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.

Polly Matzinger 于 1994 年提出的免疫危险理论认为，组织应激、损伤或感染在决定免疫反应方面起着决定性作用。从那时起，越来越多的证据支持这样一种观点，即引发同源免疫反应的能力（免疫原性）取决于抗原性（被 T 细胞受体或抗体识别的能力）和佐剂性（由于组织损伤而产生的额外信号）的组合。在这里，我们讨论了危险理论的分子基础，同时关注免疫学相关的损伤相关分子模式、微生物相关的分子模式和神经内分泌应激相关的免疫调节分子，以及它们的受体。我们批判性地评估了与患者相关的证据，研究了癌细胞和病原病毒如何抑制与损伤相关的分子模式以逃避免疫识别，肠道菌群失调如何减少免疫刺激微生物相关的分子模式并损害免疫反应，以及哪些遗传性免疫缺陷支持危险理论的有效性。此外，我们将危险假说纳入免疫耐受机制的接近故障安全的层次结构中，该机制还涉及免疫细胞的克隆缺失和失活。