Innate Immune Mechanisms: Nonself Recognition

Abstract

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.
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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. http://www.els.net [doi: 10.1002/9780470015902.a0001211.pub4]