Innate Immune Mechanisms: Nonself Recognition


The initial defence of the body against pathogens relies on the innate immune system. The innate immune system recognises unique molecular patterns expressed by pathogens, referred to as pathogen‐associated molecular patterns (PAMPs), through receptors known as pattern recognition molecules (PRMs). PRMs are a diverse range of molecules and include secreted proteins, transmembrane proteins and cytosolic proteins. These molecules sense extracellular and intracellular pathogens and induce a number of responses to help aid in pathogen destruction including phagocytosis through opsonisation, cytokine production and activation of complement. In addition to pathogen sensing, host cells express proteins, the complement regulatory proteins that protect them from attack by the alternative pathway of complement activation, whereas foreign organisms lack these protective proteins and are, therefore, susceptible to complement attack.

Key Concepts

  • The innate immune system recognises pathogen‐associated molecular patterns (PAMPs) that are unique to pathogens.
  • Cells of the innate immune system express a large range of pattern recognition molecules (PRM) that bind to PAMPs.
  • PRMs are a diverse range of molecules and include secreted proteins, membrane‐associated proteins and cytosolic proteins.
  • PRMs induce a number of host defence mechanisms upon recognition of PAMPs, including phagocytosis, cytokine production and complement activation.
  • Host cells express complement regulatory proteins that protect them from attack by innate mechanisms.

Keywords: innate immunity; self–nonself discrimination; pattern recognition molecules; pathogen‐associated molecular patterns; C‐type lectins; collectins; Toll‐like receptors; nucleotide‐binding domain and leucine‐rich repeat‐containing receptors (NLRs); complement

Figure 1. Structure of the human mannose‐binding lectin, the best‐characterised collectin molecule. Note the bouquet‐like structure of the molecule, a structure that has been validated by electron microscopy studies.
Figure 2. Structure of the mammalian macrophage mannose receptor. The molecule contains eight CRDs arranged in tandem. Only CRD4 and CRD5 possess the appropriate structural features required for calcium‐dependent carbohydrate binding.
Figure 3. ‘Nonself’ discrimination in the cytosol by NLR and RLR proteins. There are two main families of PRMs that detect PAMPS in the cytosol, the nucleotide‐binding domain and leucine‐rich repeat‐containing receptors (NLRs) and the RIG‐I‐like receptors (RLRs). NLRs form two distinct types of signalling complexes when triggered by PAMPs, the signalosome and the inflammasomes. (a) The NLR signalosome or NOD signalosome forms in response to muropeptides from bacterial cell walls. NOD proteins signal via RIP2 to activate the transcription factors NFκB and MAPK, resulting in production of cytokines and chemokines. (b) There appear to be multiple NLR inflammasomes of distinct composition that involve distinct NLRs. The IPAF inflammasome forms in response to bacterial flagellin, the NALP1 inflammasome forms in response to lethal toxins from Anthrax and the NLRP3 inflammasome forms in response to bacterial toxins such as α‐toxin and aerolysin. Upon recognition of these PAMPS, the inflammasome signals through an array of molecules including the bipartite adaptor protein apoptosis‐associated speck‐like protein containing a ‐terminal CARD (ASC) and eventually leads to activation of caspase‐1 which in turn liberates active forms of IL‐1β and IL‐18. (c) Viral nucleotides trigger the RLRs, RIG‐1 and MDA5 to signal activation of transcription factors responsible for production of IFN.
Figure 4. ‘Self–nonself’ discrimination by the alternative pathway of complement. Fluid‐phase C3 is normally hydrolysed at a slow rate by the ‘C3 tickover’ process to generate C3b. The C3b possesses a highly reactive thioester group, which can covalently attach some C3b molecules to the surface of both pathogens and self (host) cells. Following recruitment of factor B and the action of factor D, a C3 convertase (C3bBb) is formed consisting of a fragment of factor B (Bb) and C3b. On host cell surfaces, this C3 convertase is rapidly inactivated by a number of host factors. In contrast, on the surface of microorganisms, the C3 convertase is stabilised by properdin (factor P), is not inactivated by host factors and generates massive number of C3b fragments. The C3b coats the surface of the microorganism and acts as an opsonin as well as initiating the formation of the membrane attack complex and eventual cell lysis.


Barbé F , Douglas T and Saleh M (2014) Advances in Nod‐like receptors (NLR) biology. Cytokine and Growth Factor Reviews 25 (6): 681–697.

den Dunnen J , Gringhuis SI and Geijtenbeek TB (2009) Innate signaling by the C‐type lectin DC‐SIGN dictates immune responses. Cancer Immunology, Immunotherapy 58 (7): 1149–1157.

Di Paolo NC , Miao EA , Iwakura Y , et al. (2009) Virus binding to a plasma membrane receptor triggers interleukin‐1a‐mediated proinflammatory macrophage response in vivo. Immunity 31: 110–121.

Du Clos TW (2013) Pentraxins: structure, function, and role in inflammation. ISRN Inflammation 2013 Acticle ID 379040,: 22.

Canton J , Neculai D and Grinstein S (2013) Scavenger receptors in homeostasis and immunity. Nature Reviews Immunology 13: 621–634.

East L and Isacke CM (2002) The mannose receptor family. Biochimica et Biophysica Acta 1572: 364–386.

Fenton MJ and Golenbock DT (1998) LPS‐binding proteins and receptors. Journal of Leukocyte Biology 64: 25–32.

Geijtenbeek TB and Gringhuis SI (2009) Signalling through C‐type lectin receptors: shaping immune responses. Nature Reviews Immunology 9 (7): 465–479.

Gianni T , Leoni V , Chesnokova LS , et al. (2012) avB3‐integrin is a major sensor and activator of innate immunity to herpes simplex virus‐1. PNAS 109: 19792–19797.

Gupta G and Surolia A (2007) Collectins: sentinels of innate immunity. BioEssays 29 (5): 452–464.

Han C , Jin J , Xu S , et al. (2010) Integrin CD11b negatively regulates TLR‐triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl‐b. Nature Immunology 11 (8): 734–742.

Holmskov U , Thiel S and Jensenius JC (2003) Collectins and ficolins: humoral lectins of the innate immune defense. Annual Review of Immunology 21: 547–578.

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

Johnson GB , Brunn GJ and Platt JL (2003) Activation of mammalian Toll‐like receptors by endogenous agonists. Critical Reviews in Immunology 23: 15–44.

Kanazawa N (2007) Dendritic cell immunoreceptors: C‐type lectin receptors for pattern‐recognition and signaling on antigen‐presenting cells. Journal of Dermatological Science 45 (2): 77–86.

Lamkanfi M and Dixit VM (2009) Inflammasomes: guardians of cytosolic sanctity. Immunological Reviews 227 (1): 95–105.

Mantovani A , Garlanda C , Doni A , et al. (2008) Pentraxins in innate immunity: from C‐reactive protein to the long pentraxin PTX3. Journal of Clinical Immunology 28 (1): 1–13.

Mariathasan S , Newton K , Monack DM , et al. (2004) Differential activation of the inflammasome by caspase‐1 adaptors ASC and Ipaf. Nature 430 (6996): 213–218.

Martinon F , Burns K and Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL‐beta. Molecular Cell 10 (2): 417–426.

Martinon F , Mayor A and Tschopp J (2009) The inflammasomes: guardians of the body. Annual Review of Immunology 27: 229–265.

Matsushita M and Fujita T (2002) The role of ficolins in innate immunity. Immunobiology 205: 490–497.

McCormack FX and Whitsett JA (2002) The pulmonary collectins, SP‐A and SP‐D, orchestrate innate immunity in the lung. Journal of Clinical Investigation 109: 707–712.

Medzhitov R and Janeway CA (1997) Innate immunity: impact on the adaptive immune response. Current Opinion in Immunology 9: 4–9.

Mortensen RF (1993) Macrophages and acute phase proteins. In: Zwilling BS and Eisenstein TK (eds) Macrophage–Pathogen Interactions, pp. 143–158. New York: Marcel Dekker.

Pandey S , Kawai T and Akira S (2015) Microbial sensing by Toll‐like receptors and intracellular nucleic acid sensors. Cold Spring Harbour Perspectives in Biology 7: a016246.

Parish CR and O'Neill ER (1997) Dependence of the adaptive immune response on innate immunity: some questions answered but new paradoxes emerge. Immunology and Cell Biology 75: 523–527.

Peiser L , Mukhopadhyay S and Gordon S (2002) Scavenger receptors in innate immunity. Current Opinion in Immunology 14: 123–128.

Plato A , Willment JA and Brown GD (2013) C‐type lectin‐like receptors of the dectin‐1 cluster: ligands and signaling pathways. International Reviews in Immunology 32 (2): 134–156.

Rehwinkel J and Reis e Sousa C (2010) RIGorous detection: exposing virus through RNA sensing. Science 327 (5963): 284–286.

Ross GD (2000) Regulation of the adhesion versus cytotoxic function of the Mac‐1/CR3/alphaMbeta2‐integrin glycoprotein. Critical Reviews in Immunology 20: 197–222.

Runza VL , Schwaeble W and Mannel DN (2008) Ficolins: novel pattern recognition molecules of the innate immune response. Immunobiology 213 (3–4): 297–306.

Stahl PD and Ezekowitz RAB (1998) The mannose receptor is a pattern recognition receptor involved in host defense. Current Opinion in Immunology 10: 50–55.

Steel DM and Whitehead AS (1994) The major acute phase reactants: C‐reactive protein, serum amyloid P component and serum amyloid A protein. Immunology Today 15: 81–88.

Takahashi K and Theil S (2013) Ficolins. In: eLS. Chichester: John Wiley & Sons, Ltd.

Takeda K and Akira S (2003) Toll receptors and pathogen resistance. Cellular Microbiology 5: 143–153.

Takeda K and Akira S (2005) Toll‐like receptors in innate immunity. International Immunology 17 (1): 1–14.

Teh C , Le Y , Lee SH , et al. (2000) M‐ficolin is expressed on monocytes and is a lectin binding to N‐acetyl‐d‐glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101 (2): 225–232.

Theil S and Takahashi K (2013) Collectins. In: eLS. Chichester: John Wiley & Sons, Ltd.

Ting JP , Duncan JA , Lei Y , et al. (2010) How the noninflammasome NLRs function in the innate immune system. Science 327 (5963): 286–290.

Ting JP , Lovering RC , Alnemri ES , et al. (2008) The NLR gene family: a standard nomenclature. Immunity 28 (3): 285–287.

Further Reading

Baumann H and Gauldie J (1994) The acute phase response. Immunology Today 15: 74–80.

Imler JL and Zheng L (2004) Biology of toll receptors: lessons from insects and mammals. Journal of Leukocyte Biology 75: 18–26.

Janeway CA (1992) The immune system evolved to discriminate infectious nonself from noninfectious self. Immunology Today 13: 11–16.

Janeway CA , Goodnow CC and Medzhitov R (1996) Immunological tolerance: danger – pathogen on the premises!. Current Biology 6: 519–522.

Lu J , The C , Kishore U and Reid KB (2002) Collectins and ficolins: sugar pattern recognition molecules of the mammalian innate immune system. Biochimica et Biophysica Acta 1572: 387–400.

Osorio F and Reis e Sousa C (2011) Myeloid C‐type lectin receptors in pathogen recognition and host defense. Immunity 34 (5): 651–664.

Takeuchi O and Akira S (2010) Pattern recognition receptors and inflammation. Cell 140 (6): 805–820.

Underhill DM and Ozinsky A (2002) Phagocytosis of microbes: complexity in action. Annual Review of Immunology 20: 825–852.

Wu J and Chen ZJ (2014) Innate immune sensing and signaling of cytosolic nucleic acids. Annual Review of Immunology 32: 461–488.

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Quah, Ben JC, and Parish, Christopher R(Aug 2015) Innate Immune Mechanisms: Nonself Recognition. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001211.pub4]