For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.First, do no harm.-Hippocratic oathOf all the mysteries in modern science, the mechanisms of self versus nonself recognition in the immune system ranks at or near the top.-D. E. Koshland Jr.(1) As a graduate student, I was taught that the immune system functions by discriminating between self (defined early in life) and nonself (anything that comes later), tolerating self and attacking nonself. Although this elegantly simple idea seemed to make a lot of sense, it had problems from the beginning and has failed over the years to explain a great number of findings. For example, what happens when "self " changes? How do organisms go through puberty, metamorphosis, pregnancy, and aging without attacking newly changed tissues? Why do mammalian mothers not reject their fetuses or attack their newly lactating breasts, which produce milk proteins that were not part of earlier "self "? Why do we fail to make immune responses to vaccines composed of inert foreign proteins unless we add noxious substances, collectively known as "adjuvants"? Why do we fail to reject tumors, even when many clearly express new or mutated proteins? Why do most of us harbor autoreactive lymphocytes without any sign of autoimmune disease, while a few individuals succumb?To answer some of these questions, I proposed the Danger model, which suggests that the immune system is more concerned with damage than with foreignness, and is called into action by alarm signals from injured tissues, rather than by the recognition of nonself (2, 3). In the intervening 7 years, in conversations with a wide variety of people, I discovered that this simple idea not only offers answers to broad immunological questions, it also covers many details that had not been incorporated into previous models [for example, why major histocompatibility complex (MHC)-mismatched kidney transplants from living donors often perform better than MHC-compatible kidneys from cadavers (4); why liver transplants are rejected less vigorously than hearts; why women seem to be more susceptible than men to certain autoimmune diseases; why Rh disease of the newborn is a problem in the second pregnancy, but not the first; why graft-versus-host disease is less severe in recipients that have had gentle rather than harsh preconditioning treatments (5, 6); and so on] without adding special new situation-specific assumptions.This Viewpoint will first trace the history of the self-nonself (SNS) model, showing how it had to be modified over the years to accommodate new data, then give a brief description of the Danger model, and ...

For many years immunologists have been well served by the viewpoint that the immune system's primary goal is to discriminate between self and non-self. I believe that it is time to change viewpoints and, in this essay, I discuss the possibility that the immune system does not care about self and non-self, that its primary driving force is the need to detect and protect against danger, and that it does not do the job alone, but receives positive and negative communications from an extended network of other bodily tissues.

To generate an immune response, antigen-specific T-helper and T-killer cells must find each other and, because they cannot detect each other's presence, they are brought together by an antigen-loaded dendritic cell that displays antigens to both. This three-cell interaction, however, seems nearly impossible because all three cell types are rare and migratory. Here we provide a potential solution to this conundrum. We found that the three cells need not meet simultaneously but that the helper cell can first engage and 'condition' the dendritic cell, which then becomes empowered to stimulate a killer cell. The first step (help) can be bypassed by modulation of the surface molecule CD40, or by viral infection of dendritic cells. These results may explain the long-standing paradoxical observation that responses to some viruses are helper-independent, and they evoke the possibility that dendritic cells may take on different functions in response to different conditioning signals.

Dendritic cells, the most potent antigen-presenting cells, need to be activated before they can function to initiate an immune response. We report here that, in the absence of any foreign substances, dendritic cells can be activated by endogenous signals received from cells that are stressed, virally infected or killed necrotically, but not by healthy cells or those dying apoptotically. Injected in vivo with an antigen, the endogenous activating substances can function as natural adjuvants to stimulate a primary immune response, and they may represent the natural initiators of transplant rejection, spontaneous tumor rejection, and some forms of autoimmunity.

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For some time it has been thought that antigenic challenge in neonatal life is a tolerogenic rather than immunogenic event. Reexamination of the classic neonatal tolerance experiments of Billingham, Brent, and Medawar showed that tolerance is not an intrinsic property of the newborn immune system, but that the nature of the antigen-presenting cell determines whether the outcome is neonatal tolerance or immunization.

There are three possible outcomes when a T cell recognizes a cell bearing a self or foreign antigen. (i) The T cell is not sufficiently signaled and is unaffected. (ii) The T cell is activated. (iii) The T cell is turned off. The differentiation state of the T cell is critical to the outcome. Although both virgin and memory T cells can be activated by antigens presented by "professional" antigen-presenting cells such as dendritic cells, they differ in their responses to B cells. Experienced T cells respond to antigen presented by B cells, whereas virgin T cells are rendered tolerant. These findings may relate to the phenomena of low- and high-zone tolerance, neonatal tolerance, and the beneficial effect of blood transfusions on allograft survival.