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Review
. 2024 Dec;24(12):912-928.
doi: 10.1038/s41577-024-01102-9. Epub 2024 Nov 7.

The danger theory of immunity revisited

Guido Kroemer  1   2   3 , Léa Montégut  4   5 , Oliver Kepp  4   5 , Laurence Zitvogel  6   7   8   9
Affiliations
Review

The danger theory of immunity revisited

Guido Kroemer et al. Nat Rev Immunol. 2024 Dec.

Abstract

The danger theory of immunity, introduced by Polly Matzinger in 1994, posits that tissue stress, damage or infection has a decisive role in determining immune responses. Since then, a growing body of evidence has supported the idea that the capacity to elicit cognate immune responses (immunogenicity) relies on the combination of antigenicity (the ability to be recognized by T cell receptors or antibodies) and adjuvanticity (additional signals arising owing to tissue damage). Here, we discuss the molecular foundations of the danger theory while focusing on immunologically relevant damage-associated molecular patterns, microorganism-associated molecular patterns, and neuroendocrine stress-associated immunomodulatory molecules, as well as on their receptors. We critically evaluate patient-relevant evidence, examining how cancer cells and pathogenic viruses suppress damage-associated molecular patterns to evade immune recognition, how intestinal dysbiosis can reduce immunostimulatory microorganism-associated molecular patterns and compromise immune responses, and which hereditary immune defects support the validity of the danger theory. Furthermore, we incorporate the danger hypothesis into a close-to-fail-safe hierarchy of immunological tolerance mechanisms that also involve the clonal deletion and inactivation of immune cells.

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Conflict of interest statement

Competing interests: O.K. is a scientific co-founder of Samsara Therapeutics. O.K. has been working on research projects with Air Liquide, Daiichi Sankyo, Kaleido, Lytix Pharma, PharmaMar, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is in the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences. G.K. is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. L.M. is a consultant of everImmune. L.Z. has held research contracts with GlaxoSmithKline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study; in the writing of the manuscript; or in the decision to publish the results.

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References

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