford A, Mideo N, Van Baalen M. Virulence evolution and the trade-off hypothesis: history, current state of affairs and the future. J Evol Biol. 2009;22:245–259. doi: 10.1111/j.1420-9101.2008.01658.x. PubMed DOI

Ayres JS. Surviving COVID-19: A disease tolerance perspective. Sci Adv. 2020;6:eabc1518. doi: 10.1126/sciadv.abc1518. PubMed DOI PMC

Ayres JS, Schneider DS. The role of anorexia in resistance and tolerance to infections in drosophila. PLoS Biol. 2009;7:e1000150. doi: 10.1371/journal.pbio.1000150. PubMed DOI PMC

Ball P. A metaphor too far. Nature. 2011 doi: 10.1038/news.2011.115. DOI

Barton ES, White DW, Cathelyn JS, et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature. 2007;447:326–329. doi: 10.1038/nature05762. PubMed DOI

Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370:eabd4585. doi: 10.1126/science.abd4585. PubMed DOI PMC

Bastard P, Lévy R, Henriquez S, et al. Interferon-β Therapy in a Patient with Incontinentia Pigmenti and Autoantibodies against Type I IFNs Infected with SARS-CoV-2. J Clin Immunol. 2021 doi: 10.1007/s10875-021-01023-5. PubMed DOI PMC

Black M. Models and metaphors: studies in language and philosophy. Ithaca: Cornell University Press; 1962.

Bradie M. Science and Metaphor. Biol Philos. 1999;14:159–166. doi: 10.1023/A:1006601214943. DOI

Brodin P. Immune determinants of COVID-19 disease presentation and severity. Nat Med. 2021;271(27):28–33. doi: 10.1038/s41591-020-01202-8. PubMed DOI

Burnet FM. Cellular immunology: self and not-self. Cambridge: Cambridge University Press; 1969.

Burzyn D, Kuswanto W, Kolodin D, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013;155:1282–1295. doi: 10.1016/j.cell.2013.10.054. PubMed DOI PMC

Chiu L, Bazin T, Truchetet ME, et al. Protective microbiota: from localized to long-reaching co-immunity. Front Immunol. 2017;8:1. doi: 10.3389/fimmu.2017.01678. PubMed DOI PMC

Clarke WR. In defense of self: how the immune system really works. Oxford: Oxford University Press; 2007.

Crawford DH. Deadly companions: how microbes shaped our history. New York: Oxford University Press; 2018.

Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev. 2018;98:477–504. doi: 10.1152/PHYSREV.00039.2016/ASSET/IMAGES/LARGE/Z9J0041728270006.JPEG. PubMed DOI PMC

Druzd D, Matveeva O, Ince L, et al. Lymphocyte circadian clocks control lymph node trafficking and adaptive immune responses. Immunity. 2017;46:120–132. doi: 10.1016/j.immuni.2016.12.011. PubMed DOI PMC

Dunbar KN. Understanding the role of cognition in science: the science as category framework. In: Carruthers P, Stich S, Siegal M, editors. The cognitive basis of science. Cambridge: Cambridge University Press; 2002. pp. 154–170.

Eberl G. A new vision of immunity: homeostasis of the superorganism. Mucosal Immunol. 2010;3:450–460. doi: 10.1038/mi.2010.20. PubMed DOI

Eberl G. Immunity by equilibrium. Nat Rev Immunol. 2016;16:524–532. doi: 10.1038/nri.2016.75. PubMed DOI

Eberl G, Pradeu T. Towards a general theory of immunity? Trends Immunol. 2018;39:261–263. doi: 10.1016/j.it.2017.11.004. PubMed DOI

Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383:2255–2273. doi: 10.1056/NEJMra2026131. PubMed DOI PMC

Files JK, Boppana S, Perez MD, et al. Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection. J Clin Invest. 2021 doi: 10.1172/JCI140491. PubMed DOI PMC

Fleck L. Genesis and development of a scientific fact. Chicago: The University of Chicago Press; 1979.

Fox Keller E. Refiguring life: metaphors of twentieth-century biology. New York: Columbia University Press; 1995.

Guarda G, Braun M, Staehli F, et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011;34:213–223. doi: 10.1016/j.immuni.2011.02.006. PubMed DOI

Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–185. doi: 10.1038/nature21363. PubMed DOI

Hussell T. Heterologous immunity meets tissue-specific training. Nat Rev Immunol. 2016;165(16):275–275. doi: 10.1038/nri.2016.41. PubMed DOI

Institute of Medicine . Ending the war metaphor: the changing agenda for unraveling the host-microbe relationship. Washington, DC: National Academies Press; 2006. PubMed

Kampourakis K. Why does it matter that many biology concepts are metaphors? In: Kampourakis K, Uller T, editors. Philosophy of science for biologists. Cambridge: Cambridge University Press; 2020. pp. 102–122.

Keller M, Mazuch J, Abraham U, et al. A circadian clock in macrophages controls inflammatory immune responses. Proc Natl Acad Sci U S A. 2009;106:21407–21412. doi: 10.1073/pnas.0906361106. PubMed DOI PMC

Kitano H. Biological robustness. Nat Rev Genet. 2004;5:826–837. doi: 10.1038/nrg1471. PubMed DOI

Krizhanovsky V, Yon M, Dickins RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134:657–667. doi: 10.1016/j.cell.2008.06.049. PubMed DOI PMC

Lakoff G, Johnson M. Metaphors we live by. Chicago: Chicago University Press; 1980.

Larsen MD, de Graaf EL, Sonneveld ME, et al. Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity. Science. 2021 doi: 10.1126/SCIENCE.ABC8378. PubMed DOI PMC

Laurent P, Jolivel V, Manicki P, et al. Immune-mediated repair: a matter of plasticity. Front Immunol. 2017;8:24. doi: 10.3389/fimmu.2017.00454. PubMed DOI PMC

Lee S, Kim T, Lee E, et al. Clinical course and molecular viral shedding among asymptomatic and symptomatic patients with SARS-CoV-2 infection in a community treatment center in the Republic of Korea. JAMA Intern Med. 2020;180:1447–1452. doi: 10.1001/jamainternmed.2020.3862. PubMed DOI PMC

Liang G, Bushman FD. The human virome: assembly, composition and host interactions. Nat Rev Microbiol. 2021 doi: 10.1038/s41579-021-00536-5. PubMed DOI PMC

Lochmiller RL, Deerenberg C. Trade-offs in evolutionary immunology: just what is the cost of immunity? Oikos. 2000;88:87–98. doi: 10.1034/j.1600-0706.2000.880110.x. DOI

Long QX, Tang XJ, Shi QL, et al. (2020) Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020;268(26):1200–1204. doi: 10.1038/s41591-020-0965-6. PubMed DOI

Löwy I. Metaphors of immunology: war and peace. Hist Cienc Saude Manguinhos. 1996;3:7–23. doi: 10.1590/S0104-59701996000100002. PubMed DOI

Lucas C, Klein J, Sundaram M, et al. Kinetics of antibody responses dictate COVID-19 outcome. medRxiv. 2020 doi: 10.1101/2020.12.18.20248331. DOI

Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584:463–469. doi: 10.1038/s41586-020-2588-y. PubMed DOI PMC

Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11:519–531. doi: 10.1038/nri3024. PubMed DOI

Marin I, Kipnis J. Learning and memory … and the immune system. Learn Mem. 2013;20:601–606. doi: 10.1101/LM.028357.112. PubMed DOI PMC

Martin E. Flexible bodies: tracking immunity in American culture from the days of polio to the age of AIDS. Boston: Beacon Press; 1994.

Martins R, Carlos AR, Braza F, et al. Disease tolerance as an inherent component of immunity. Annu Rev Immunol. 2019;37:405–437. doi: 10.1146/ANNUREV-IMMUNOL-042718-041739. PubMed DOI

Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science. 2012;335:936–941. doi: 10.1126/science.1214935. PubMed DOI PMC

Méthot P-O, Alizon S. What is a pathogen? Toward a process view of host-parasite interactions. Virulence. 2014;5:775–785. doi: 10.4161/21505594.2014.960726. PubMed DOI PMC

Muriuki JM, Mentzer AJ, Kimita W, et al. Iron status and associated malaria risk among African children. Clin Infect Dis. 2019;68:1807–1814. doi: 10.1093/cid/ciy791. PubMed DOI PMC

Murphy K, Weaver C. Janeway’s immunobiology. 9. New York: Garland Science; 2017.

Nicholson DJ. The machine conception of the organism in development and evolution: a critical analysis. Stud Hist Philos Sci Part C Stud Hist Philos Biol Biomed Sci. 2014;48:162–174. doi: 10.1016/J.SHPSC.2014.08.003. PubMed DOI

Pereyra F, Jia X, McLaren PJ, et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010;330:1551–1557. doi: 10.1126/science.1195271. PubMed DOI PMC

Pradeu T. The limits of the self: immunology and biological identity. Oxford: Oxford University Press; 2012.

Pradeu T. Mutualistic viruses and the heteronomy of life. Stud Hist Philos Sci Part C Stud Hist Philos Biol Biomed Sci. 2016;59:80–88. doi: 10.1016/j.shpsc.2016.02.007. PubMed DOI PMC

Pradeu T. The many faces of biological individuality. Biol Philos. 2016;31:761–773. doi: 10.1007/S10539-016-9553-Z/FIGURES/1. DOI

Pradeu T. Philosophy of immunology. Cambridge: Cambridge University Press; 2019.

Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–241. doi: 10.1016/j.cell.2004.07.002. PubMed DOI

Rankin LC, Artis D. Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell. 2018;173:554–567. doi: 10.1016/j.cell.2018.03.013. PubMed DOI

Reynolds AS. The third lens: metaphor and the creation of modern cell biology. Chicago: University of Chicago Press; 2018. PubMed

Reynolds AS. Understanding metaphors in the life sciences. Cambridge: Cambridge University Press; 2022.

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–1355. doi: 10.1126/SCIENCE.AAR4060. PubMed DOI PMC

Rich RR, Fleisher TA, Shearer WT, et al. Clinical immunology: principles and practice. 5. Elsevier; 2019.

Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192:547–556. doi: 10.1083/jcb.201009094. PubMed DOI PMC

Sachs DH. Tolerance: of mice and men. J Clin Invest. 2003;111:1819–1821. doi: 10.1172/JCI18926. PubMed DOI PMC

Sakaguchi S. Regulatory T cells: Meden Agan. Immunol Rev. 2006;212:5–7. doi: 10.1111/j.0105-2896.2006.00425.x. PubMed DOI

Schneider DS. Immunology’s intolerance of disease tolerance. Nat Rev Immunol. 2021;21:624–625. doi: 10.1038/s41577-021-00619-7. PubMed DOI

Schneider T. The holobiont self: understanding immunity in context. Hist Philos Life Sci. 2021;43:1–23. doi: 10.1007/S40656-021-00454-Y. PubMed DOI PMC

Schneider DS, Ayres JS. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol. 2008;8:889–895. doi: 10.1038/nri2432. PubMed DOI PMC

Schultze JL, Aschenbrenner AC. COVID-19 and the human innate immune system. Cell. 2021;184:1671–1692. doi: 10.1016/j.cell.2021.02.029. PubMed DOI PMC

Shaw AC, Joshi S, Greenwood H, et al. Aging of the innate immune system. Curr Opin Immunol. 2010;22:507–513. doi: 10.1016/j.coi.2010.05.003. PubMed DOI PMC

Stefan KL, Kim MV, Iwasaki A, Kasper DL. Commensal microbiota modulation of natural resistance to virus infection. Cell. 2020;183:1312–1324.e10. doi: 10.1016/j.cell.2020.10.047. PubMed DOI PMC

Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol. 2004;5:575–581. doi: 10.1038/ni1078. PubMed DOI

Swiatczak B. Immune balance: the development of the idea and its applications. J Hist Biol. 2013;47:411–442. doi: 10.1007/S10739-013-9370-Z. PubMed DOI

Swiatczak B, Tauber AI (2020) Philosophy of Immunology. In: Zalta EN (ed) The Stanford Encyclopedia of Philosophy (Summer 2020 Edition)

Tauber AI. The immune self: theory or metaphor? Cambridge: Cambridge University Press; 1994. PubMed

Tauber AI. Immunity: the evolution of an idea. New York: Oxford University Press; 2017.

Thibodeau PH, Boroditsky L. Metaphors we think with: the role of metaphor in reasoning. PLoS ONE. 2011;6:e16782. doi: 10.1371/journal.pone.0016782. PubMed DOI PMC

Truchetet ME, Pradeu T. Re-thinking our understanding of immunity: robustness in the tissue reconstruction system. Semin Immunol. 2018;36:45–55. doi: 10.1016/j.smim.2018.02.013. PubMed DOI

Turnbaugh PJ, Ley RE, Hamady M, et al. The human microbiome project. Nature. 2007;449:804–810. doi: 10.1038/nature06244. PubMed DOI PMC

Wang EY, Mao T, Klein J, et al. Diverse functional autoantibodies in patients with COVID-19. medRxiv. 2020 doi: 10.1101/2020.12.10.20247205. PubMed DOI

Welsh RM, Selin LK. No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol. 2002;26(2):417–426. doi: 10.1038/nri820. PubMed DOI

Yel L. Selective IgA deficiency. J Clin Immunol. 2010;30:10–16. doi: 10.1007/s10875-009-9357-x. PubMed DOI PMC

Zach M, Greslehner GP. Towards an extended view of immunity: a philosophical perspective. Anaesth Crit Care Pain Med. 2022;41:101156. doi: 10.1016/J.ACCPM.2022.101156. PubMed DOI