Immunological Danger Signals

Abstract

The conventional role of the immune system has been viewed as the first line of defence discriminating self from nonself. However, in the past decade, the innate immune response has proven to be more advanced sensing signals of danger, such as pathogen‐specific molecules (PAMPs, pathogen‐associated molecular patterns) or endogenous host‐derived signals released during cellular damage, while remaining unresponsive to normal host molecules, dietary antigens or commensal bacteria. The host response to invading microbial pathogens relies on both the innate and adaptive immune response. The danger theory of Matzinger (1994) proposed a similar model for the adaptive immune response in discriminating self from nonself. This theory proposed that the immune system does not react to foreign substances but instead responds to situations that are potentially harmful. These danger signals, or damage‐associated molecular patterns (DAMPs), released by damaged cells, can provide for a second signal which is necessary to activate the immune response while avoiding collateral damage in situations in which harmless nonself is present.

Key Concepts

  • According to the danger theory of Matzinger, the immune system does not merely distinguish whether an entity is foreign or not, it mainly determines whether it will cause damage to the body.
  • Damage‐associated molecular patterns (DAMP) are danger signals released during inflammatory stress such as burns, trauma and infection.
  • Each pathogen is recognised by its specific molecular signature or pathogen‐associated molecular pattern (PAMP).
  • Activation of the innate immune system relies on both pathogen‐specific molecules and endogenous danger signals.
  • DAMPs can be recognised by pattern‐recognition receptors on antigen‐presenting cells or by distinct receptors such as the receptor for advanced glycation end products (RAGE).
  • Key DAMPs that are recognised by Toll‐like receptors (TLRs) include heat shock proteins (HSPs), high‐mobility group box 1 (HMGB)‐1 and the S100 proteins.

Keywords: DAMPs; danger signals; innate immunity; pattern‐recognition receptors; PAMPs; inflammasome; HMGB‐1; heat shock proteins

Figure 1. Recognition of both PAMPs and DAMPs by PRRs activates the proinflammatory immune response during sterile and nonsterile inflammations. During infection, pathogen‐associated molecular patterns (PAMPs) are recognised by pattern‐recognition receptors (PRRs) on host cells, such as Toll‐like (TLRs) and NOD‐like receptors (NLRs). These receptors in turn activate the proinflammatory immune response releasing chemo‐ and cytokines, initiate cell death, recruit leucocytes and activate the coagulation and complement cascade. However, when cells become necrotic they can also release endogenous molecules called damage‐associated molecular patterns (DAMPs), which can be recognised either by PRRs or DAMP‐specific receptors (e.g. RAGE). Furthermore, on going infection can lead to tissue destruction, which propagates further release of DAMPs creating a vicious circle. On the other hand, sterile inflammation (trauma or burn) can also cause tissue destruction with the release of excessive amounts of DAMPs via necrotic cells causing inflammation in a similar manner as is seen during microbial invasion.
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Further Reading

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de Jong, Hanna K, and Wiersinga, W Joost(Jan 2016) Immunological Danger Signals. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001210.pub2]