Evolution of the Human Immune System


Human immune system is an orchestra of various defence mechanisms functioning at different levels, from individual cells to the whole body. Specialised immune mechanisms can be subdivided into innate and adaptive immune systems. Innate immune mechanisms use receptors recognising conserved molecular patterns of pathogens. Adaptive immune system depends on the production of vast repertoires of immune receptors and selective expansion of pathogenā€specific ones. Some basic cellular functions such as ubiquitination and autophagy as well as stress response pathways also contribute to the immune defence. Various immune defence systems work autonomously but in communication with each other. All responses are coordinated at the body level by hormones and other mediators. Layered and redundant structure of the human immune system offers great efficiency in the detection and elimination of pathogens. All immune mechanisms evolve interactively in concordance with human environment and history.

Key Concepts:

  • Human immune system is a multilayered structure that includes various mechanisms.

  • Basic cellular mechanisms may contribute to immune defence.

  • Specialised immune mechanisms are subdivided into innate and adaptive based on the receptors used for antigen recognition.

  • Immune mechanisms comprise those based on humoral factors and those based on cells.

  • Most immune defence mechanisms work semiautonomously in interaction with other systems.

  • Immune mechanisms can be controlled at the body level by hormones and other mediators.

  • Immune receptors evolve by gene duplication, balancing selection, changes in coding and regulatory sequences, and other mechanisms.

  • Human immune system continues to evolve.

  • Individual immune mechanisms evolve in interaction with other mechanisms and basic cellular machinery.

Keywords: innate; adaptive; defence mechanisms; pathogen; positive selection

Figure 1. Human immune system is a multilayered network of various defence mechanisms. Each cell in a human body has various means to fight pathogens. Basic cellular mechanisms such as ubiquitination, RNAi and apoptosis contribute to immune defence. Specialised immune cells such as B cells and macrophages and humoral systems such as complement work autonomously but in communication with other mechanisms. All responses are coordinated at the body level by various mediators. Skin and epithelial barriers of the body are protected by the secretion of antimicrobial substances.
Figure 2.

Coevolution of humans and Staphylococcus aureus. FcaR1, a receptor for IgA‐Fc, expressed on myeloid cells mediates phagocytosis of IgA‐coated pathogens. S. aureus produces a bacterial decoy SSL7 that binds IgA‐Fc region preventing FcaR1 binding and phagocytosis. Immunoglobulin duplication and diversification took place in primates (step 1). FcaR1 was positively selected for binding with the new IgA (step 2). Bacterial decoy proteins developed high affinity to this IgA (step 3). Next, IgA forms with low binding to the bacterial decoy were selected (step 4). Now, FcaR1 needs to change again to bind the new IgA (step 5) and so on. If FcaR1 fails to keep up, it may be lost from the genome.

Figure 3.

IgG4 is a regulatory antibody inhibiting the formation of immune complexes, inflammation and allergy. It is under the dual selection pressure. Pressure from pathogens requiring stronger immune response can lead to loss of G4, whereas pressure from inflammatory/allergic diseases can lead to its duplication.



Abi‐Rached L , Dorighi K , Norman PJ , Yawata M and Parham P (2007) Episodes of natural selection shaped the interactions of IgA‐Fc with FcalphaRI and bacterial decoy proteins. Journal of Immunology 178(12): 7943–7954.

Abi‐Rached L , Jobin MJ , Kulkarni S et al. (2011) The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334(6052): 89–94.

Allen S , Turner SJ , Bourges D , Gleeson PA and van Driel IR (2011) Shaping the T‐cell repertoire in the periphery. Immunology and Cell Biology 89(1): 60–69.

Balachandran P , Dragone L , Garrity‐Ryan L et al. (2007) The ubiquitin ligase Cbl‐b limits Pseudomonas aeruginosa exotoxin T‐mediated virulence. Journal of Clinical Investigation 117(2): 419–427.

Bird CP , Stranger BE , Liu M et al. (2007) Fast‐evolving noncoding sequences in the human genome. Genome Biology 8(6): R118.

Brusco A , Cinque F , Saviozzi S et al. (1997) The G4 gene is duplicated in 44% of human immunoglobulin heavy chain constant region haplotypes. Human Genetics 100(1): 84–89.

Burnet FM (1957) A modification of Jerne's theory of antibody production using the concept of clonal selection. Australian Journal of Science 20(2): 67–69.

Carroll MV and Sim RB (2011) Complement in health and disease. Advanced Drug Delivery Reviews 63(12): 965–975.

Compton AA and Emerman M (2013) Convergence and divergence in the evolution of the APOBEC3G‐Vif interaction reveal ancient origins of simian immunodeficiency viruses. PLoS Pathogens 9(1): e1003135. doi: 1003110.1001371/journal.ppat.1003135.

Crisci JL , Wong A , Good JM and Jensen JD (2011) On characterizing adaptive events unique to modern humans. Genome Biology and Evolution 3: 791–798.

Demuth JP , De Bie T , Stajich JE , Cristianini N and Hahn MW (2006) The evolution of mammalian gene families. PLoS One 1: e85.

Eisenbarth SC , Williams A , Colegio OR et al. (2012) NLRP10 is a NOD‐like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484(7395): 510–513.

Fayngerts SA , Najakshin AM and Taranin AV (2007) Species‐specific evolution of the FcR family in endothermic vertebrates. Immunogenetics 59(6): 493–506.

Ferrer‐Admetlla A , Bosch E , Sikora M et al. (2008) Balancing selection is the main force shaping the evolution of innate immunity genes. Journal of Immunology 181(2): 1315–1322.

Galluzzi L , Kepp O and Kroemer G (2012) Mitochondria: master regulators of danger signalling. Nature Reviews Molecular Cell Biology 13(12): 780–788.

Galvani AP and Slatkin M (2003) Evaluating plague and smallpox as historical selective pressures for the CCR5‐Delta 32 HIV‐resistance allele. Proceedings of the National Academy of Sciences of the USA 100(25): 15276–15279.

Gokcumen O , Babb PL , Iskow RC et al. (2011) Refinement of primate copy number variation hotspots identifies candidate genomic regions evolving under positive selection. Genome Biology 12(5): R52.

Hernandez RD , Kelley JL , Elyashiv E et al. (2011) Classic selective sweeps were rare in recent human evolution. Science 331(6019): 920–924.

Hill AV , Allsopp CE , Kwiatkowski D et al. (1991) Common west African HLA antigens are associated with protection from severe malaria. Nature 352(6336): 595–600.

Jaeger BN and Vivier E (2012) Natural killer cell tolerance: control by self or self‐control? Cold Spring Harbor Perspectives in Biology 4(3): pii.

Janeway CA and Medzhitov R (2002) Innate immune recognition. Annual Review of Immunology 20: 197–216.

Kaiser SM , Malik HS and Emerman M (2007) Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein. Science 316(5832): 1756–1758.

Klein L , Hinterberger M , Wirnsberger G and Kyewski B (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nature Reviews Immunology 9(12): 833–844.

Lee YK and Mazmanian SK (2010) Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330(6012): 1768–1773.

Leslie M (2013) The immune system's compact genomic counterpart. Science 339(6115): 25–27.

Levine B , Mizushima N and Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469(7330): 323–335.

Liou AP , Paziuk M , Luevano JM et al. (2013) Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Science Translational Medicine 5(178): 178RA41: DOI:10.1126/scitranslmed.3005687.

Matzinger P (2002) The danger model: a renewed sense of self. Science 296(5566): 301–305.

Maynard CL , Elson CO , Hatton RD and Weaver CT (2012) Reciprocal interactions of the intestinal microbiota and immune system. Nature 489(7415): 231–241.

Medzhitov R (2010) Inflammation 2010: new adventures of an old flame. Cell 140(6): 771–776.

Mendez FL , Watkins JC and Hammer MF (2012) A haplotype at STAT2 introgressed from Neanderthals and serves as a candidate of positive selection in Papua New Guinea. American Journal of Human Genetics 91(2): 265–274.

Nei M and Rooney AP (2005) Concerted and birth‐and‐death evolution of multigene families. Annual Review of Genetics 39: 121–152.

Nguyen DH , Hurtado‐Ziola N , Gagneux P and Varki A (2006) Loss of Siglec expression on T lymphocytes during human evolution. Proceedings of the National Academy of Sciences of the USA 103(20): 7765–7770.

O'Bleness M , Searles VB , Varki A , Gagneux P and Sikela JM (2012) Evolution of genetic and genomic features unique to the human lineage. Nature Reviews Genetics 13(12): 853–866.

Pabst O (2012) New concepts in the generation and functions of IgA. Nature Reviews Immunology 12(12): 821–832.

Parham P and Moffett A (2013) Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nature Reviews Immunology 13(2): 133–144.

Rabbani H , Pan Q , Kondo N , Smith CI and Hammarstrom L (1996) Duplications and deletions of the human IGHC locus: evolutionary implications. Immunogenetics 45(2): 136–141.

Rast JP , Smith LC , Loza‐Coll M , Hibino T and Litman GW (2006) Genomic insights into the immune system of the sea urchin. Science 314(5801): 952–956.

Saleh M , Vaillancourt JP , Graham RK et al. (2004) Differential modulation of endotoxin responsiveness by human caspase‐12 polymorphisms. Nature 429(6987): 75–79.

Schrago CG and Voloch CM (2013) The precision of the hominid timescale estimated by relaxed clock methods. Journal of Evolutionary Biology 26(4): 746–755.

Sorci G , Cornet S and Faivre B (2013) Immunity and the emergence of virulent pathogens. Infection, Genetics and Evolution 16: 441–446.

Tabas I and Glass CK (2013) Anti‐inflammatory therapy in chronic disease: challenges and opportunities. Science 339(6116): 166–172.

Triboulet R , Mari B , Lin YL et al. (2007) Suppression of microRNA‐silencing pathway by HIV‐1 during virus replication. Science 315(5818): 1579–1582.

Trivedi NH , Guentzel MN , Rodriguez AR et al. (2013) Mast cells: multitalented facilitators of protection against bacterial pathogens. Expert Review of Clinical Immunology 9(2): 129–138.

Underhill DM and Goodridge HS (2012) Information processing during phagocytosis. Nature Reviews Immunology 12(7): 492–502.

van der Neut Kolfschoten M , Schuurman J , Losen M et al. (2007) Anti‐inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317(5844): 1554–1557.

Varki NM , Strobert E , Dick EJ Jr , Benirschke K and Varki A (2011) Biomedical differences between human and nonhuman hominids: potential roles for uniquely human aspects of sialic acid biology. Annual Review of Pathology 6: 365–393.

Wu J , Sun L , Chen X et al. (2013) Cyclic GMP–AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339(6121): 826–830.

Zasloff M (2002) Antimicrobial peptides of multicellular organisms. Nature 415(6870): 389–395.

Zheng YH , Jeang KT and Tokunaga K (2012) Host restriction factors in retroviral infection: promises in virus–host interaction. Retrovirology 9: 112. DOI: 10.1186/1742‐4690‐9‐112.

Further Reading

Janeway CA , Travers P , Walport M and Shlomchik M (2005) Immunobiology: The Immune System in Health and Disease. New York: Garland Science. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10.

Larrea CL (ed.) (2011) Self and Non‐self. Austin: Landes Bioscience.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Danilova, Nadia(Sep 2013) Evolution of the Human Immune System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020781.pub2]