The Danger Model: A Renewed Sense of Self Polly Matzinger For over 50 years, immunologists have based their understanding of the immune system on the idea that it distinguishes between self and nonself. However, this model has faced many challenges and has failed to explain several phenomena. The Danger model proposes that the immune system is more concerned with damage than with foreignness, and is activated by alarm signals from injured tissues rather than by the recognition of nonself. The original self-nonself (SNS) model, proposed by Burnet, suggested that lymphocytes recognize and respond to foreign entities, while self-reactive lymphocytes are deleted. However, this model has been modified over the years to accommodate new findings. For example, the discovery that activated B lymphocytes hypermutate and create new, potentially self-reactive cells led to the addition of a helper cell and a new signal. The SNS model has been further modified to account for the role of costimulation in immune responses. The Infectious-Nonself (INS) model, proposed by Janeway, suggests that antigen-presenting cells (APCs) can recognize evolutionarily distant pathogens. However, this model has also faced challenges in explaining certain immune responses. The Danger model, which builds on the SNS and INS models, proposes that the immune system is activated by danger signals from injured cells rather than by the recognition of nonself. The Danger model has been supported by the discovery of endogenous alarm signals, including mammalian DNA, RNA, heat shock proteins, and interferon-alpha. These signals can be constitutive or inducible, intracellular or secreted, and can be part of the extracellular matrix. The model suggests that danger signals are not sent by healthy cells or cells undergoing normal physiological death. The Danger model has provided new insights into the immune system, suggesting that the "foreignness" of a pathogen is not the main trigger for an immune response, and that "self-ness" is not a guarantee of tolerance. The model has also helped explain several immune phenomena, including why some individuals develop autoimmune diseases while others do not. The Danger model has also led to a renewed understanding of self-recognition, suggesting that the immune system is more concerned with damage than with foreignness. This model has provided a new framework for understanding the immune system and has led to new insights into how the immune system responds to different types of threats.The Danger Model: A Renewed Sense of Self Polly Matzinger For over 50 years, immunologists have based their understanding of the immune system on the idea that it distinguishes between self and nonself. However, this model has faced many challenges and has failed to explain several phenomena. The Danger model proposes that the immune system is more concerned with damage than with foreignness, and is activated by alarm signals from injured tissues rather than by the recognition of nonself. The original self-nonself (SNS) model, proposed by Burnet, suggested that lymphocytes recognize and respond to foreign entities, while self-reactive lymphocytes are deleted. However, this model has been modified over the years to accommodate new findings. For example, the discovery that activated B lymphocytes hypermutate and create new, potentially self-reactive cells led to the addition of a helper cell and a new signal. The SNS model has been further modified to account for the role of costimulation in immune responses. The Infectious-Nonself (INS) model, proposed by Janeway, suggests that antigen-presenting cells (APCs) can recognize evolutionarily distant pathogens. However, this model has also faced challenges in explaining certain immune responses. The Danger model, which builds on the SNS and INS models, proposes that the immune system is activated by danger signals from injured cells rather than by the recognition of nonself. The Danger model has been supported by the discovery of endogenous alarm signals, including mammalian DNA, RNA, heat shock proteins, and interferon-alpha. These signals can be constitutive or inducible, intracellular or secreted, and can be part of the extracellular matrix. The model suggests that danger signals are not sent by healthy cells or cells undergoing normal physiological death. The Danger model has provided new insights into the immune system, suggesting that the "foreignness" of a pathogen is not the main trigger for an immune response, and that "self-ness" is not a guarantee of tolerance. The model has also helped explain several immune phenomena, including why some individuals develop autoimmune diseases while others do not. The Danger model has also led to a renewed understanding of self-recognition, suggesting that the immune system is more concerned with damage than with foreignness. This model has provided a new framework for understanding the immune system and has led to new insights into how the immune system responds to different types of threats.