The immune system was identified as a protective factor during infectious diseases over a century ago. Current definitions and textbook information are still largely influenced by these early observations, and the immune system is commonly presented as a defence machinery. However, host defence is only one manifestation of the immune system’s overall function in the maintenance of tissue homeostasis and system integrity. In fact, the immune system is integral part of fundamental physiological processes such as development, reproduction and wound healing, and a close crosstalk between the immune system and other body systems such as metabolism, the central nervous system and the cardiovascular system is evident. Research and medical professionals in an expanding range of areas start to recognise the implications of the immune system in their respective fields.
This chapter provides a brief historical perspective on how our understanding of the immune system has evolved from a defence system to an overarching surveillance machinery to maintain tissue integrity. Current perspectives on the non-defence functions of classical immune cells and factors will also be discussed.
- Immune system
- ‘Danger hypothesis’
- ‘Tissue integrity’
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Retief FP, Cilliers L. The epidemic of Athens, 430-426 BC. S Afr Med J. 1998;88(1):50–3.
Plotkin SA. Vaccines: past, present and future. Nat Med. 2005;11(4 Suppl):S5–11.
King LS. Dr. Koch’s postulates. J Hist Med Allied Sci. 1952;7(4):350–61.
The Nobel Prize in Physiology or Medicine 1905: Nobel Media; 2013 Available from: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1905/.
Woolhouse ME, Webster JP, Domingo E, Charlesworth B, Levin BR. Biological and biomedical implications of the co-evolution of pathogens and their hosts. Nat Genet. 2002;32(4):569–77.
Decaestecker E, Gaba S, Raeymaekers JA, Stoks R, Van Kerckhoven L, Ebert D, et al. Host-parasite ‘Red Queen’ dynamics archived in pond sediment. Nature. 2007;450(7171):870–3.
Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1–13.
Janeway CA Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today. 1992;13(1):11–6.
Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–76.
Bailey M. Evolution of the immune system at geological and local scales. Curr Opin HIV AIDS. 2012;7(3):214–20.
Leulier F, Lemaitre B. Toll-like receptors--taking an evolutionary approach. Nat Rev Genet. 2008;9(3):165–78.
Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045.
Land W, Schneeberger H, Schleibner S, Illner WD, Abendroth D, Rutili G, et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation. 1994;57(2):211–7.
Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damage-induced inflammation. Br J Surg. 2012;99(Suppl 1):12–20.
Chan JK, Roth J, Oppenheim JJ, Tracey KJ, Vogl T, Feldmann M, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711–9.
Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S, et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med. 2005;202(8):1131–9.
Basu S, Binder RJ, Ramalingam T, Srivastava PK. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity. 2001;14(3):303–13.
Ahrens S, Zelenay S, Sancho D, Hanc P, Kjaer S, Feest C, et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity. 2012;36(4):635–45.
Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191–5.
Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol. 2008;9(10):1179–88.
Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One. 2008;3(10):e3331.
Eigenbrod T, Park JH, Harder J, Iwakura Y, Nunez G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells. J Immunol. 2008;181(12):8194–8.
Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11(2):136–40.
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–61.
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440(7081):228–32.
Tauber AI. The birth of immunology. III. The fate of the phagocytosis theory. Cell Immunol. 1992;139(2):505–30.
Desjardins M, Houde M, Gagnon E. Phagocytosis: the convoluted way from nutrition to adaptive immunity. Immunol Rev. 2005;207:158–65.
Solomon JM, Rupper A, Cardelli JA, Isberg RR. Intracellular growth of Legionella pneumophila in Dictyostelium discoideum, a system for genetic analysis of host-pathogen interactions. Infect Immun. 2000;68(5):2939–47.
Lichanska AM, Hume DA. Origins and functions of phagocytes in the embryo. Exp Hematol. 2000;28(6):601–11.
Aderem A, Underhill DM. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol. 1999;17:593–623.
Pfeifer JD, Wick MJ, Roberts RL, Findlay K, Normark SJ, Harding CV. Phagocytic processing of bacterial antigens for class I MHC presentation to T cells. Nature. 1993;361(6410):359–62.
Oakley OR, Frazer ML, Ko C. Pituitary-ovary-spleen axis in ovulation. Trends Endocrinol Metab. 2011;22(9):345–52.
Care AS, Diener KR, Jasper MJ, Brown HM, Ingman WV, Robertson SA. Macrophages regulate corpus luteum development during embryo implantation in mice. J Clin Invest. 2013;123(8):3472–87.
Carlock CI, Wu J, Zhou C, Tatum K, Adams HP, Tan F, et al. Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis. J Immunol. 2014;193(1):161–9.
Brannstrom M, Mayrhofer G, Robertson SA. Localization of leukocyte subsets in the rat ovary during the periovulatory period. Biol Reprod. 1993;48(2):277–86.
Cohen PE, Nishimura K, Zhu L, Pollard JW. Macrophages: important accessory cells for reproductive function. J Leukoc Biol. 1999;66(5):765–72.
Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci U S A. 1994;91(20):9312–6.
Van Nguyen A, Pollard JW. Colony stimulating factor-1 is required to recruit macrophages into the mammary gland to facilitate mammary ductal outgrowth. Dev Biol. 2002;247(1):11–25.
Ingman WV, Wyckoff J, Gouon-Evans V, Condeelis J, Pollard JW. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn. 2006;235(12):3222–9.
Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development. 2000;127(11):2269–82.
Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4(4):155–64.
Erlebacher A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nat Rev Immunol. 2013;13(1):23–33.
Tayade C, Black GP, Fang Y, Croy BA. Differential gene expression in endometrium, endometrial lymphocytes, and trophoblasts during successful and abortive embryo implantation. J Immunol. 2006;176(1):148–56.
Habbeddine M, Verbeke P, Karaz S, Bobe P, Kanellopoulos-Langevin C. Leukocyte population dynamics and detection of IL-9 as a major cytokine at the mouse fetal-maternal interface. PLoS One. 2014;9(9):e107267.
von Rango U. Fetal tolerance in human pregnancy--a crucial balance between acceptance and limitation of trophoblast invasion. Immunol Lett. 2008;115(1):21–32.
Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med. 2003;198(8):1201–12.
Zhang J, Chen Z, Smith GN, Croy BA. Natural killer cell-triggered vascular transformation: maternal care before birth? Cell Mol Immunol. 2011;8(1):1–11.
Trundley A, Gardner L, Northfield J, Chang C, Moffett A. Methods for isolation of cells from the human fetal-maternal interface. Methods Mol Med. 2006;122:109–22.
Houser BL. Decidual macrophages and their roles at the maternal-fetal interface. Yale J Biol Med. 2012;85(1):105–18.
Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. Macrophages and apoptotic cell clearance during pregnancy. Am J Reprod Immunol. 2004;51(4):275–82.
Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol. 2006;6(8):584–94.
Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, et al. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature. 2005;437(7057):417–21.
Rao S, Lobov IB, Vallance JE, Tsujikawa K, Shiojima I, Akunuru S, et al. Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switch. Development. 2007;134(24):4449–58.
Wood W, Turmaine M, Weber R, Camp V, Maki RA, McKercher SR, et al. Mesenchymal cells engulf and clear apoptotic footplate cells in macrophageless PU.1 null mouse embryos. Development. 2000;127(24):5245–52.
Nishikawa A, Murata E, Akita M, Kaneko K, Moriya O, Tomita M, et al. Roles of macrophages in programmed cell death and remodeling of tail and body muscle of Xenopus laevis during metamorphosis. Histochem Cell Biol. 1998;109(1):11–7.
Baer MM, Bilstein A, Caussinus E, Csiszar A, Affolter M, Leptin M. The role of apoptosis in shaping the tracheal system in the Drosophila embryo. Mech Dev. 2010;127(1–2):28–35.
Stanley ER, Chen DM, Lin HS. Induction of macrophage production and proliferation by a purified colony stimulating factor. Nature. 1978;274(5667):168–70.
Van Wesenbeeck L, Odgren PR, MacKay CA, D’Angelo M, Safadi FF, Popoff SN, et al. The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification. Proc Natl Acad Sci U S A. 2002;99(22):14303–8.
Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990;87(12):4828–32.
Reemst K, Noctor SC, Lucassen PJ, Hol EM. The indispensable roles of microglia and astrocytes during brain development. Front Hum Neurosci. 2016;10:566.
Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Neuron. 2004;41(4):535–47.
Michaelson MD, Bieri PL, Mehler MF, Xu H, Arezzo JC, Pollard JW, et al. CSF-1 deficiency in mice results in abnormal brain development. Development. 1996;122(9):2661–72.
Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456–8.
Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, et al. Evidence for synaptic stripping by cortical microglia. Glia. 2007;55(4):360–8.
Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C, et al. CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci. 2004;24(39):8500–9.
Yokoyama A, Sakamoto A, Kameda K, Imai Y, Tanaka J. NG2 proteoglycan-expressing microglia as multipotent neural progenitors in normal and pathologic brains. Glia. 2006;53(7):754–68.
Butovsky O, Bukshpan S, Kunis G, Jung S, Schwartz M. Microglia can be induced by IFN-gamma or IL-4 to express neural or dendritic-like markers. Mol Cell Neurosci. 2007;35(3):490–500.
Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632–7.
Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302(5651):1760–5.
Mallat M, Houlgatte R, Brachet P, Prochiantz A. Lipopolysaccharide-stimulated rat brain macrophages release NGF in vitro. Dev Biol. 1989;133(1):309–11.
Elkabes S, DiCicco-Bloom EM, Black IB. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci. 1996;16(8):2508–21.
Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol. 1994;55(3):410–22.
Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161(6):1163–77.
Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010;116(5):829–40.
Mirza R, DiPietro LA, Koh TJ. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol. 2009;175(6):2454–62.
Goren I, Allmann N, Yogev N, Schurmann C, Linke A, Holdener M, et al. A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme M-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes. Am J Pathol. 2009;175(1):132–47.
Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.
Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007;204(5):1057–69.
Frantz S, Hofmann U, Fraccarollo D, Schafer A, Kranepuhl S, Hagedorn I, et al. Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction. FASEB J. 2013;27(3):871–81.
Sattler S, Rosenthal N. The neonate versus adult mammalian immune system in cardiac repair and regeneration. Biochim Biophys Acta. 2016;1863(7 Pt B):1813–21.
Gallego-Colon E, Sampson RD, Sattler S, Schneider MD, Rosenthal N, Tonkin J. Cardiac-restricted IGF-1Ea overexpression reduces the early accumulation of inflammatory myeloid cells and mediates expression of extracellular matrix remodelling genes after myocardial infarction. Mediat Inflamm. 2015;2015:484357.
Tonkin J, Temmerman L, Sampson RD, Gallego-Colon E, Barberi L, Bilbao D, et al. Monocyte/macrophage-derived IGF-1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Mol Ther. 2015;23(7):1189–200.
Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci U S A. 2010;107(9):4194–9.
Zhang MZ, Yao B, Yang S, Jiang L, Wang S, Fan X, et al. CSF-1 signaling mediates recovery from acute kidney injury. J Clin Invest. 2012;122(12):4519–32.
Meijer C, Wiezer MJ, Diehl AM, Schouten HJ, Schouten HJ, Meijer S, et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver. 2000;20(1):66–77.
Glod J, Kobiler D, Noel M, Koneru R, Lehrer S, Medina D, et al. Monocytes form a vascular barrier and participate in vessel repair after brain injury. Blood. 2006;107(3):940–6.
London A, Cohen M, Schwartz M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci. 2013;7:34.
Seno H, Miyoshi H, Brown SL, Geske MJ, Colonna M, Stappenbeck TS. Efficient colonic mucosal wound repair requires Trem2 signaling. Proc Natl Acad Sci U S A. 2009;106(1):256–61.
Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 2005;15(11):599–607.
DiPietro LA. Wound healing: the role of the macrophage and other immune cells. Shock. 1995;4(4):233–40.
Russell SE, Walsh PT. Sterile inflammation - do innate lymphoid cell subsets play a role? Front Immunol. 2012;3:246.
Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity. 2011;35(4):596–610.
Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2012;129(1):191–8 e1-4.
Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science. 2012;336(6077):91–5.
Kim HY, Chang YJ, Subramanian S, Lee HH, Albacker LA, Matangkasombut P, et al. Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J Allergy Clin Immunol. 2012;129(1):216–27 e1-6.
Sattler S, Smits HH, Xu D, Huang FP. The evolutionary role of the IL-33/ST2 system in host immune defence. Arch Immunol Ther Exp. 2013;61(2):107–17.
Allen JE, Wynn TA. Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog. 2011;7(5):e1002003.
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(11):889–95.
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Sattler, S. (2017). The Role of the Immune System Beyond the Fight Against Infection. In: Sattler, S., Kennedy-Lydon, T. (eds) The Immunology of Cardiovascular Homeostasis and Pathology. Advances in Experimental Medicine and Biology, vol 1003. Springer, Cham. https://doi.org/10.1007/978-3-319-57613-8_1
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