A fairly simple explanation
The general perception of how the immune system (IS) works (particularly the adaptive IS) has traditionally been rather like this:
"Hey guys!" (that is, immune cells and antibodies) "there are bugs out there. Let's go find and kill 'em. While we're about it, we'll remember what they looked like last time so that we can recognise and kill 'em faster next time around."
A morphostatic system works in a different way:
"Ooopppss! Something's making a tissue mess. Better go tidy up the mess and fix any losses. While we're about it we'll take a snapshot of this mess. Then we'll remember the most unusual signature of it. Then, if we meet a similar mess in the future, we'll ramp up the accumulation of mess eaters and make these act more aggressively when they get there."
In the first view, the bugs are the primary target. In the second view, the bugs (and their debris) are only noticed when they can't help make and become part of the tissue mess or they have properties that are characteristic of tissue mess (or, perhaps, more specifically, "potential fuel" – eg, primary fuel like bacteria or fuel for recycling in the form of degenerating self tissues).
I propose that there is no focus (by the adaptive immune system) on targeting and killing micro-organisms per se.
Individual cells (and particularly phagocytes) have an ancient capacity to recognise potential microbial "food" and my guess is that this is where PAMPs and PRRs will eventually be shown to owe their origin. Macrophages are amoeboid cells and the parallel with the amoeba is probably a deep evolutionary connection. Phagocytes in mammals probably act in the same primitive fashion, seeking out biological food (eg, decaying matter and various micro-organisms) for their sustenance. The immune system relies on this central and ancient capability in managing the debris produced within the zygote derived colony. (Don't forget that to be a successful intracellular pathogenic organism your first task is to get yourself invited in. At least some PAMP signals will be directed here.)
Note: The complement system ensures that all biological material is tagged as "suitable for degeneration", unless it is protected by complement inhibitors. Long straight molecules do not poke into the "basket" where the reactive part of the C3 complement molecule is situated (ready to latch onto its targets). Thus, long straight molecules, like collagen, are spared but "ligandy" ("sticky-uppy") sort of material, that pokes in easily, is soon tagged. This is the closest the system comes to "attacking" foreign organisms but, even here, the attack (tagging really) is focused on biological material that is largely not "foreign" – it is derived from the turnover of self tissues. When healthy self cells become tagged by complement, they ensure that they escape from this degeneration by using complement inhibitors to divert the downstream response away from aggression (it may even be into co-operation). The overall process is not an immune cell attack on foreign – even though it does create the illusion that this is what is happening.
Fundamentally simple, hey?
A good analogy
– is that of a city that has mess removal systems for garbage, sewerage dead bodies etc.. In particular, mess that might be used as potential fuel (fires) or food (vermin/infestations) needs to be controlled. If, say, the garbage part fails, certain diseases will become rife (particularly those associated with vermin) and if the sewerage fails, diseases like typhoid and cholera become rife. (Note that we have long since "realised" it is not sensible to leave dead flesh lying around.) No one in their right mind suggests that these collecting systems are primarily designed to kill the organisms responsible. That they have an effect in suppressing them is beyond question.
Then there is the tautology of a morphostatic system (tissue homeostatic system). Its existence is so obvious that it is essentially tautologous to have to emphasise it. But, sadly, we need to. Where are the vast tomes and mountains of articles dedicated solely to this subject? They ought to be there in view of its importance.
It is worth asking yourself this set of questions:
- Do phagocytes have anything to do with morphostasis? (tissue homeostasis).
- Do gap junctions have anything to do with morphostasis?
- Is gap junction activity altered when a healthy cell becomes sick?
- Are gap junctions important in macrophage activity?
- Is it possible to look at everything we have considered to be self/non-self (or pathogen/non-pathogen) discrimination and restructure it under a morphostasis paradigm? (holding back the tide of entropy – Zlatko Dembic's approach).
And ..... talking about pathogens
This is one of the most bizarre features of the common, extant language of immunology and microbiology. The term pathogen has been generally used as a lazy abbreviation for a pathogenic organism. Consequently, the word pathogen has gradually become synonymous – and now legitimately interchangeable – with "an invading (foreign) organism". But, by etymological definition, a pathogen is nothing more than an agent that provokes damage in the tissues it affects. This can be a living, organic, inorganic or a physical agent (a non-exhaustive list). Examples include, for example, heat or even a hammer; I can attest that hammers are really potent pathogens when they hit your thumb. I agree, unreservedly, that the immune system (or, rather, the morphostatic system) is constantly on the alert for pathogenic stimuli – these litter the extra-cellular fluid with the debris of damaged tissues. And, what is more, I agree that the immune system "memorises" these pathogenic stimuli so that it responds rapidly and in an amplified manner the next time that they are encountered. And this damage is probably a good sensor of the deployment of invasion tools by microbial agents.
An analogy might help; though some people (analogous to micro-organisms) decide to behave as burglars (analogous to pathogens) they do not conveniently oblige by proffering an outward appearance that marks them out as burglars except inasmuch as they might need to carry swag bags, wrenches, lock picks etc that are the necessary "tools" for the action intended. Naked, in the bath back home, they are just like ordinary people (micro-organisms). It is only their behaviour, their equipment and the consequences of their actions, that mark them out as a burglars (pathogens).
I contend that this uncritical use of the term pathogen, as a legitimate alternative for "an invading (foreign) organism", has led us to adopt one of the most remarkable conceptual blind spots in the history of science. Being a micro-organism is neither necessary nor sufficient for it also to be a pathogen. Pathogenicity is a discrete, distinct and additional property. But, in this world of "dog eats dog" it is a safe bet that, given the opportunity, many micro-organisms will have a go at it. However, it is worth thinking around the following point. It has recently been estimated that one gram of soil contains over a million microbial species. Only a very small proportion of these have the "skills" (dedicated genetic repertoire) to become pathogens.
I propose that we should establish an alternative name (a suitable substitute could be pathogerm) to help us focus on what we mean and avoid confusion. A pathogerm could then be described as "a micro-organism that commonly acts on tissues to induce disruption and pathology". (It's "purpose" is to generate nutritional resources.) "Pathobiont" is an alternative term (already coined) that would cover this but this has become particularly linked with intestinal organisms.
It should be readily apparent, using simple logic, that this uncritical view helps to perpetuate the "self/nonself" view of lymphocyte activation. Further, it shows how the protagonists of "self/nonself discrimination by lymphocytes" may, actually, be scoring an own goal in favour of the "danger" protagonists.
You can probably see that I, too, have fallen under this "Emperor's new clothes" spell when you read my published articles. It was only during the proof reading of the "Terra firma to terra plana" article (follow "published" link) that it began to dawn on me that the term pathogen was being used both inappropriately and far too loosely.
Should you doubt the importance of this conceptual blind spot, then try this exercise.
The Scandinavian J Immunology has now published my article that explores the origin of this trend to use pathogen as a synonym for pathogenic (micro-)organism (follow the PUBLISHED link on the left).
(Note that in his "Immunity in infectious diseases", Elie Metchnikoff frequently refers to "pathogenic [micro-] organisms". He never once abbreviates this phrase to the term "pathogen". Cambridge Univ Press 1905, reprinted 1907.)
Lastly (and this is like a city's mess disposal system):-
A critical function for the body's clearance systems is to rapidly remove debris that might serve as food (energy supplies and building materials) for micro-organisms and so starve them out of contention. (Go and take a look at a healthy sponge in an aquarium to realise that invertebrates manage this very well; then contrast this with the stinking - infected - mess of something like a beached dead fish.) Further, this debris is an important source of the material needed for self regeneration.
Conversely, pathogenic organisms must acquire two important properties. First, they must ensure the generation of (intra- or extra-cellular) tissue debris (to serve as food) and, second, they need to (focally) disable the inflammatory clearance process. Either suppression or gross over-stimulation are sufficient to achieve this. Also, remember that, for each affected host species, the number of "all pathogenic micro-organism species" represents a very small fraction of "all micro-organism species" (even though we are painfully aware – and constantly reminded – of the pathogens).
Glucose homeostasis (minimising the persistence of extracellular glucose) and oxygen transfer (haemoglobin to myoglobin transfer) act in a similar way to minimise access, by invaders, to important metabolites.
It is almost a scorched earth (scorched extracellular space) policy that sequesters away nutrients and metabolites from potential invaders (particularly apoptotic/necrotic self cells). Invaders must dedicate genetic resources to ensuring the generation of supplies and other metabolites – or, alternatively, get themselves invited into the host's cells where there are more accessible resources. These conditions are, naturally, proinflammatory for phagocytes and APCs so the invading organisms are obliged to be proinflammatory (pathogenic) themselves.
So, microbes have two distinct influences when encountered by phagocytes (including antigen presenting cells like dendritic cells). First they have features characteristic of microbes (in general) and the phagocyte remembers these, from its evolutionary roots, as potential food: an encounter with them up-regulates the phagocyte's activity (probably, in part, by TLRs). The vast majority of the world's microbes are opportunists – they either live on inorganic material and some free energy gradient (eg, a hydrothermal vent) or feed on the corpses of dead plants and animals. So far, the majority of micro-organisms have little or no ability to attack living cells but they can become rapid colonisers once tissues die. This is the general micro-biological norm and the majority politely wait their turn. Second, a small proportion of microbes have evolved mechanisms to generate their own cellular debris within living tissues (and this equates to pathogenicity). They aim to create microcosms of disruption and death (to which they need to dedicate precious genetic resources) to furnish themselves with the conditions they have long since evolved to utilise in dead flesh. Little wonder, then, that a macerated wound (from a physical pathogen like, for example, excessive heat) is a breeding haven for microbes.
So a plea. Please, please, please – will all immunologists cease using this imprecise talk of "pathogens" when they mean "potentially pathogenic organisms" (organisms with an historically proven capacity to damage living tissues) or, at least, make it plain that they understand the importance of the distinction rather than demonstrate that they have have been bamboozled, by the repetition of an imprecise catchword, into thinking that the two are synonymous.
And a final comment – tissue resident dendritic cells would be well advised to take note of all instances of "potential food" (microbes) in the extracellular spaces surrounding tissue cells and regard them as threats (potential dangers) to tissue homeostasis. So it is probably not pathogenic organisms alone but any and all extracellular microbes that stimulate dendritic cells. So, are PAMPs (pathogen associated molecular patterns) really MAMPS (microbe associated molecular patterns)? Comparison with a plant's host resistance genes suggests that it is not the general recognition of microbial patterns that blocks the specific diseases. These diseases are caused by pathogenic mechanisms that are deployed by certain micro-organisms. In plants (and likely us too) these lead to highly specific countermeasures that close the loopholes that these pathogenic processes are exploiting (very much like Microsoft's responses to closing the security weaknesses that are targeted by computer virus attacks).
So are PAMPs really non-existent? No, not at all. The real pathogen associated molecular patterns, to my way of thinking (and remembering the lump hammer message from above), are the molecular signatures of spilt cells and general disorder lurking around in extracellular fluids (see this article).
The implications for micro-organisms
(The "shells" I refer to below are described in "Morphostasis: an evolving perspective" and in "Flushing out the phlogiston".)
(This page is still being worked on; the ideas here are not final and should be regarded as conjectures rather than firm beliefs.)
A consequence of the foregoing points is that micro-organisms, for example bacteria, need cellular or tissue debris as a substrate for their growth and survival within the tissues. Debris can decribed as "mess" – for example, unhealthy cells, apoptotic cells and disrupted tissue debris. Microbes are far too small to "eat" whole animal cells. Now, if the prime goal (purpose, aim, etc) of the immune (morphostatic system) is to tidy up tissue debris, then a major "purpose" of those genes that code for pathogenesis in a micro-organism will be to disrupt the normal physiology of debris clearance. For example, viruses can fool the system so that it doesn't recognise the unhealthy status of infected cells. Pathogenic micro-organisms will generate debris and may then impede its clearance; the injection of toxins to macerate a cell's contents, using a molecular syringe, is a common technique. Genetic disorders (eg, immune deficiencies) or acquired disorders (eg, diabetes, trauma) that impair the "scorched earth" efforts of the morphostatic system will all lead to an increased susceptibility to infection.
It's a good idea to get firm definitions before we get too far. So, here goes:
- Pathogen ~ an agent (living or inanimate) that has caused tissue damage.
- Potential pathogen ~ an agent that has previously been known to damage tissues.
- Pathogenic micro-organism (M-O) ~ a M-O that has caused tissue damage.
- Potentially pathogenic M-O ~ a M-O that is capable of causing tissue damage (pathogerm might be a suitable word to adopt to encompass this).
- Pathogen ~ is not synonymous with pathogenic M-O
- Adaptive, cognate, anamnestic immunity ~ are alternative terms to describe immune mechanisms that learn to deal quickly with any challenge should it be encountered again.
Extant (conventional) explanations regard micro-organisms (M-Os) as elements that must be eradicated from the body's tissues: "microbes present" is deemed bad, "microbes absent" is deemed good. However, a morphostatic system may well be much more tolerant and lenient to their simple presence. Nevertheless, if innate immune cells do come across them, they are likely to remember them as potential fuel and ingest them (an ability probably acquired from our free living amoebocyte ancestors from well over 700 my ago). Should microbes develop the capacity to delay the clearance of – or create further – debris, then antigen presenting cells that pick up representative debris will prime the anamnestic immune system to treat similar debris in a much more aggressive way when it is re-encountered and, in consequence, excite phagocytes to go into an aggressive and voracious overdrive.
The anamnestic immune system is primed to respond in proportion to the level of the triggering pathogenic stimulus (including tissue debris processed without inflammation – like tidy apoptosis: this leads to tolerance). The outcome is to augment or dampen inflammation on any re-encounter of a similar stimulus. The evolutionary advent of anamnestic immune systems seems to have altered the capacity for regeneration. Sometime during the evolution from invertebrates to mammals, this increasing reliance on lymphocytes has been accompanied by the acceptance of a less than perfect but quick repair mechanism (fibrotic scarring) particularly when the damage has been intense (eg, burns) and in mature animals.
Invertebrates species are in good balance with their pathogenic M-Os (not individuals: some of these will easily succumb to infection). Look at sponges in an aquarium to illustrate this. Consider whether the sponges are unusually susceptible to infections because they don't have "sophisticated anamnestic immune systems". That implies that the increasing complexity of the immune (morphostatic) system carries with it an expanding number of potential Achilles heels to attack (see Footnote 1). The pathogenic M-Os get back in balance with their chosen host. But they also become more specialised and, therefore, more dependent on their host (they can't afford to annihilate this species). Don't forget this point; saprophytes pose the morphostatic (immune) system little significant challenge, whilst pathogenic M-Os have evolved devious and sophisticated mechanisms to disrupt the clearance of debris.
To become pathogenic, micro-organisms will have evolved hand in glove with the "morphostatic system" (immune system if you like). It has been a general assumption that the complexity of the immune system is driven to ever greater sophistication by its battle with micro-organisms. The problem with this view is that this is a war that can't be won. Microbes evolve far too quickly. Although they have a small and limited number of genes, the evolution of this genome can be blisteringly fast in comparison with the germ line evolution of new animal-immune-system-genes (the somatic evolution of immune system processes is relatively fast – like, for example, learning the pattern of debris provoked by smallpox viruses so that a recurrence of full blown smallpox is soon prevented). These pathogenic M-Os are likely to find the Achilles heels of any new morphostatic (immune) system technique soon after it is "invented". Hedrick's article discusses this in detail.
Remember, the mechanistic shells of the immune (morphostatic) system become more specialised and more specific to each individual (ie, less generic) with each new enveloping shell. That means that the pathogenic M-O has to dedicate already sparse genetic resources to breaching each new Achilles heel. When that Achilles heel is located in the outer shells, the pathogenic M-O is forced to become more specialised, less generalised and therefore more dedicated and dependant upon its chosen host (eg, consider avian, bovine, human TB and, a topical example, avian flu). The survival and procreation of its chosen host species becomes the pathogenic M-O's vested and critical interest; it is not wise to annihilate your host reservoir. With the breaching of each new Achilles heel, the pathogenic M-O commits more limited genetic resources to parasitizing a more and more specific and restricted host (order, species, race – even individuals).
Phagocytes have no problem whatsoever in recognising saprophytes as food/fuel and treating them accordingly. This is a no contest situation – "tiger and mouse" could be a more appropriate analogy than "cat and mouse". If the mouse wants a chance to use the tiger as food/fuel it will have to evolve some pretty devious approaches – or wait till the tiger dies. The latter is what most saprophytes do. Many of the virulent pathogenic M-Os aim to induce premature death in a small portion of their chosen host and then they set upon this feast with gusto. With increasing specialisation and commitment to their chosen host, they run the risk of becoming extinct if they don't quickly reach a balanced compromise between killing their chosen species and self propagation. Simultaneously, they allocate a limited repertoire of DNA (or RNA) to pathogenesis and, in doing so, forfeit survivability in the saprophyte's chosen arena. (This might be relevant to the observation that influenza is often much more lethal when it first jumps from one host species to another.)
I have a sneaking suspicion that the increasing complexity of the immune system, through the aeons, is related more to its role in morphogenesis, damage management and repair than to its role in defence against micro-organisms.
Why do I suspect this? First and foremost, invertebrates are in good balance with their pathogenic M-Os. So, is the increasing sophistication of the immune system a response to pressure from these new pathogenic M-Os? Does each new barrage of debris-clearing-mechanisms require a new ring fencing barrage to sort out the new wave of debris that is provoked by the culprits that learn to "breach" every new Achilles heel?
That led me to thinking; what are the primary differences between simple invertebrate species (that are in good balance with their pathogenic M-Os) and mammalian species like homo sapiens (that are in good balance with their pathogenic M-Os)? Well, complex nervous systems constitute one attribute that seems to coincide with the emergence of adaptive immune systems (there's lots of evidence to indicate that nervous system complexity evolves in tandem with immune system complexity). Homeothermy is another but, then, much of the anamnestic immune system had already evolved in poikilotherms. Placentation became possible in mammals. However, it evolved late; so, while placentation may have been facilitated by an increasingly complex immune system, I don't think we can add this to the list of possible "purposes" that led to the evolution of complex adaptive immune systems. The notochord and segmented structure of vertebrates coincided with the emergence of cognate immune systems. Gills and jaws occurred around that time though gills were already used by some invertebrates. Highly structured and ordered cephalic structures, however, became commonplace, including complex front end nervous systems with the protrusions that constitute the receptors of the eyes (see Footnote 2). Perhaps the driving force that leads to the greater complexity of the immune system is the increasing complexity of morphogenesis, damage management and repair (particularly that related to the nervous system and eyes). The sophistication of the mechanisms leading to tissue homeostasis may need to become more complex with the hand in glove emergence of (cephalic) neural tissues. So, more morphostatic shells develop and perhaps not, primarily, because of pressure from pathogenic M-Os. It seems that something about how higher cognitive functions are achieved and maintained may well require more complex immune systems.
Apoptosis – as a defence mechanism – is not that desirable in the central nervous system where preservation of neurones is all important. It is now being noted that autophagy is the preferred way of coping with intracellular pathogens (pathogerms !) in the CNS. Autophagy leads to cross presentation (intracellular debris that would normally provoke a Tc response – CD8 presentation in the endoplasmic reticulum – is internally processed through the CD4 endosomal pathway and that leads to Th responses). So, Tc responses are down regulated in the CNS and substituted with Th1 and preferably Th2 responses. The appearance of autoreactive antibodies to CNS or eye antigens is associated with a good prognostic outcome in EAE and EAO (experimental allergic encephalomyelitis and experimental allergic ophthalmitis) compared with Tc/Th1 responses.
Coincidentally, there may be a need to guard against the debris created by emerging pathogenic M-Os as they breach each new Achilles heel. But perhaps, and again this is no more than a suspicion, we have got that last point wrong too. Pressure from micro-organisms may prove to be nowhere near the potent driver for the increase in complexity of immune (morphostatic) systems that we have previously credited. This would be quite contrary to extant belief; and all because pathogenic M-Os are forced to become increasingly committed to and dependant on their host and because they are able to evolve into their new niche and achieve balance quickly.
The one thing that, I believe, can be stated with some confidence is that the detection and elimination of micro-organisms from the zygote derived colony (self) uses techniques inherited from the very early evolutionary origins of multicellulates. Once free living protozoans started to group together into colonies and then started to organise into distinctive internal divisions and structures (early organogenesis) they needed new morphogenetic techniques and exposed new Achilles heels that became available to be capitalised upon. In mammals the dominant contributors to micro-organism detection and elimination will rely principally upon the central shells used by the immune system (RNAi, NF-kappaB, p53, autophagy, apoptosis, prostaglandins, phagocytes, complement). The "higher" (anamnestic) elements of the immune system are mainly targeted by (and – possibly, perhaps – reciprocally targeted at) pathogenic M-Os that have become progressively more specialised and dedicated to their host. The traditional idea of an immune system that is responsible for "bug hunting and elimination" will, if it exists in any sense other than being the consequence of "mindless" tissue homeostasis, most probably occupy the more central shells of the mammalian immune system (so, definitely not the adaptive IS which remembers debris characteristics – a combined memory of antigenic specificity and the antigens' (nb, plural) associated levels of tissue disruption).
So what creates the strong illusion that the micro-organism is remembered and destroyed? I guess it goes like this. Remember, the M-O needs to create a substrate of debris for its nurture. The anamnestic immune system remembers the signature of previously encountered tissue debris (this includes representative peptides from degenerating M-Os). With reinfection and infiltration of the M-O, there is initial growth that leads to debris that is reminiscent of the earlier encounter; this is quickly identified and targeted for accelerated clearance. The M-O's intended substrate is quickly and efficiently removed so that it is denied the nurture it needs. Now it becomes little different from a commensal or saprophytic organism and is treated as such by the more central shells of the immune system. Its survival tactic (debris generation) has been severely disrupted. Note that the deliberate generation of damage opens up the possibility that opportunists can cash in on the debris created by the specialised pathogenic M-Os. There is ample evidence that this does occur.
Now, so far I have talked about tissue debris but the really critical "structure" is the extracellular space (ECS) where the somatic cells live and construct their scaffold. As noted before, the system plays a "scorched earth" policy or, should I say, a scorched ECS policy. The critical process is to manage all potential resources in this space so that they do not become readily available to interlopers. Several techniques help: glucose is managed (with insulin) in such a way that it is only fleetingly available across the ECS (except in diabetes); oxygen is transferred rapidly from haemo- to myo-globin – it is "sucked" quickly from one to the other; haemoglobin helps to reduce the concentration of iron (essential for bacteria) by trapping it and amplifying its properties; and lastly gap junctions (GJs) are well set to act as conduits that allow cells to bypass the transfer of nutrient substrate across the ECS. When cells absorb apoptotic bodies and reprocess their molecules, the proceeds could, perhaps, be efficiently redistributed to adjacent cells without ever being exposed in the ECS. Perhaps this "scorched ECS" process might help us to guess some of the pressures that led to the evolution of GJs and plasmodesmata.
What then of the clear indication that microbes seem to influence things like Mhc pleomorphism? With a "horror autotoxicus system" that works on the specific recognition of a sort of "combination lock" identity profile (of cell surface ligands/receptors), this exposes an Achilles heel susceptibility where identity mimicry becomes a means of gaining a Trojan Horse style of entry. The Mhc apparatus makes this "combination lock" identity more complex and more individual. But, once again, this drive by micro-organisms might be overemphasised. The need for it may be related to debris recognition, removal and repair mechanisms rather than "bug hunting and killing". The immune system, I guess, does not add major shells to its armamentarium to help identify and destroy micro-organisms; my guess is that new shells are required for extra morphogenetic processes (including debris removal and repair). An analogy with Microsoft Windows (or any other operating system) may be helpful. Programme additions and revamps are made to improve its function (they are rebuilds); soon after the rebuild, the virus creators discover loopholes (Achilles heels) that they can exploit. In response Microsoft releases patches (tinkering) to close these loopholes. The mammalian immune system probably does much the same. The responses rely on both somatic and germ line evolution. Somatic solutions can be quick to evolve but cannot be passed on down the germ line. Advantageous germ line solutions evolve to patch up blind spots that are not routinely dealt with by the somatic evolution of appropriate immune responses (the least fit are either disadvantaged or die – so they have fewer descendants). Nevertheless, the basic "purpose" could still be "debris disposal and tissue repair" and this is what may be made more robust – rather than any improvement in the recognition and killing of pathogenic M-Os.
The two perspectives do end up being very similar so you might question why we should bother with such a "sleight of hand" mental gymnastic. However, the advantage of shifting perspectives is that the simplistic "bug-hunting" view has allowed us to (largely) ignore the active role of the pathogenic M-O in tweaking out loopholes (pathogenesis) and the coercion of the immune system into damaging its own tissues to provide nurture for the invaders. It has also allowed us to regard bug-hunting and killing as the prime object – and that has left us wondering why transplant reactions, auto-immunity, atheroma, cancer and injury responses also seem to have links with the immune system. And as for horror autotoxicus, it just does not function in the simplitic way so far anticipated. You may be able to think of more examples that are anomalies for the conventional view but resolve under a tissue homeostasis view (or under the broader principle of morphostasis).
The situation, when it comes to immunisation against infectious diseases, is different. Here, human intervention ensures that the purpose that emerges (potentially out of many failed attempts) is the provocation of a response that is dominantly focused on some epitope of the pathogenic M-O (other induced responses are abandoned as ineffective). We need to inflict minimal collateral damage and achieve early immobilisation (often by interfering with the pathogenic mechanism) and the effective – though not necessarily complete – clearance of the pathogenic M-O (usually by reducing the organism's pathogenic status to that of a commensal or saprophyte). And, this is not always easy to achieve. One of the common techniques is to deliver "mashed up" bits (mess/debris) of the pathogenic M-O together with adjuvant (mess/debris). This works well for the less dedicated and less sophisticated pathogenic mechanisms (eg, tetanus) but is much less effective for the more dedicated and more sophisticated pathogenic mechanisms (eg, HIV, malaria and TB). The human intervention that redirects the underlying purpose (morphostasis/tissue homeostasis) to our own goals inflates the impression that the purpose was, all along, bug hunting and killing.
The "take home" message
Stop thinking (restrictively) about pathogens and pathogen recognition. Instead, view the (overall) immune system as a process that is on alert to respond to and deal with all debris and in particular pathogenic stimuli, the latter provoking aggressive adaptive immune responses. And, view the adaptive immune system as a process "designed" to "remember" the signature of previously encountered pathogenic stimuli and respond more vigorously to them when they are re-encountered. Second, start thinking about the body and its zygote derived colony as a population that inhabits a localised ecological system; the dominance of beneficial populators (healthy self cells being the predominant type) must emerge as a "goal" and the growth of intrusive, disruptive and malign populations must be suppressed - dominantly by the withdrawal of easily available nurture.
- In simple systems, the component units tend to be more versatile, less specialised and less dependent on other units when there is a failure of part of the system (they are still versatile enough to "stand in"). In complex systems, it is the opposite. The component units tend to be less versatile, more specialised and more dependent on other units when there is a failure of part of the system (they are no longer versatile enough to "stand in").
- The role of the morphostatic system in the vertebrate eye may ultimately provide a deeper understanding of this need for the system to become more complex. Another important point may be that, in non-vertebrates, the morphogenesis of their nervous systems is largely "hard-wired". On damage, the system "knows" how to regenerate back into a functional entity. In vertebrates, and in particular in mammals like apes, we know that the morphogenesis of their developing brains (particularly in children) have a great capacity for adaptation to experience rather than being fully hard wired (we humans have to learn to walk over many months unlike more "primitive" vertebrates where this ability is hard-wired). Thus we humans have "an adaptive nervous system": I have deliberately chosen this phrase to emphasise the analogy with our "adaptive immune system". Because our nervous systems are highly adaptive we cannot afford to allow inflammation and primitive regenerative processes to run amok – or we would forfeit survivability.