Essay 1: The Danger Model in Its Historical Context
Because I have been asked many times to delineate the differences between the Danger model [1] and models based on self-nonself discrimination (SNSD), intensively discussed in [2] I would like to start by pointing out one similarity. Both types of models agree that there is a need for some sort of discrimination at the effector stage of the immune response. As Mel Cohn puts it, the immune system cannot use a universal glue as an effector molecule [3]. It must make some distinctions so that it can eliminate pathogens without destroying the body's own tissues in the process, and this need has important evolutionary consequences. It is one of the reasons for the specificity of T and B cells. The more antigen specificity shown by the effector cells and molecules of the immune system, the more the response can be tailored to the pathogen and the less autodestruction will occur during an immune response. The critical need to discriminate is thus the evolutionary selection pressure behind the complex set of mechanisms that endow T-cell receptors (TCRs) and antibodies with their enormous range and exquisite degrees of specificity. Up to this point the Danger model does not differ from the others. Where the Danger model parts company with the SNSD models is that it does not assume that the discrimination between self and nonself is the critical element in the decision to initiate an immune response. All SNSD models have made this assumption and suggested that an immune response is generated whenever the body encounters something that is foreign. Although this has been a useful concept, many phenomena have surfaced over the last 50 years that do not fit with it. The Danger model instead suggests that an evolutionarily useful immune system should concentrate on those things that are dangerous, rather than on those that are simply foreign. There are two reasons for this shift in viewpoint. Firstly, there is no need to make a response to everything foreign. There is a lot of harmless foreign material in the air we breath and the food we eat. Why should we make an immune response to these things? There is also no need to make a response to a virus that enters a cell, makes a few copies of itself and leaves without doing any damage. (We might even want to welcome such viruses for the genes that they could bring us.) There is no need to eliminate the commensal bacteria in our guts that provide us with vitamin K, or the foetuses that make the next generation. The second reason is that ‘self’ changes. Classical SNSD models generally assume that each individual's immune system ‘learns’ the difference between self and nonself early in life. This is usually thought to be accomplished by the deletion of self reactive T and B cells early in their ontogeny in the thymus or bone marrow. Thus, early in (and throughout) life, only the lymphocytes that do not react to the self components are allowed to mature. If bodies never changed, and if there were no tissue-specific antigens that are not expressed in the thymus or bone marrow, this would be a useful way to create a definition of self. However, peripheral antigens do exist [4], and bodies do change. We go through puberty, pregnancy, ageing. We are not the same ‘self’ throughout life. How can the immune system keep up? Why don't frogs, mice and humans kill themselves at puberty? Why don't mammalian females reject their own newly lactating breasts when they begin to produce milk proteins that were not part of self until that time? In short, how can the immune system deal with a changing self? In addition, there are a wealth of other questions that classical SNSD models do not answer very well. For example, if the immune system fights anything that is foreign or new, why do we so often need to use adjuvant? Why doesn't the immune system rid the body of those tumours that are known to express tumour-specific antigens? Why are livers more easily transplanted than other organs? Why is the hamster cheek pouch (a place in which hamsters carry nuts, with all of their concomitant fungi and bacteria), an immunologically privileged site? Why does oral administration of antigen sometimes lead to vaccination (as in the polio vaccine) and sometimes to tolerance? What is the difference that leads to gene therapy versus DNA vaccination? Why do so many people have autoreactive T and B cells without any sign of autoimmunity? Why do others get autoimmune diseases? Musing on these kinds of questions led to the creation of the Danger model, which proposes that damage, rather than ‘foreignness’, is what initiates an immune response. Many parts of the model are not new, as it incorporates a series of features from familiar SNSD models, but it adds a small twist, a twist that takes us down a new path, that has rather surprising consequences, and that allows for explanations for almost all of the questions above. It starts (of course) with Burnet, who proposed that B cells carry clonally distributed antigen-specific receptors and that the interaction of these receptors with antigen initiates a signal (now known as signal one or stimulation) that is sufficient to turn on the B cell and initiate an immune response (Fig. 1). To ensure that immune responses are directed only against nonself, Burnet and Medawar incorporated Lederberg's suggestion that autoreactive cells are deleted early in ontogeny [5–7]. The antigen is in control (Burnet): recognition of antigen (signal one) leads to B- and T-cell activation. The same principle was later applied to T cells. This elegant and simple version of the SNSD model lasted until 1969, when Bretscher and Cohn added a new cell and a new signal, creating the Associative Recognition model, more commonly known as the Two Signal model [6], which has been updated and expanded over the years by Langman and Cohn [2, 9]. They were driven to do this by the finding that B cells, upon activation by an antigen, hypermutate their antigen-specific receptors, thus allowing the possibility that new, autoreactive specificities could appear and lead to unstoppable autoimmunity. Realizing that autoimmunity would be rare if the initiation of an immune response required the activation of two cells recognizing different specificities on the same antigen, they invented a second signal, called ‘help’(Fig. 2). They suggested that recognition of antigen (signal one) would lead to death of the B cell unless it was rescued by the receipt of timely and appropriate help from a helper cell. After many years of study, this part of the two-signal model has become well established. It is now known that the B cell takes up the antigen to which it has bound, internalizes it, processes it and re-expresses it in the groove of MHC class II molecules [10], waiting for recognition by the T-helper cell, which then sends helper signals using such molecules as CD40, CD40 ligand, interleukin (IL)-2, IL-4, IL-5, etc. The B cell can wait about 24 h, after which it dies if no help appears [9](Fig. 2). The helper cell is in control (Bretscher and Cohn): signal one leads to B-cell death, but the addition of help (signal two) leads to activation. This version of the SNSD model lasted until 1974, when Lafferty and Cunningham modified it by adding yet another new cell (the accessory cell, now known as the antigen-presenting cell (APC)) and a new signal (costimulation). The problem they were trying to solve stemmed from the finding that T cells tend to respond more strongly against cells from a member of their own species than from a member of another species. For example, chicken lymphocytes respond more strongly to other chicken cells than to quail cells [11, 12], and human T cells respond better to cells from another human than to mouse cells [13], but dog T cells seem not to be so picky. In other words, alloreactivity is often stronger than xenoreactivity. To explain these findings Lafferty and Cunningham proposed that T-helper cells are not constitutively active and that, like B cells, the signal they receive from the recognition of antigen is not enough to bring about full activation. They proposed a two signal model for helper cells (Fig. 3), suggesting that these T cells need a costimulatory signal that is supplied by the APC and that the costimulatory signals are species specific [14]. In a later article, they followed Bretscher and Cohn's lead and proposed that signal one alone would lead to tolerance of the T cell [15]. The APC is in control (Lafferty and Cunningham): T helpers die if they recieve signal one alone and are rescued and activated by the receipt of co-stimulatory signals (signal two) from an APC. For the next 13 years, Bretscher, Langman and Cohn's second signal (help) was studied while Lafferty and Cunningham's second signal (costimulation) was all but ignored. Then, in 1987 Jenkins and Schwartz discovered that gluteraldehyde-fixed APCs were unable to stimulate T-cell clones (see Appendix, note I) [16], and the immunological community rapidly began to collect evidence for costimulatory interactions discovering such moleulces as B7.1, B7.2, CD28, CTLA-4, CD40 and it's ligand, etc. Why had it taken so long? Why had the T helpers and their helper signals been applauded and carefully studied while the costimulatory signals of APCs remained ignored? I believe that the main reason is that costimulation did not fit into a self-nonself model. Unlike help, which comes from populations of T-helper cells that are antigen specific and can be depleted of self-reactive cells, costimulation comes from APCs, which cannot distinguish self from nonself because they have no clonally distributed antigen-specific receptors. They can present anything they pick up. If immune responses are initiated by signals from APCs, it is very difficult to see how the immune system can focus only on nonself antigens. Therefore APCs and costimulation made people uncomfortable. Even after its re-discovery, costimulation was often dismissed [9] or ignored [17] until, in 1989, Charlie Janeway found an ingenious way to meld costimulation with self-nonself discrimination. He expanded the SNSD model to include a set of genetically encoded able to recognise evolutionarily distant nonself [18, 19]. To explain the finding that responses to many antigens do not occur unless adjuvant is coadministered, he suggested that macrophages (later including other cells and molecules of the innate immune system [20]), like their counterparts of the adaptive immune system (T and B cells), are not constitutively active. This was an extremely important suggestion, counter intuitive to the prevailing concept of an active and constantly surveilling immune system, in which he essentially proposed that the baseline state of the immune system is ‘OFF’. In order to maintain a form of self–nonself discrimination, he then suggested that the innate immune system discriminates between ‘infectious non self’ and ‘noninfectious self’[19]. To do this, he proposed that APCs express pattern-recognition receptors (PRRs) that recognize conserved patterns of molecules found only on evolutionarily distant organisms, like bacteria (Fig. 4). (For example, resting macrophages carry PRRs for bacterial products like lipopolysaccharides (LPS)). Binding of the bacteria (or bacterial adjuvants) to PRRs induces activation of the APCs, which then internalize the bacteria (and any associated antigens), re-express the bacterial antigens as peptides in MHC class II molecules, and upregulate costimulatory molecules in order to activate T cells and initiate adaptive immune responses (Fig. 4). PRRs are in control (Janeway): APCs are not constitutitively active. They receive activating signals through pattern recognition receptors (PRRs) that recognise conserved molecules on evolutionary distant oranisms like bacteria. Thus, there were now two different types of nonself recognition. A genetically encoded set of PRRs assigned to the cells and molecules of the innate immune system and a somatically generated set of receptors expressed by the cells of the adaptive immune system. Only in the presence of the evolutionarily distant patterns recognized by the innate PRRs would costimulation be upregulated and an immune response be triggered: a neat solution to the problem of how to incorporate costimulation into a SNSD model. Taken together, the models of Burnet, Bretscher/Langman/Cohn, Lafferty/Cunningham, and Janeway comprise a rather complete SNSD model that attempts to deal with the findings of the past century under the premise that the immune system functions primarily to clear the body of foreign material. Because the critical event in all of these theories is the recognition of foreign antigen, immunologists have put a lot of energy into the study of antigens and the receptors that recognize them. For half a century, we studied the genetics of antibodies and TCRs and the intricacies of their mutational mechanisms. We analyzed the structure and minimal sizes of the carbohydrates and peptides seen by B cells. We studied the structure of the MHC molecules seen by T cells and the structure of the agonist, antagonist, dominant and cryptic peptides they display. We discovered superantigens and immune response genes. We finally incorporated adjuvants into the model by suggesting that they stimulate the innate recognition by the PRRs against bacterial nonself. In short, we spent half a century studying self–nonself discrimination. We have learned a lot, however, we have not yet achieved a consistent, interrelated set of answers for most of the questions listed above. Janeway himself pointed out [21] that the addition of PRRs, though explaining immune responses to bacteria and other evolutionarily distant pathogens, cannot explain the immune response to transplants or tumours, nor the dysfunction(s) that lead to many autoimmune diseases. How then can we explain these responses? The Danger model, like Janeway's proposal of PRRs, was also driven by the quest to incorporate costimulation into a functioning model of immunity. However, many discussions with Ephraim Fuchs [19] made it clear that this was exceedingly difficult to do as long as we continued to hold on to the self–nonself viewpoint. We therefore abandoned the concept that the immune system is primarily concerned about nonself, whether individually determined or evolutionarily conserved, and took a step even further back in evolution to look for the controlling elements of immunity. The Danger model is based on the idea that the ultimate controlling signals are endogenous, not exogenous. They are the alarm signals that emanate from stressed or injured tissues. In effect, Ephraim Fuchs and I followed tradition and added another cell and another signal [1,22–24]. We brought into the conversation every tissue in the suggesting that these are the cells that are in ultimate control of (and the of to its ultimate because there are no cells to We proposed that the cells of when which we or or signal that to activate Thus, like Janeway's expanded model, the Danger model that APCs are not constitutively able to costimulatory signals and that they must be activated note However, the expanded SNSD model, which that a nonself signal is the Danger model suggests that the activation state of an APC on the of the cells in its that are do not signals and in signals to APCs injured cells, cells that are die an death, or are should activate their APCs In cells that die by a of cell death signals to a that should not the of costimulation (Fig. (see Appendix, note The tissues are in control APCs receive activating signals from injured cells, but not from cells or from cells by cell Thus, the idea is that the of a pathogen or a is not the for an immune response. 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The is that each model has a different definition of anything present from the the immune system anything present at a enough anything present in the anything present in the thymus present at a enough and for long enough in the all and anything part of the immunological In at a tolerance in immunologists could not up with a definition of self that we could all agree to even for the How can we to if we have different for the we The other problem is that has a second that is so in our immunological that it is almost as it is commonly does not simply that is not It also usually that an immune The most important between the Danger model and other models is that it this from the definition of and it to the alarm signals from tissues. Both Janeway and have taken in this one that only can a response and the other suggesting that must the tissues in order to immunity. However, though of these models assume that is not they that it is a In models their different of self antigens should not a response. What then of autoimmunity? 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Although versus death are often with versus this be an as there are to be of I to use the or cell death versus We do not yet the that differ between the but the to be is to be one of them. that are do not their into the of If they have by cell death, they are also to have other alarm signals and thus should not activate There is at one If a harmless foreign enters an it for some and then be as the of an immune response that has because the APC activated by alarm signals that from the by an