May I add my opinion to this debate?
Whilst I am not a professional immunologist, my interest in this subject is long. It started with a study of the neurological complications of Behçet's syndrome. It struck me that the encephalitis of this disease was a much more fulminant version of the encephalitis of multiple sclerosis. Now, Behçet's syndrome comprises a number of component disorders, all of which are more common as isolated component disorders. The same applies to other component features of the sero–negative arthritides. There is clinical continuum from the mild components to the severe syndrome complexes. It may seem to be a jump from these statements to saying that this group of disorders are essentially "auto–rejective" but a detailed argument can be made for this and it makes sense (I have two extensive, unfinished and unpublished articles concerning this). The inference is that milder forms of auto-rejection – like for example the common disorder of recurrent aphthous ulceration – are so common as to be physiologically normal. So, the anamnestic immune system, far from observing a rigorous aversion to attacking self tissues, uses the "auto–rejective" process as a mechanism to clear pockets of disordered cells.
Note that physiological auto–rejection invokes the need for regeneration. Regeneration is resurgent morphogenesis. In a rapidly growing animal, extensive auto–rejection and subsequent regeneration could (and do!) stunt growth. The luxury of extensive auto–rejection as a morphostatic technique can only be afforded to its maximum in fully grown animals. So, immunological "immaturity" is an illusion – the aggressive, anamnestic immune system is deliberately down regulated in newly born animals to avoid undesirable tissue rejection (1). Pockets of such down regulation persist into adulthood in immunologically privileged sites (eg, eye and brain) where extensive auto–rejection would (and does! – Nb Behçet’s) seriously disadvantage the colony. This is reflected in the age incidences of the auto-rejective disorders.
These conclusions led, eventually, to an article published in Medical Hypotheses entitled "Morphostasis and Immunity". I have had no feedback yet to suggest that any professional immunologist has heeded anything presented in that article. The abbreviation list was, unfortunately, omitted and later published as an erratum (44:428) and this reduced its impact. I contend that this article has a great deal to add to this debate. The sequel, "Morphostasis: an evolving perspective", accepted in May for publication in the same journal, advances the argument substantially. In particular, by arguing dominantly from an evolutionary viewpoint, it becomes clearer what the morphostatic (tissue homeostatic) system is "trying to do".
It is fatuous to argue that the immune system does or does not discriminate self from non-self – except as a provocative means of forcing us to rethink the paradigm. After all, it is a perfectly justifiable viewpoint for each one of us to contend that the centre of the universe lies within the confines of our own body. But this perspective ain't too helpful when it comes to navigating space probes through the solar system. And so it is with the lymphocentric (anamnestic) immune universe. Everything is relative. To gain a better understanding we must adopt a new perspective. At least the absolute adherence to a lymphocentric perspective has been eroded over the past 3 or 4 years - but it was highly prevalent before that. The fact that the anamnestic immune system tends to tolerate self and attack foreign is beyond dispute. What should, though, be said with force is that this is not its primary "raison d'être". A phagocentric immune system is closer to the truth but even this does not go deep enough. Morphostasis is rooted in the process of intracellular surveillance for sickness (malfunction) within each individual cell of the zygote derived colony. All immune activity stems from the success or failure of intracellular surveillance for malfunction in order to clear away danger. Only when the danger "signal" (IL–1 being a major contender) breaks free from its containment within the affected cell membrane need it stimulate the aggressive anamnestic immune system.
I believe rapid advances will come once everyone accepts that the immune system is an (important) arm of a cell colony's morphostatic system. To re–emphasise, the system revolves around intracellular surveillance, within individual cells, for malfunction. Malfunction is identified by and within each and every nucleated cell of the colony. Danger is signalled when such cells cannot complete a successful and controlled shutdown (apoptosis) as things go wrong. My own ideas have focused on cell lysis as the dominant "danger" signal but any lesser manifestation of failed, controlled shutdown might suffice. The value of this concept becomes abundantly clear (I believe!) when considering the roles of Class I and Class II presentation of antigen – and that is amplified in "Morphostasis: an evolving perspective".
The earlier versions of the "Morphostasis" hypothesis were rejected by a succession of journals from as early as 1992. But, the component ideas presented in those articles have gradually born fruit and many have already been vindicated. The most contentious deduction, of course, concerns gap junctions, and is still only supported by "logic" and observational "rumour". But is it is far stronger now than when first adopted in the earliest versions. Of all the arguments to support the hypothesis, this gradual vindication of earlier assumptions, with a minimum of correction being required, is, I believe, the strongest. The late 92/early 93 article contains a more extensive discussion of the need for a change in perspective. It is available should you show an interest.