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 Tcell 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 Scand. J. Immunol. 54, 4±9, 2001