The following are examples of other theories of immune system function that have been proposed, or subject to some discussion in the last five years. Regardless of their merits they have not received the same attention as Matzinger’s danger model, but then none of them have been set out with the same attention to the details of mechanism. One feature they generally share is a shift away from associating the function of the immune system with making the discrimination between ”self and nonself” (whatever that might be). There is a trend towards seeing the immune system as involved in preserving homeostasis of cellular
function. If the immune system is seen as making any sort of self discrimination it is that between “healthy” and “not healthy” cellular function. This is compatible with Matzinger’s danger model, as her model details the mechanisms by which
disturbances in cellular function and disruptions to homeostasis may be identified and dealt with.
3.5.1 JANEWAY’S STRANGER
Janeway holds to the central importance of the self/nonself paradigm. However he holds that the main evolutionary selection pressure exerted on the immune system was, until the recent advent of antibiotics, a microbial one. Other functions of the immune response such as graft rejection, tumour responses and autoimmune diseases have only seriously arisen this century. The immune system has therefore evolved to be activated by recognition of:
Conserved patterns of molecules made by microbial pathogens but not by vertebrate cells. . . . The receptors for this signalling are known in some cases: the scavenger receptor expressed by macrophages and dendritic cells is one such case, but there are many others. (Janeway, Goodnow & Medzhitov 1996, p 521)
These are presented to T cells with an appropriate co-stimulatory signal.
This is very close to the associative antigen recognition theory of Cohn & Langman, except that Janeway claims that the recognition of nonself (or stranger) is easily accomplished because the immune system is genetically programmed to recognise certain types of distinctive foreign peptides. This correlates with the well
documented immunostimulatory effect of various microbial molecules such as lipopolysaccharides, bacterial DNA and double-stranded RNA (Roitt, Brostoff & Male 1998, Ch10) and their use as adjuvants in vaccines.
Janeway’s theory holds that the ability to recognise these molecules is an inherited trait, or “germline encoded”. Cohn argues that although this germline encoding is characteristic of invertebrate immune systems, long-lived, peripatetic vertebrates are exposed to such a wide variety of pathogens that “a learned self/nonself discrimination became obligatory” (1992, p 323). The ability to recognise and respond to pathogens therefore continues to be developed by the immune system after birth. It is learned by the cells, or “somatically learned”, rather than “germline
encoded”. It is probable, however, that the vertebrate immune system operates with a mixture of the two.
Cohn also points out that proving the existence of some easily identifiable nonself (or stranger) markers on some microbial pathogens does not constitute sufficient grounds for a comprehensive theory for immune system function. It fails to explain the existence or mechanisms of autoimmunity.
Janeway’s stranger model is therefore best seen, not as a comprehensive theory, but rather as an interesting elaboration of mechanism, bringing in a reminder that some aspects of immune recognition may be germline encoded rather than entirely somatically learned.
3.5.2 DEMBIC’S INTEGRITY
Dembic’s integrity model (Dembic 1996) holds that the primary function of the immune system is to preserve integrity, or homeostasis of function. The molecular signals involved in this function are not necessarily involved in making a
self/nonself discrimination, although aspects of this might be included in their operation.
Like the danger model, the integrity model postulates a third signal. The third signal in the danger model is an indicator of cellular distress, in the integrity model it is an indicator of disruption of homeostasis. Although Dembic provides a detailed
account of the way the three signals operate “the question of the nature of the third signal remains open” (1996, p 549).
His main contribution is a subtle shift in the core axiom of the self/nonself discrimination away from the importance of “preformed defence” (1996, p 550).
[The] immune system helps to preserve the state of balanced integrity of signals within any tissue, bodily part, or organism, and by doing so it learns to discriminate when disturbed. In conclusion, the reason why the immune system functions is the fundamental need to preserve self signals and not to discriminate the nonself from self, which is merely a consequence. (1996, p 550)
Dembic shares this perspective with Cunliffe, who instead of homeostasis, talks of morphostasis. Instead of danger, he talks in terms of preserving tidiness and clearing up the mess.
3.5.3 CUNLIFFE’S MESS
Cunliffe believes that it is not just time to redefine the primary function of the immune system, it is time to get rid of the concept of having an immune system.
I believe that the conventional view has got it drastically wrong. The anamnestic T-cell system never was an immune system. It is a morphostatic system. (Cunliffe 1999, p 217)
[The] conventional perspective misses important points. It is stalled on the idea that antigens are used to discriminate S [self] from NS [nonself]. Here, I argue that this emphasis on antigens is a quagmire conviction, bogged down in an outmoded perception. . . . the critical function of the immune (or morphostatic) system is the discrimination of healthy-self cells from other- than-healthy-self cells. (p 214)
While Cohn & Langman’s adamant defence of the self/nonself discrimination is dismissed as being little better than a “flat earth” presumption, observing that “stale paradigms are held like religious beliefs” (p 213), Cunliffe’s morphostasis
perspective easily integrates Matzinger’s danger model. In fact he talks readily of the notion of danger before converting it into “mess”.
Each zygote-derived cell is charged with monitoring and maintaining its own health. The overwhelming majority of all sick (dysfunctional) somatic cells are identified in house, within and by the disordered cell itself, using internal checkpoint controls. Sick cells (infected, aging, ectopic . . . etc.,) elect to apoptose [programmed suicide] on this internal realization of dysfunction: first they try to resolve the problem, but when this fails they trash their contents. Resident intracellular pathogens will be trashed in the process. . . . Immune aggression acts as a backstop - or mop up - mechanism that is poised to remember some caricature of sick cells that previously failed to successfully trash (and so sanitize) themselves. These
cells and their debris are a danger. (p 214)
Cunliffe takes a similar line with the various types of autoimmunity. He also holds that the origin of immune memory is
. . . rooted in the classification of whole cell death into safe or dangerous: the next time that similar cells are encountered, they can be left to get on with it themselves (for safely trashed cells) or encouraged to adopt a lowered threshold to apoptosis (for dangerous . . . cells). (p 214)
This idea is expanded in other papers (Cunliffe 1995, 1997), but the details are generally compatible with those outlined by Matzinger.
However, Cunliffe takes his terminology a step further, replacing danger with mess and safe with tidy.
Now even the danger analogy becomes outmoded. . . The thymus-
dependent immune system is a mess/non-mess discriminator and the whole morphostatic system is dedicated to maintaining a tidy household! (p 217) All cytoplasm has to remain membrane packaged, and preferably
communicating, for it to be tolerated in the zygote derived colony: it is exquisitely simple. . . . Virtually by definition pathogens make a mess; but, there are many viruses and bacteria that don’t make a mess. Anything is welcome . . . provided it doesn’t make a mess or get in the way. (p 217)
Cunliffe’s morphostasis complements Coutinho’s emphasis on the network aspect of the immune system and the need to keep in mind its “global properties” and not just the minutiae of its functions. However Coutinho’s work has focused on
addressing the self/nonself discrimination, whereas Cunliffe finds the danger model more compatible.
3.6 TRENDS
The theories presented in this section have covered a variety of perspectives from supporting the status quo to discarding it completely. Some models, such as those
of the network theorists and Matzinger’s danger simply sidestep the self/nonself issue. They find other ways of accounting for observed immune function, other criteria on which the immune system may discriminate. More recently still, the models of Dembic and Cunliffe show a trend towards seeing the maintenance of homeostasis or smooth function in the system.
One thing is very clear from this overview, and that is a general movement away from the traditional self/nonself discrimination model. A viable future probably lies in a melding of the danger model with a homeostasis model such as that by Dembic or Cunliffe, while keeping a “global perspective” on the way the immune system interacts with other biological systems in the body .