Further notes about the morphostasis concept – split files

(12) Here are some extra thoughts generated whilst reading current articles

(begun 11/09/12). Note, they are my opinions.

• Very few people can drop the assumption that a (the!) primary purpose of the adaptive immune system is to identify and eliminate "pathogens". The adaptive immune response, particularly, is seen as a war fought against microbes. My view is that the primary purpose of the adaptive immune system is to classify self–cell–debris into "tidily–packaged" and "spilt–debris". It does NOT "target" "pathogens" for elimination, although the ultimate outcome has very much that trend; pathogenic organisms do tend to be given "a bad time" when re–encountered by antibodies and T–cell receptors. But, only because they were processed by APCs (mostly dendritic cells) in the vicinity of (self–)cell damage. Damage to and spillage of any cell (including bacteria – eg, the Herxheimer reaction) is likely to act as an equal inflammatory trigger. But it will be mostly self–cells that are involved (they are by far the most dominant population in the living flesh of a single animal – though they are outnumbered 10:1 if we include the immediate surfaces of the skin and mucosae).
• Extending this theme a little, the conventional view of the adaptive immune system is that it acts as a memory for previous encounters with "pathogens" (pathogerms from now on to avoid the obfuscating misappropriation resulting from "pathogen"). Thus, it remembers certain antigens of these pathogerms so that, on any future encounter, it can identify and kill them quickly. I believe this is wrong.
• Let's continue by defining "pathogerm": a reproducing organism that has a reputation for causing damage in a host animal or plant and of proliferating within that host. Once it has achieved this status in a fresh host, it has – of course – become a pathogen (an agent – ANY agent – that damages its host). But that "pathogen" title says no more than it has damaged its host. It can equally apply to non–living agents that damage their "host" (eg, asbestos).
• I contend that the old view is conceptually WRONG. The adaptive immune system, instead, acts as a memory for patterns of (mostly self–) tissue death. On the "good" hand, the spectrum can range from a controlled, safe and tidy shutdown – leading to non–inflammatory disposal that causes little collateral damage. On the "bad" hand it remembers catastrophic, dangerous and messy cytoplasmic spillage – leading to attempts at disposal (successful or otherwise) that can become intensely inflammatory and may cause much collateral damage. Tolerance is "attached" to the first encounter and aggression to the second. Both caricaturise and amplify the inflammatory (or non–inflammatory) response of the first encounter and aim to reproduce this response on subsequent encounters. Although the result is to give "pathogerms" a hard time, this is NOT the "purpose" of adaptive immune memory. Effectively, the adaptive immune system gives the innate immune system a memory. So, all "divisions" into innate and adaptive immune systems are simply a concession to human weakness in conceptualising what is happening. There is no actual division. This preoccupation with tissue debris results in a scorched earth effect. To complement this, an animal body needs devices that preferentially nourish self cells (oxygen, glucose and iron management are obvious ones: gap junctions, plasmodesmata and other intercullular conduits probably contribute too).
• (Ignore other pathogenic organisms for the moment). Remember, the overwhelmingly vast majority of bacteria are dealt with in a minimally inflammatory way by the inner, most phylogenetically primitive shells, of the innate immune system (or innate immune process). Pathogenic organisms breach these inner shells (barrages) of the innate process and disrupt self–cells; they then begin their banquet (an event most unwelcome to the host). At these "inner shells", the most phylogenetically ancient immune cells (phagocytes) are acting like free living amoebocytes that are looking for their next meal: bacteria, viruses and decaying organic material.
• The adaptive (anamnestic) immune system does NOT discriminate self from non–self (either whole self cells or self epitopes).
• Self non–self discrimination DOES occur but is carried out by all cells on the basis of ligand/receptor interactions between WHOLE cells. It is certainly NOT established epitope by epitope (in the foetal thymus) as the conventional view envisaged.
• Self epitopes are NOT part of, or the basis of, a "horror autotoxicus" principle. Self (epitope) reactivity is ALLOWED and can be triggered into aggression. However, the massive apoptosis of effete self cells that occurs both in the thymus (particularly in embryo) and all over the body – every day – favours the promotion of immunological tolerance to self epitopes. But this does NOT result in a rigid observation of tolerance to self epitopes. It only commits the majority of T–cells, that can react with that epitope, into tolerance. The bone marrow is continually generating naïve T–cells – some of which will have an appropriate specificity. So, given time and a sufficiently prolonged inflammatory stimulus, aggressive clones to self epitopes will slowly emerge (as in adjuvant arthritis).
• For my money, "danger" is far from an ideal metaphor. "Damage" would be better (and is implicit in later Matzinger interpretations). The adaptive/anamnestic immune system is largely preoccupied with categorising cellular debris into well–packaged–debris (successful controlled cellular shutdown – largely apoptotic debris) and spilt–cellular–debris (messy death). The categorisation into "well–packaged–debris" allows the system to leave the successful inner shells of the immune system to get on with another successful (and minimally inflammatory) job whenever a similar incident is reencountered. However, it ramps up a inflammatory reaction on re–encountering characteristic messy–death–debris. This gives inflammation a memory. As an aside, if apoptotic debris is dealt with by neighbouring cells (not by professional trashers like the phagocyte lineage) then the "immune system" will remain "unaware" of that particular event.
• Thymic tolerance is established in the same way as peripheral tolerance – on the back of tidily packaged, controlled cell shutdown – apoptosis.
• The evolutionarily older innate immune response is dominated by an inflammatory ingress of phagocytes (inflammation). In invertebrates, this response is not dependant on adaptive immunity. In vertebrates, the initiation of an inflammatory (phagocyte led) response has been substantially isolated from its execution; the adaptive immune system now bridges this divide and is able to greatly amplify and accelerate the inflammatory response when a particular pathogenic stimulus is re–encountered. A dampening of inflammation is desirable in the eye and the brain and this may be a substantial "raison d'être" in the origin of these outer shells. An intense amplification of inflammation by the adaptive immune system would be most unwelcome here.
• It is generally assumed that the adaptive immune system responds with equal force to epitopes for which it has developed paratopes (antibodies or T–cell receptors). However, if we assume that the system is NOT remembering an epitope of a "pathogen" but is remembering a signature of damaged tissues (represented by a suite of differing epitopes that characterise a particular "pathogenic stimulus") then it is probably a safe bet to assume that a "memorised" pathogenic stimulus is composed of a pattern (or system) of epitopes. On re–encounter, the level to which inflammation is amplified is probably going to rise (perhaps exponentially) with the progressive recruitment of more and more of the different members of that "suite" of identifying paratopes. These were the ones used to record a snapshot of an earlier encounter with the same or a similar "pathogenic stimulus". So, rather like pinning a crime on a suspect, the certainty of identification rises as the number of different identifying and incriminating features coincide. I think that this is a likely scenario and this ought to be an easily investigable phenomenon.
• I note that, occasionally, it has been stated that I have suggested that the immune system is NOT involved in self/non–self discrimination but in mess/non–mess discrimination. It is important to get the context of this precisely right. It is the adaptive immune system that acts as a mess/non–mess classifier (the immune bits dependant on RAG genes). And, because the adaptive system is under the direct control of the innate system (and acts as the servant of it), it ends up looking pretty much like a self/non–self discriminating system. The innate system identifies self by the "combination lock" presence of appropriate "healthy self" markers (ligands) that have "sub"–identies according to tissue site, species and individual zygote–derived–colony (Mhc) markers (or ligands). These revolve around Ig–like domains, cadherins and other cell adhesion molecules.
• Re–reading Alex Bukovsky brought this former point to mind. His article also suggested a possible extension to the morphostasis hypothesis. The old interpretation of mammalian immune activity is that it is dominantly (if not exclusively) aggressive in action. My view is that, throughout its function, every element can have a spectral action ranging from co–operative/tolerant activity to rejective/aggressive activity. That extends to the complement system. At the end I will list these co–operative/aggressive contrasts for each element. So what is the co–operative function for the perforin/C9 family? To understand this suggestion, let me digress a moment – back to plants and plasmodesmata. If you can accept the principle of "denial of nutrient substrate" – particularly in the extra cellular spaces, then it is important to devise a "conduit" to move nutrients from one cell to another without crossing the extracellular space so that we have a "symplastic" continuum of cytoplasms. Options to achieve this include plasmodesmata, self cell engulfment (and "co–operative cannibalisation"), intercellular tubules and, in animals, gap junctions. Now, Alex Bukovsky talks of trephocytes – lymphocytic cells that support local cells and their regeneration. It is tempting now to conjecture that the perforin/9 family have an important co–operative role in transferring nutrients to regenerating cells as they aim for resolution of tissue damage. I guess that this might be a relatively achievable investigation point. (A suitable reference appeared shortly after writing this – Tegla et al – and is on the Supportive" page).
• One further point about the article by Alex Bukovsky is that there is now increasing belief in the accumulation of mesenchymal stem cells adjacent to the endothelium of blood vessels (part of what Bukovsky calls pericytes – perhaps). This is all part of the inflammatory process (the pro–resolving M2 phase). I find this an exciting development.
• Quote: "The immune system needs to be able to identify and ultimately destroy foreign invaders." To my mind, this statement highlights what I see as a confusion. The core cells of the immune system (phagocytes and, probably, but to a lesser dedication to this action – all cells of the ZDC) can recognise a vast array of different bacteria and have no trouble, whatsoever, in achieving this and "eating" them. So, unless you are a bacterium with special pathogenicity genes (mostly pathogenicity–island genes) you will be noticed and you will be eaten. There will be minimal need to recruit specialist phagocytic cells by an inflammatory reaction. Phagocytes have little trouble in identifying the vast majority of bacteria (and other pathogenic organisms) that they meet in day to day life. They are simply repeating an assimilation action that they leaned more than a 1000 million years ago. What the immune system (the morphostatic system) needs to do well is to immobilise these pathogenesis strategies so that it returns the status of pathogenic organisms back to a state that is similar to any other non–pathogenic organism (clostridium tetani is a good example to consider).
• Back at the beginning of the 20th century, the battle between Metchnikoff's phago/inflammocentric views and the "serum" views of Bordet (a battle largely waged by the "serum gang") had the effect of amputating inflammation from its central role in the immune response. In retrospect, it should never have become thus amputated and detached. Unfortunately the perception grew up that they were separate systems with just chance overlap of interaction. It would have been far better if the two investigative avenues had remained fundamentally integral. Then, the course of investigation would have continued along parallel and integrative lines rather than divergent and differentiative lines.
• When you are in the business of trying to get people (including your own self) to reorder perceptions, it is necessary – not only to note elements of the new perception but – to (grossly) caricaturise it so that it helps to shatter older perceptions. My experience – with myself, let alone anyone else – is that I have often written a point down that agrees with the new perception but have failed to fully take on board its caricaturised significance and its implications. To break older perceptions it is helpful to employ a degree of caricatured exaggeration and to formulate these from a variety of different "angles". I think this is rather like that favourite black and white image that can at one time be interpreted as a crooked old lady and at another time as an elegant young woman. The mind can flit between the two but there are times when you just can't make one image disappear for the other to re–appear. Caricaturisation and anchor points are the keys to being able to see the image you want immediately and to order. And so it is, I suggest, with the immune system.
• "Harmful pathogens". Did you quickly spot the tautology/pleonasm? This phrase is born out of the mis–appropriation of pathogen and it is the consequence of it becoming an accepted synonym for a pathogenic (micro)organism. It reflects the free (and unnoticed) way that the properties of a (true) pathogen and a micro–organism vacillate in this corrupt misappropriation. It should have read "Harmful (micro)organisms".
• I have just read this (I have paraphrased it a bit but the meaning is true to the original): "The innate immune system ...//... must be able to recognize any type of infectious agent and confine or destroy it." Let's take this apart a little. "Any type of infectious agent" is, I suggest, a micro–organism that has found and developed itself a pathogenic niche. It is multiplying within the host's Zygote Derived Colony and causing disease (damage). Unlike those myriad other organisms (mostly bacteria considered here), these agents are managing to sidestep becoming a feast for phagocytic cells (both professional and occasional phagocytes) by some devious and varied devices. Metaphorically, if you are a mouse attempting to use a tiger for a meal, you will need to be very devious. The MAMPs on microbe surfaces will still shriek out "favoured food". But, something is happening that is stopping the characteristic and usual response – the ingestion and assimilation of all the available bacteria. They would normally be ingested, "destroyed" (a "splat the bug" perspective) and assimilated before they can proliferate and insinuate their expanding population into the tissues of the host. What typifies potentially pathogenic organisms (pathogerms) is their ability to avoid this (for it is, with most organisms, a 100% effective strategy that leads to their assimilation by phagocytes and also triggers minimal if any inflammation !!!!). So, pathogenic organisms are distinguished from non–pathogenic organisms, not by their MAMPs (for they both have these – these just identify the interacting agent as an organism or a characteristic feature of an organism – like flagellin or DNA) but by additional contextual features that are consequent upon their pathogenic consequences – essentially damaging devices or impairment of debris clearance. That is not to deny that MAMPs magnify macrophage/APC activation. However, to produce an aggressive adaptive immune amplified response, they must do this in the additional context of damage and/or damage indicators. "And confine or destroy it" could be re–interpreted as "focal inflammation is ramped up – either with or without adaptive immune system amplification".
• So – MAMPs identify a "substance" or "agent" as an organism (or an organism associated feature) and damage associated signals (or molecular patterns – often termed DAMPs) log the pathogenic consequences of that "substance/agent". It is quite likely there are also LAMPs (location associated molecular patterns). Thus, nod1 and nod2 act as LAMP sensors of an intracellular location of MAMPs. (Lathrop et al have just published an article in Nature that establishes that tolerant [T–reg] immune response are invoked to gut commensals .)
• As many are probably aware, the 2011 Medicine and Physiology Nobel prize went jointly to Ralph Steinman (who sadly died before he was aware of the recognition of his contribution), Bruce Beutler and Jules Hoffmann for their work in identifying mechanisms involved in the very roots of the innate immune response . These researchers have made outstanding contributions, as has Ruslan Medhitov. Medzhitov, Beutler and Hoffmann were honoured with the Shaw Prize in the same year, for their work in the same arena of innate immunity. The Nobel and Shaw were awarded for helping to identify some, if not most, of the detail of how phagocytes recognise the presence and characteristics of various micro–oganisms. The existence of these molecular mechanisms involving TLRs and PAMPs is heralded as a great discovery/realisation. However, the principle should not have come as a surprise to us (even if the detail was) for it has been evident, since Metchnikoff's contribution, that phagocytes have some way of recognising micro–organisms. He even pointed out – very clearly – that this process is probably related to the favoured "dietary palate" of free living amoebocytes. I think that what has happened in the immunology field, since Metchnikoff, is that investigators has been bamboozled into concentrating on what is most apparent and most easily measurable and they have largely lost sight of Metchnikoff's deep insights. It is good to see that his primary area of interest has now been reignited by a fresh set of awards. But, let's clarify what has been achieved: this is the increasing detail of the mechanisms by which phagocytes "know" what to eat and it is now important to clarify an extension – how the system responds when it loses control. Metaphorically, how does the system respond when the "mouse" devises schemes to make a meal of the "tiger"? If you can accept the premise that the ontogeny of individual immune responses to tissue disruption are engaged in a shell like fashion (inner to outer barrages engaged in sequence as each shell fails to contain the insult), then it is more obvious that, though the adaptive immune responses follow TLR engagement and microbe ingestion, they are also and dominantly the consequence of a failure of the inner shells to contain the disruption. (The best description of shells is in the – unpublished, serially rejected – Phlogiston article.)
• The 2011 Nobel press release about the Medicine and Physiology prize was commendable in using "pathogenic organism" where it might have substituted "pathogen". However, if all the instances of "pathogenic microorganism" are substituted by "microorganism" on its own, the Press release remains both accurate and more inclusive. Arguably, it would also be more exact. Here is yet another example of how the misappropriation of the word "pathogen" continues to bamboozle; it is this historical (mis)use of "pathogen" that has led to the imperative to include "pathogenic" in this press statement.
• I have just been reading a statement that says "T–cells patrol the body looking for foreign antigens". Now T–cells do not do anything that they have not been told to do by antigen presenting cells (dominantly dendritic cells). And dendritic cells "patrol" the body in search of debris – essentially anything that does not have the stamp of a Healthy–Self–Cell. (Complement inhibitors constitute one such a stamp of a HS–cell; connective tissues are especially constructed so that they do not provoke the debris identifying processes – largely by simple repetitive structures that don't have many "poky–out" bits for the C3/4 dormier basket to latch onto). Debris is internalised by the APC that will then migrate to a local lymph node. When there, it delivers this internalised debris together with snapshot information on the inflammatory/non–inflammatory context in which it was encountered. Tolerant or aggressive actions are then encouraged to these antigens when they are re–encountered and this caricaturises the environment of the earlier encounter. Self/non–self discrimination DOES NOT occur at the level of T–cells. It only occurs on the basis of Healthy–Self–Cell vs Other–Than–Healthy–Self cell discrimination (OTHS includes ruptured cell debris) and is an innate immune response.
• I mentioned above that I would list the co–operative to aggressive spectrum of known immune mechanisms.
• Macrophages – M1 – mostly aggressive – M2 mostly pro–resolving (see Charlie Mills' papers)
• Various T–cells – actions range from aggressive to tolerance (both as amplified responses)
• The complement system – can act aggressively to various biological agents whilst self–cells are protected and it probably also has a more directly co–operative role (note the earlier mention of the C8–C9 sequence)
• The complement system probably contains all the important features of a morphostatic system within a microcosm of immune (or morphostatic) activity. because complement is evolutionarily primitive, much of the "immune system", that we have traditionally conceived, grew up around it and, even to this day, these "bolt–ons" enhance its discriminatory actions.
• Antibodies – can act as amplifiers of aggression or, as in the eye with allergic ophthalmitis, the development of auto–antibodies can be associated with a protective effect.
• Gap–junctions – can promote a cordon sanitaire of apoptotic death or strengthen their neighbours' healthy self status.
• There are probably others that I will think of – the lesson is "never assume that a process/cell is exclusively involved in either destruction or protection . Both the response and consequent action will be contextual.