The article by Polly Matzinger introduces the Danger Model, a new perspective on how the immune system functions. Traditionally, immunologists have relied on the self-nonself (SNS) model, which posits that the immune system distinguishes between self and nonself entities to mount an immune response. However, this model has faced numerous challenges and failed to explain certain phenomena, such as why organisms do not reject newly changed tissues or why mammalian mothers do not reject their fetuses. Matzinger proposes the Danger Model, which suggests that the immune system is more concerned with damage than with foreignness. The model posits that immune responses are triggered by alarm signals from injured or stressed cells, rather than by the recognition of nonself entities. This model has been supported by the discovery of various endogenous and exogenous alarm signals, such as mammalian DNA, RNA, heat shock proteins, and breakdown products of hyaluron. The Danger Model offers a more nuanced view of self-recognition, suggesting that "danger" can be induced by both foreign pathogens and harmful self-entities. It also provides a framework for understanding why transplants are rejected more easily from living donors than from cadavers, why women are more susceptible to certain autoimmune diseases, and why graft-versus-host disease is less severe in recipients who have undergone gentle preconditioning treatments. Matzinger further discusses the implications of the Danger Model, including its potential to explain the role of "innate lymphocytes" in local immunity and the possibility that tissue-specific responses may determine the type of immune response generated. The article concludes by highlighting the shift in thinking that the Danger Model inspires, emphasizing the importance of considering the internal conversation between tissues and the immune system in understanding immunity.The article by Polly Matzinger introduces the Danger Model, a new perspective on how the immune system functions. Traditionally, immunologists have relied on the self-nonself (SNS) model, which posits that the immune system distinguishes between self and nonself entities to mount an immune response. However, this model has faced numerous challenges and failed to explain certain phenomena, such as why organisms do not reject newly changed tissues or why mammalian mothers do not reject their fetuses. Matzinger proposes the Danger Model, which suggests that the immune system is more concerned with damage than with foreignness. The model posits that immune responses are triggered by alarm signals from injured or stressed cells, rather than by the recognition of nonself entities. This model has been supported by the discovery of various endogenous and exogenous alarm signals, such as mammalian DNA, RNA, heat shock proteins, and breakdown products of hyaluron. The Danger Model offers a more nuanced view of self-recognition, suggesting that "danger" can be induced by both foreign pathogens and harmful self-entities. It also provides a framework for understanding why transplants are rejected more easily from living donors than from cadavers, why women are more susceptible to certain autoimmune diseases, and why graft-versus-host disease is less severe in recipients who have undergone gentle preconditioning treatments. Matzinger further discusses the implications of the Danger Model, including its potential to explain the role of "innate lymphocytes" in local immunity and the possibility that tissue-specific responses may determine the type of immune response generated. The article concludes by highlighting the shift in thinking that the Danger Model inspires, emphasizing the importance of considering the internal conversation between tissues and the immune system in understanding immunity.