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  • Review Article
  • Published:

How dying cells alert the immune system to danger

Nature Reviews Immunology volume 8, pages 279–289 (2008)Cite this article

Key Points

  • A large number of pathological processes can damage cells in ways that lead to the common end result of cell death. Therefore, when non-physiological cell death occurs in vivo, it indicates that a potentially dangerous situation is developing in a host.

  • The innate immune system has evolved mechanisms to identify potential danger by detecting abnormal cell death. This is accomplished by sensing the release of a subset of molecules (damage-associated molecular patterns, DAMPs) that are normally hidden in living cells or their local environment but are released or exposed when cells die and lose integrity of their plasma membrane.

  • Upon detecting the presence of DAMPs, the innate immune system initiates an acute inflammatory response that rapidly delivers soluble and cellular defences to the site of damage. This response is a double-edged sword that can contain and repair the damage but can also damage normal tissues and in so doing cause disease.

  • DAMPs also stimulate antigen-presenting cells of the innate immune system to migrate to lymphoid tissues and become immunostimulatory for T cells. In this way, the innate immune response alerts the adaptive immune system to potential danger in a manner that helps to initiate responses to any immunogenic antigens at the site of damage. This might have an important role in initiating T-cell responses to tumours, to transplants and in autoimmunity.

  • There has been recent progress in identifying some of what are probably many DAMPs. There remains much to be learned about these molecules, the cells and receptors that sense them, and the pathways they stimulate.

Abstract

When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes — that is, it is part of normal physiological processes — then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.

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Figure 1: Stranger and danger models.
Figure 2: Discriminating between viable cells, necrosis and apoptosis.
Figure 3: Cell death and inflammation.

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Acknowledgements

This work was supported by grants to H.K. from the Kanae Foundation, Japan, and to K.L.R. from the National Institutes of Health, USA.

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  1. Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    Hajime Kono & Kenneth L. Rock

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Natural IgM antibodies

Natural antibodies are present in individuals without immunization (although they might be stimulated by the host flora). They are mainly of the IgM isotype, have not undergone somatic mutations, and have low affinity but high crossreactivity for many microbial pathogens and self antigens.

Defensins

Defensins and cathelicidins are members of a family of small antimicrobial polypeptides that are abundant in neutrophils and epithelial cells. They contribute to host defence by disrupting the cytoplasmic membrane of microorganisms.

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Kono, H., Rock, K. How dying cells alert the immune system to danger. Nat Rev Immunol 8, 279–289 (2008). https://doi.org/10.1038/nri2215

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