Further notes about the morphostasis concept

A letter sent, 1st January 1997

You may find this of interest. You certainly ought to be aware that biology could be heading for a "Richter scale 8" earthquake iconclasm.

This concept is either rubbish – "dung heap tripe" – or it is an earthquake iconoclasm that is set to radically alter the whole of biological/medical thinking. Once refined, it could do for biology what general relativity did for physics. It is a realisation that immediately unleashes the bounds of a constrictive conventional perspective into a vastly better paradigm of metazoan life. You cannot possibly understand the body's response to any disease (auto–immune, infective, cancer) until you have understood these principles. You certainly cannot understand immunology until you have.

I think that I have been remarkably patient waiting for peer review to realise the importance of this concept. After all, I don't want to repeat an event like the premature claims made about "cold fusion". So, I have stayed away from the media. BUT....... it seems as though peer review is being "an ass" (see David Horrobin's article in the Lancet, 9/11/96 p 1293 et seq – I quote "History suggests a near universal rule – that innovation comes from an unexpected direction, and it is usually opposed by leading authorities in the field" – he sent me the paper partly in reply to receiving a copy of article (c) below). I am ignored by just about everyone in the field. I have a few letters that may help to highlight the responses that I have received. The general trend is, now, the cold shoulder. To me it seems like a conspiracy of silence.

What is different about this concept? Well, it is not crippled by a radically incorrect assumption. Read any textbook of immunology and you will soon discover that immunologists are convinced that the immune system is dominantly interested in combating infection in the body. In fact, the body troubles itself little, in its primary response, about the presence or absence of infection per se. What it troubles itself about is "sick cells". The vast majority of these are identified "in house", within and by the affected cell itself. Apoptosis is its elected response and this deals effectively with the vast majority of sick cells. This single (missing) factor is the critical, core point that current immunology fails to raise to a position of dominance. The aggressive immune system is only brought into action when cells fall sick and fail to "shut themselves down in a controlled fashion" (ie, elective apoptosis). These cells are dangerous and the immune system recognises them as such. For future reference, the immune system makes sure it remembers something characteristic about these cells – and it is engineered to favour latching onto the most unusual looking peptide junk that is being cleared away from inside the sick cell. The fact that the immune system is good at identifying and preventing infection is a consequence of sick cells dying in an uncontrolled way. Because infection is a frequent cause of this, it gives the illusion that aggressive immune activity is particularly interested in infection per se. It is not! It is interested only in cells that die in an uncontrolled fashion. All the rest is "consequence": we have misinterpreted it because we are looking at it from the wrong direction.

Where did this radically incorrect assumption (the wrong direction) come from? – the way circulating antibodies bind to bacteria and viruses and immobilise them! Antibodies are latecomers in the evolution of immune systems. So, it is a gross error to have crystallised all subsequent opinion around this early observation. It was a presumption to have assumed that "attacking infective agents" was the immune system's primary "raison d'être". But the idea sticks – like a limpet!

I have attached abstracts of three articles.

Please remember that the contents of the last two (b and c) are not yet in the public domain and, should you wish to see them, they should not be reproduced.

There are three more articles in my possession

I think it is time that the establishment is stirred up. They may not like my style. They may find it cavalier or far too speculative in its approach. They might not like the general concept of "theoretical immunology". But.... they cannot forever continue to deny that this hypothetical approach is finding answers that conventional research methods will take an age to uncover.

There is a lot of potential glory in these ideas. It would be fun to have them attributed to me but that is a self centred rather than a social response. However, it is a social crime that the fundamental understanding of cancer, infection and auto–immune diseases is being held in limbo now the fast track to a radically improved understanding has been laid out – yet still no–one appears to be taking it.

I have attached a series of quotes that set the scene. Do not underestimate that this is a potentially shattering realisation.

This is big, big, big!

I suspect, like the rest of the establishment, you will end up filing this in the cranks bin.

General email letter to various immunologists, 18th May 1997

I am not sure why no one wishes to speak to me on this subject. All communication so far has been one way. As far as I can tell I must live on a different planet to you. Nevertheless, I am not so daft that I am missing the importance of these concepts and I'm certain some of you know this too. Peer review seems to be being a total "ass" as far as I can see. My approach might be unconventional; it might be cavalier; it might offend those who think of themselves as professional scientists. But science has got itself into the rut of believing that speculation is an inadmissible act – only to be done in private, behind closed doors and amongst consenting adults in case someone finds you out. I heartily agree that Scientists should, and must, accept nothing (as gospel truth) that has not been rigorously proven. However, the problem with broad paradigms is that they are, at best, only guesses. They are a necessary evil and they should only be held so long as a better one doesn't turn up. Show me a major conceptual advance in science that was easily testable when it first appeared! These three quotes are from Thomas Kuhn.

Let me point out that any statement saying that the morphostasis hypothesis (or paradigm) is untestable (like the current criticisms of the "danger" hypothesis) apply with equal force to the currently accepted paradigm that self/non–self discrimination is learned in utero. Perspective depends on the position from which you view an object. While the current paradigm does have appeal and has been a useful framework to date, it is now creating more problems than it resolves. A change is overdue. Like Newton's Principia, it was great in its day, still works for many situations but it is now holding up the advance of the subject.

Two journals have now rejected "From terra firma to terra plana (I must add it has matured since the first submission but not since the last – rejected 15th May).

I will accept that rejection is justifiable on grounds other than: (a) it is not a thoroughly more predictive paradigm –– and (b) it is not the most important thing to happen to biology and medicine for years.

I am sick of peddling this round and being told it is worthless when it clearly is not. You could now line up a million professional immunologists to tell me my amateur contributions are worthless and I would know they are deluded.

I have attached the article as a file. If you cannot read this, I will send it as a plain text e–mail should you request this.

E–mail to someone, 3rd July 1997

This is opinion but, again, I will use an authoritative style for good flow!

S/NS discrimination is the same as it has always been since metazoans first evolved. It is based on cadherins, selectins and IgSF CAMs plus others. It is the process that leads to one cell docking with another. It varies according to necessity (see the points I made about sorting in embryos, sperm–egg interactions and the general principal of identity recognition). All the clues go to point out that cells in junctional communication can be ignored – they'll be OK – Klas Kärre's "don't call us if you see one of these variety". I don't know which version of "From terra firma to terra plana ... etc" I sent you but it is mentioned in the latest version.

You say something in paragraph 2 that makes me wonder if you have completely thrown off the yolk of a redundant perception – it was probably just a slip of the tongue. Doug Green kicked off Day1 of the "Models of Immunological Tolerance" debate by saying that "the immune system (non–existent for me) evolved to maximally damage parasites while minimally damaging us." Wrong, wrong, wrong if he is talking (as I'm sure he is) about adaptive immunity. Forget antibodies – their role comes late in evolution. The innner shells of the adaptive immune system are the NK (Tnk said but NK meant) like cells, Tc cells and Th1 cells – appearing in that order. Individual cells have to stand up for themselves – they are expected to keep themselves healthy and deal with their own interlopers. If they don't succeed in this they are then expected to do the decent thing (apoptosis) and mulch their dangerous contents in the process. If they fail in this, then they can't expect any mercy from the phagocytic system. Any cell exhuding cytoplasmic contents is in for the rapid chop. Now this is what the Tc cell system evolved to enhance. By remembering the strangest caricature of cells that made a mess last time, similarly caricatured cells can be encouraged into an early suicide on any future encounter. What follows is tidy, enhanced, early apoptosis followed by neighbour replication to fill the gap. And, apart from pathogens (or grafts for that matter) that sport alloantigens in their ruse for mimicry, the only cells attacked by the Tc system are self cells sporting self class I + nonapeptide (the addition of various nonapeptides probably makes many of the self–class–I–molecules+nonapeptides look like allo–class I antigens). So Tc cells are specifically interest in attacking suspect self–cells!! So where is horror autotoxicus? Again, it is there but it is nothing like the lymphocyte brigade's perception. It is the protection of healthy, self cells, in quiet communication with their neighbours. (This is where the cancer story becomes so strong). Various bits of evidence suggest that NK and Tc cells are selectively aggressive to cells that have detached themselves (worked out that they are sick). The aggressive Tc cell pays hardly any attention to foreign organisms per se. It simply looks for (self) cells sporting internally generated (nonapeptide) debris like the debris that the terminally sick cell (that primed the respective Tc cell) sported as it died catastrophically.

Th1 cells evolved as an extension of Tc cells to enhance and focus inflammation. They gave it a memory. But any induced response simply delivers lots of angry phagocytes that then search round for "other than healthy self" cells. The angrier the induced inflammatory response, the more difficult it is to masquerade as a healthy self cell. And the ultimate can happen (aggression to all local self cells however healthy) and that is why a focal cut off is so necessary.

The whole of the morphostasis hypothesis was built on the structure of recurrent aphthous ulceration, Behcet's syndrome, multiple sclerosis, adjuvant arthritis and their relationship to tuberculosis. Tuberculosis, in particular, shows how the bacterium deliberately flouts the system by getting the adaptive immune process to concentrate on class–I+self–nonapeptide rather than strange class–I+tubercular–nonapeptide. In so doing it creates its own field of macrophage paralysis and a caseous soup that acts as a culture medium. The adaptive immune system, far from observing a horror autotoxicus to self cells, is designed to turn on them when they make a mess. And if they present no clearly strange class–I–nonapeptide specifities then a combination typical of the stressed tissue cell will be chosen (eg, adjuvant arthritis).

In short, Tc cells are designed to attack suspect, detached self cells.

So, yes, I agree with what you said about about lymphocyte receptors provided you are pointing out that this is part of their docking mechanism that brings them into the "communicating fold". But you say that it makes it more likely to leave self alone while dealing with the pathogen. I say that, in morphostasis, aggression is focussed on the potentially sick cell (one like this died catastophically last time), not the pathogen that makes it sick. The closest it gets to that is recognising some of the debris that the (potentially) sick cell is hanging off its cell surface as an advertisement of what is going on inside. The prime purpose is to enhance the apoptotic intracellular destruction of potentially mess making pathogens – just like the hypersensitivity response in plants. But plants are (evolutionarily) stuck with rigid cell walls.

Was that close to what you think?

Comment on a published article dismissing the danger hypothesis, 8th August 2000

Two quotations come to mind

When a thing was new people said, "It is not true." Later, when its truth became obvious, people said, "Anyway, it is not important," and when its importance could not be denied, people said, "Anyway, it is not new." (William James)

Anyone who conducts an argument by appealing to authority is not using his intelligence, he is just using his memory. (Leonardo da Vinci)

My first impressions were that there are many value comments with much opinion promoted as fact. It struck me that there was no humility in it; no sign of a possibility that "I could have this wrong but ..". I respect and admire the latter.

The first page is mainly a posturing ready for the attack at the jugular. However, two points are worth noting. He says, "the notion that the immune system has evolved to recognise (dangerous) pathogens is not new." Pardon – are we talking about the same thing? He seems to think so. I doubt that you or I do. This is, to my mind, the fuzziness that comes from an inability to exorcise the old (distorting) ideas and a good advert for saying that a polarised caricaturisation is the only way to achieve exorcism. Much later on, we can return to the old ideas and appreciate their (parochial) value afresh. It also shows that he has not assimilated the perspective.

Second, he calls the danger theory a reductionist approach. Now, the ****** Journal is the very bastion of "blind reductionism". Cutting things into smaller pieces, looking in more detail, fitting around the "known principles" is the main liking of its editorial board. I never hold out much hope of finding a conceptually rich article in this journal. I think he is implying that the danger model is simplistic (we would see it as simplifying – a way of getting our heads around the broader issues).

He writes, "It should be distinguished from PROFITABLE attempts to integrate what is known about the innate and acquired immune response." Wow! – can he now deny that what I have written so far is valid comment?

He skirts around signal 1 and signal 2. He mentions the "relative importance of signal 1 and signal 2". I think this probably comes from the idea that (in vitro) absence of signal 2 is associated with tolerance so they see signal 1 as more important. But I will, here, reword them as "step 1" and "step 2" both of which are essential for lymphocyte commitment. In step 1 the respective peptide–MHC epitope is engaged. In step 2 it is awarded a binary contextual value of either "aggression on" or "aggression off". We believe that the first leads to clonal expansion and the second leads to apoptosis and so, tolerance. We have not yet (I think) absolutely dismissed the possibility that there may be clonal expansion of tolerance–promoting–T–cells. My view, and I suspect yours, is that ALL cells die and the Tc/Th system uses the step 2 switch to classify this previous mode of death (apoptosis/tolerance and necrosis/aggression). It is possible that the system has extended so that irreversibly sick cells may also provoke an aggressive step 2 stimulation (adjuvanticity of HSPs). There may not be strong in vivo relevance to the observation that peptide binding to a T–cell in the absence of "help" may encourage tolerance. Unhealthy (detached) cells, necrotic cells and apoptotic debris are cleared from the tissues to the local lymph nodes where the precursor (step 1 committed) T–cells are finally committed to tolerance or aggression.

He says, "The truth is that no serious immunologist today really believes ... etc". In the 1980s very few serious immunologists believed that the mammalian immune system was NOT lymphocentric. Very few doubted that self–nonself discrimination occurred by thymic conditioning in utero. Very few believed that plant defence had any similarities to mammals. Very few considered that the innate immune system had much influence on the adaptive system. Very few considered that every nucleated cell of the colony (of cells that constitute and animal) have the primary responsibility for looking after their own health and notifying adjacent cells and the "immune system" if something serious goes wrong. Very few considered that gap junctions were at all relevant to the immune system. Very few doubted that the immune system avoided self attack at all costs (the horror autotoxicus). What we are seeing here is conceptual erosion and *****'s article seems, to me, to be a manifestation of the terminal convulsions of a dying perspective. The immunological community is unwillingly changing its views – it is being forced, reluctantly and slowly into "revolution".

He writes, "Why should we discard the idea of "self" when really all that is needed is to recognise – as immunologists already do – that it cannot be the whole story." Simple answer: when the extant conception of self–nonself discrimination forces us up a conceptual blind alley from which it is difficult if not impossible to escape. Then it needs exorcism and a hysterical exorcism at that. One thing that I am convinced of is that – while self/nonself discrimination may be occurring – it is NOT occurring by T–cell commitment. This, for me, is an ABSOLUTE.

He writes, "One is tempted to agree that, of course, the immune system protects against danger: so do eyes, legs, teeth, and practically every other feature of anatomy and physiology (one could even argue that the stomach protects against the danger of starvation)" ... if this isn't a description of "beating back the tide of entropy" I'll eat my hat.

He writes, "Without specifying these features, the notion of danger would lack critical depth." This, I believe, should be reworded to shed its value judgement into "Until these features are specified, the notion of danger lacks the maturity to warrant abandoning other perspectives." But you (and many others) are working hard on that and the runes are already looking good.

He then gets into this "tainted think" about dangerous–antigens. I notice this often. They do not separate signal (step) 1 from signal (step) 2. Signal 2 has nothing to do with any property of the antigen OTHER than where it was met and in what inflammatory or non–inflammatory environment it made its debut. They still (conceptually) need to award the antigen a quality (a relic of self–epitope/nonself–epitope concepts). It is JUST an epitope. All epitopes – self and non–self – are just epitopes: nothing more: nothing less: all equal: a truly egalitarian system. It is only their context of presentation that leads to aggressive or tolerant responses. How often does that need to be repeated before they DO appreciate it? And what gets left out of the reckoning is the staggering volume of apoptotic death that is the daily consequence of housekeeping. All self epitopes are far more likely to be met in a non–inflammatory (tolerance favouring and paratope "mopping up") environment than in an inflammatory environment. Chance favours the prepared. The commitment to aggression is (for self/nonself) a non discriminatory, mindless event. Simply make older precursor T–cells more susceptible to aggressive commitment than young precursor T–cells, add the mopping up by apoptosis and you strongly augment the favouring of strange over common epitopes as fodder for aggression.

He then relents a bit and starts to concede that certain aspects uncovered by the danger hypothesis may have value (but danger remains anathema). I doubt if you would deny that there is a limited hit list of things that the system has learnt to regard as harbingers of doom (like LPS). But these must be germ line encoded, consequently limited in number and, even so, the value attached to them may be better understood as agents that are "potentially dangerous (mess making)" rather than agents that are non–self. David Lo's team found a lovely quotation on this:–

"The gram negative bacteria . . . display LPS endotoxin in their walls, and these macromolecules are read by our tissues as the very worst of bad news. When we sense LPS, we are likely to turn on every defence at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area ... All this seems unnecessary, panic–driven . . . It is, basically, a response to propaganda . . ." (Lewis Thomas, The Lives of a Cell)

He finally stops "convulsing" with the last 2 sentences above the title "Can the danger theory be tested". Implicit in these two sentences is a reluctant acceptance that it DOES have value – even if parochial. I guess that your position is that danger (mess for me) is such a dominant driving force that all other theories will be subsumed as special cases of (potential) danger (mess for me).

He next delves into philosophical bits where I think he is off beam. Essentially, I think he has replaced the reigning paradigm with a vaccuum but leaves the reigning paradigm as the covert (vs overt) explanation.

On Kuhnian revolutions and analogies to Copernican revolutions, I know where I will be placing my bets. I suspect that he will be the loser. New paradigms tend to show that older ones can be incorporated as special cases of the new. That is looking good too. Every extant perspective probably has value (they are each built on logic) and a good theory will encompass these in a such a way that it makes better sense of them all – and shows up their warts in the process.

Notes, 6th January 2000

I suspect that many or the executives of normal science (particularly in immunology) are incensed that I have not done (and have no plans to do) any personal (conventional) research. The dominant paradigm of "normal science" is that it works hard towards exploring a current paradigm by a process of conventional exploration by laboratory or observational research. In contrast, my pre–occupation is probably seen as parasitic – feeding off the hard work and perceptual efforts of the most notorious extant workers in the field. From the start, my belief has been that the conventional view is absurd – it's not a front runner. It has also been my view that we are probably awash with basic, reductive research. We have no absolute need for new research to restructure the paradigm. New research has undoubtedly been helpful in pointing the way more clearly; but why do it (particularly if you can't because of your circumstances and commitments) when there is enough to find already to shore up a new perception?

Thomas Kuhn had this one sussed out too. He realised that paradigm shifts don't occur on the back of new research – the need to shift paradigms is already evident in extant work (nb the evolutionary analogy). If it wasn't there would be no justification for shifting paradigms in the first place.

Reply to Melvin Cohn (dated August 2003

(Added here because it exemplifies and clarifies some of the arguments.)

First!

I came to a need to understand the immune system from an unusual point. It is probably helpful to understand the sequence so you can see where I feel the extant perception is flawed. There is a file that describes this in more detail but here is a short synopsis. (C=comment,Q=question, A=answer).

Well, at this point, and knowing little (molecular) immunology, I decided that the IS was not observing a rigid horror autotoxicus to self tissues. The pathophysiology of TB and common diseases like acne, mouth ulcers, psoriasis and a host of other component disorders (seen in syndrome form in the SNAs) was – to my mind – "all due to immune auto–aggression" directed at self tissues.

So! That is the starting block. Even if "self" is recognised as such by the immune system it is still a long way from avoiding immune auto–aggression to it. So, there is no substantial horror autotoxicus to self antigens. Indeed, as with acne, the major attack seems to be on self and there is, simultaneously, little (and certainly ineffectual) clearance of the pathogen.

Several articles at my web site expand on Behcet's syndrome, clinical morphostasis and the evolving perception of morphostasis.

Second!

Here are some general points about successive "paradigms" of explanation. Let's call them models for simplicity. All previously popular models probably have some parochial value – parochial in both temporal and focused qualities. Thus, Aristotelian explanations seem totally off beam to us today whereas they had value in their own eras in beginning to focus our reasoning into better and better models. To call them "wrong" is as absurd as saying Newton was wrong and that Einstein will prove to be wrong (string theory seems, already, to be highlighting the parochial limits of his theories – it certainly loses definition at Planck distances and with quantum effects). They were appropriate for their era.

When you look back on earlier models, you can begin to see that, within their own bubble of applicability, the details of many theories have continuing value. New models, to be successful, rarely annihilate earlier models. However, they do highlight the presumptions that were made in extrapolating from these parochial observations to implications of a more universal significance. The true facts do not change with models. However, many of these "facts" have been burdened with interpretations that have stretched them into fables. The interpretation of the facts may be radically altered.

One salient point – that is perfectly obvious from both the "Sense of self" debate and the recent Seminars debate on self/non–self – is that there are many models of how the Immune System (IS) works and there are virtual science wars in progress between the competing conceptual camps. Now, history would dictate that they are all, to varying degrees, right. What is missing is a conceptual glue that will weld them all together into a whole. In doing so, such a perception will highlight the presumptions that have stopped their protagonists from moving forward and together. It will also highlight the parochial virtues of the older views. The older models will be subsumed as special cases of the emergent successor. A more universal perception will have been achieved.

That is history. And it will repeat itself. Perhaps not yet – but it will sometime.

Now let's get started on the specifics.

Let me start with some simple questions. Is it likely that the body uses a homeostatic system to maintain the order and form of its tissues? Even the most hardened antagonist of my view of the IS should find it hard to avoid a "yes". Is the IS likely to play a role in tissue homeostasis? If you are tempted to say "no", then step back one. Is it likely that inflammation and its retinue of inflammatory cells have a role to play in tissue homeostasis? To answer "no" to this one would, I submit, fly in the face of a tautology.

Another question. Do simple multicellular organisms, as well as mammals, have a tissue homeostatic mechanism? Do invertebrates, as well as mammals, have inflammatory cells? Do invertebrates, as well as mammals, have an anamnestic immune system?

A last set of questions. Do lymphocytes originate from a stem cell population that is closer to heart (or muscle or skin or what–you–like) than monocytes (macrophage precursors)? Do the surface markers of myeloid–lymphoid cells show a progression from phagocytes to lymphocytes? Could lymphocytes be regarded as amplifiers of the inflammatory response?

Your specific questions.

"How does the IS assay 'maintenance' and 'health'?" Essentially, it doesn't. "Assay" is a teleology that may come from a conviction that lymphocytes patrol the body "looking" for invaders. As David Lo's team have pointed out (1), a block of tissue cells form a network that effectively monitors the health of its own cells and tissue in general. Inflammation does not start until this network has cried "foul" and released chemicals that invite an inflammatory ingress. Individual cells monitor their own health and respond accordingly. Should you doubt these views – and the parallels in various multicellulates that range from plants to mammals – then it is worth getting a copy of a synoptic article by Trisha Gura in the New Scientist (Evolution and comparative immunology section in Supportive Research).

I think the preceding paragraphs have put up a good case to answer "how was it selected for?"

"It might be well to recall that your assumption has a long history . . ." I will answer this with a quotation: "Originality is nothing but judicious imitation." [Voltaire.] I am not staking a claim to intellectual property – I do have well defined views of what constitutes a better perception.

These have gone nowhere because they have not been mapped out onto a reasonable mechanism. I guess that you may not have read or, at least, properly assimilated the "Phlogiston" article at my web site. I do not think that the mechanism is unclear there.

"All that we can do is argue about the semantics of the terms self and non–self." Well, that's not a bad place to start. Now, one thing I think is worth considering (ignoring the teleology of "discrimination" for the moment) is what logical pairs we can consider. The body may discriminate on the basis of one or many of the following opposites.

We can look at each of these in turn and think "how much does this one contribute and when?" However, it is not – to my view – permissible to look at crossed pairs. For example, it is illogical to look at "self–animal/pathogen" discrimination or "non–foreign–organism/pathogen" discrimination or "self–peptide/pathogen–peptide" discrimination. To be logical, we must tie our parameters down as tightly as possible. Then we must consider how the system might feasibly carry out each tightly–defined discrimination.

I perceive that the way you have freely interchanged foreign–organism and pathogen is inadmissible and illogical. And I suspect it also leads to confusion.

"The straightforward assumption that the IS was selected to protect against parasitism, infectious disease and the like is so obvious. . . ." And the world is flat, the earth is at the centre of the universe, there has to be a creator, time and distance are rigidly fixed throughout the universe – and others. No one in their right mind used to doubt these obviously obvious assumptions. Revolution is science has regularly hinged around counterintuitive proposals. The immune system may be no exception. Indeed, when agreement cannot be obtained it is very likely that there is a false assumption somewhere in the prior conceptualisations. I think this would fall under the general description "Bacon's idols".

Now that does NOT dictate that the IS does NOT tend to produce the effect of protecting against parasitism, infectious disease and the like. It hinges around the danger of the teleology "selected to protect". We cannot help talking and explaining with teleologies – the closest we can get to avoiding them is to use a mathematical rather than a social language for description. because we can't avoid them we must be extremely sensitive of their dangers. My point is that the IS is quite mindless of the need to protect against parasitism etc. The effect occurs because it is tidying up the mess that these agents cause.

". . . tied into the regulation of the biodestruction function." So what is happening? Agreed, and without question, is the principle that the IS is capable of biodestruction. But most of this biodestruction is focused around subsets of self cells. Why? – for the following reasons.

Let's start with complement. First, C3 is secreted by phagocytes and actively concentrated in the plasma (by liver phagocytes). It is designed to constantly "condense" onto biological surfaces. Once there a cascade begins that results in the formation of C3b. If you are a healthy self cell then you secrete a C3–inhibitor that averts the C3b from triggering a pro–inflammatory cascade by moving it along to an inactive (non-aggressive) form of C3. This also applies to C4 when a cell gets coated with Ig. Two things might lead to self–cell lysis or fatal opsonisation; reduced C3–Inhibitors (do these downregulate just like Mhc Class I in sick cells?) or excessive Ig attachment. Either way, it is clear to see that there will still be a differentially greater opsonisation of other–than–healthy–self cells compared with healthy–self cells. And this can only start in the presence of plasma and/or phagocytes (ie, after an inflammatory ingress). Coating with Ig results only in bypassing the early stages of the alternative cascade. It attaches a marker to say "get on with complement assessment".

Now let's look at the biodestructive functions of cytotoxic and helper T–cells. Cytotoxic T–cells (Tnk and Tc) are designed to encourage self cells into early apoptosis. Unless some foreign organism could manage to incorporate self–class–I/peptide into its membrane, Tc cells will have no part to play in their disposal. So, cytotoxic T–cells are designed to encourage the melting away (by apoptosis) of self cells.

So what about T helper cells? Now, I think there may be a difference of belief here. You seem to hold that helper T cells are encouraged into aggression by primer T–cells whereas the Lafferty/Cunningham view is that APCs are the primers. Let me assume that APCs are the primers. What is it that the Th1 cell will respond to on epitope re–encounter. It will be another APC presenting a similar peptide in the jaws of its Class II Mhc antigen. It is responding to the presence of a self cell and sets off an intense inflammation in its proximity – an "inflammatory bomb". The biodestructive effect is caused by a cascade that intensifies inflammation at the location of this TCR/APC encounter; nothing more, nothing less. So where is the direct attack on the pathogen? It is, I submit, non–existent. It boils down, in effect, to a hard time for both healthy–self and other–than–healthy–self cells but it is differentially more destructive with other–than–healthy–self cells. But this is differentially cruel to organisms that are outside self cells. For organisms that reside inside self cells, the most effective response is to differentially encourage these flawed cells to die early. Otherwise, it must rely on a differential reduction in the infected cell's healthy self signature.

There is a tendency to look on the biodestructive mechanism of the IS as something that is directed at foreign organisms. For the reasons given above, this simplistic perception is far too naïve.

"You have given me no argument that Ig/TCR have a role in regulating normal physiology." Now, I think that this is your caricaturisation of what I have said. Strictly it is right but you go on, a few sentences later, to demonstrate that you equate this normal physiology with the normal physiology of chemical homeostasis (like glucose control). That is a very liberal and literal stretch of the original thesis. However, since you raise it then it is worth noting that the insulin receptor is closely related to growth factors and that islet cell physiology is intimately affected by gap–junctional communication. So you are, perhaps, not that far out in extending it to be a morphostatic mechanism: but I guess, the effect you sought was to question the perspective. (Gamma-delta T-cells now generally recognised to be involved in tissue homeostasis.)

"This is to be contrasted with their roles in guiding phagocytosis, cytotoxicity, C' lysis, 'transmitter and cytokine' production, etc. all biodestructive." I think that I have already shown how a different perspective can be laid out for these – and in favour of a morphostasis perspective. The facts don't change: the interpretation baggage does. (Both your view and the morphostasis view equally carry such baggage: as will any fresh, usurping view.)

"What is there about that you can't buy?" I buy all the facts! But I don't buy the interpretation baggage. I suspect other views more than I suspect my own but I don't even believe my own represents "the truth" or that it is secure.

"Try to answer for me; what will it take to have you change your mind?" Mel, I think I see your point of view. It is not that I cannot appreciate your perspective. It is that I think another perspective is possible and, once realised, it is better because it opens up a new vista on things. I don't feel tempted to abandon my views and replace them with yours. You quote Occam's razor in support of simplicity. But, I think that we should not be seeking simple mechanisms (biology is replete with the opposite) but simple principles that follow a limited number of common themes. Find a principle or theme that is simple to state, then see that it makes sense of ideas across a whole raft of previously disparate areas of study, and you truly have found an Occam's razor.

"The existence of debilitating autoimmunity shows that Ig/TCR mediated effector functions can destroy self cells and tissues." I have acceded this and even added my contention is that this is but the tip of a very large iceberg.

The Ig/TCR mediated ability to destroy cancer cells only confirms this, as the difference between cancer and non–cancer as seen by the I.S. is the presence of a "foreign" antigen. Sorry but I would say that they are not foreign (in the way we humans might conceive to be foreign). They are antigens expressed during retrodifferentiation and they are germ line encoded. The only exception might be if the mutant oncogene were a surface protein that gave rise to an entirely new peptide species. Macrophages have no trouble in recognising cancer cells in vitro. It is the anergy, necessitated by the T–cell system, that has led to their apparent in vivo invisibility as sick cells.

"The destruction of virally infected cells is another illustration." I think that you are providing further arguments that come to my concept's rescue, not to its demise – see above.

". . . when there is an insufficiency of eTh (delivery of Signal[2])." So, you are out on a committed limb here in persisting to believe that signal 2 is delivered by an eTh, NOT an APC (à la Lafferty/Cunningham). It might, of course, be the right limb. You claim this is simple, an Occam's razor solution: but you risk danger. Is it simplistic rather than simple? – and where is the objective evidence to support your contention? As tacit support for the perspective that I hold, it is instructive to follow the argument through carefully with both aggression or/tolerance selection and with thymic selection. By this view they end up as being the product of a repeating and much more general theme.

Let me set out, again, how I think that T–cell commitment is being made. It is important to exorcise the "tainted think" that attaches some quality to the Mhc/peptide epitope. My impression is that it is hard for people to cast it off. Many still need to (conceptually) award the antigen a quality (a relic of self–epitope/nonself–epitope perspectives). It is JUST an epitope. All epitopes – self and non–self – are just epitopes: nothing more: nothing less: all equal: it is a truly egalitarian system. It is only their context of presentation that leads to aggressive or tolerant responses. I think this last sentence cannot be repeated often enough to ensure that it is appreciated. (Nb, "context" subsumes your "time" as a special case). Let me, for emphasis of function, create the terms Step 1 and Step 2 that represent the precursor T–cell's response to Signal 1 and Signal 2 respectively. In the thymus in step 1 (part A) the T–cell spontaneously develops a particular specificity. This is the bit that ensures the Class I or Class II molecular clasp (not the peptide) is selected for. I suspect this is promoted by a gap junctional "kiss of life" and it turns the precursor T–cell into a selectable T–cell. Effectively, it is going to restrict the recognition of peptides to those that are carried in a self Mhc clasp. Then in Step 1 (part B) the lymphocyte refines its specificity to add in specificity for the peptide groove. Both parts of Step 1 are randomly generated. From now on, selection for aggression or tolerance is the same in the thymus as it is in the periphery. Thymic presentation is almost always non––inflammatory (there may be actual or experimental exceptions). In selecting only self Mhc carriers for the "kiss of life", a lot of precursor T–cells go on to apoptosis by neglect. These apoptosing cells are presented to the carrier specific and peptide specific (but uncommitted) T–cells. The result is the demise of both CD8 +ve T–cells capable of recognising any peptide presented by a dying T–cell: or the demise of any CD4+ve T–cell capable of recognising the debris derived from an apoptosing T–cell that is ingested and then presented by a thymic APC. Effectively this step amounts to the same process as Step 2. Other thymic cells might join in this apoptosis and also be presented to encourage tolerance (thymic epithelial cells, thymic APCs, thymic macrophages). Whatever, the result is tolerance to any peptide/Mhc antigen presented after efficient apoptosis in the thymus. I don't think that we have finally excluded the possibility of suppressor T–cells that can amplify tolerance on re–encounter – so these are also possible complicators of the tolerance mechanism. Now, this process of tolerance will use the same mechanism in the periphery as it does is in the thymus – efficient apoptosis. Inefficient apoptosis (due either to some mutant defect in its silent clearance or overwhelming apoptosis where apoptotic bodies – packed with Il–1 – spill their contents before ingestion) may invoke an aggressive response. SLE is a good example.

Aggression is induced when an APC presents (almost certainly in the lymph nodes) in an inflammatory condition (eg, rich in split Il–1, eicosanoids and interferons). Step 2 has nothing to do with any property of the antigen OTHER than in what inflammatory or non–inflammatory environment it made its debut. The lymphocytes are subsequently (or simultaneously) awarded a location address so that they are preferentially sticky to venules with a similar address code (part of Zinkernagel's localisation). So why do self cell signatures not provoke aggression? Part of the reason is that they share many peptide signatures with the apoptosing, precursor lymphocytes (and etc?) in the thymus. But the other part, and what gets left out of the reckoning, is the staggering volume of apoptotic cell death that is the daily consequence of housekeeping. All self epitopes are far more likely to be met in a non–inflammatory (tolerance favouring and paratope "mopping up") environment than in an inflammatory environment. Chance favours the prepared. The commitment to aggression is (for self/nonself) a non discriminatory, mindless event. Simply make older precursor T–cells more susceptible to aggressive commitment than young precursor T–cells, add the massive mopping up by apoptosis and you strongly augment the favouring of strange over common epitopes as fodder for aggression. The response to strange epitopes will be fast – like lighting a bonfire of thin dry timber: the response to self epitopes will be slow: like trying to start a sodden wet bonfire in a downpour.

In a way, this accords with your idea that older i–Th cells spontaneously move towards aggression. This is supported by experimental evidence (chapter and verse I would have to find). However, in denying that it is the APC that provokes Step 2, you distance yourself from my view.

"Do you wish to conclude that germline selected recognition of nonself markers like Danger, Morphostasis, integrity, localization etc. can be translated into decisions made somatically at the level of recognition of epitopes (which include MHC bound peptide)?" I am a little bemused about what you have in mind here. The germline "markers" of tissue mess will be analogous to the mess you and I see on our streets. First there will be the bits that get presented, nicely wrapped up in plastic bags, concentrated for quick collection. However, one or two of these gets ripped open by the foxes and the rubbish is progressively scattered all over the road. When the garbage collectors go on strike then entropy ensures that these neatly ordered packages progressively spill their contents (foxes, storms, vandals). Normally, the garbage collectors know what the bags look like and can sort them into paper waste, food waste and etc on their bag coding. It is plainly obvious for all what spilt rubbish looks like and I guess, that from time immemorial, animal cells have had a fair idea what constitutes the equivalent of connective tissue and cellular garbage. Macrophages (amoebocytes) are particularly attuned to mopping this up. Inside out membranes, spilt mitochondrial markers, spilt cytoplasmic markers will all have recognisable signatures and then there are the spilt chemicals – like Il–1 and eicosanoids – that shriek "mess ahoy".

I think that the morphostasis concept can subsume aspects of the AAR (provided you can drop your objection to APCs being the deliverers of Signal 2), stranger, integrity (order disorder discrimination), localisation and the immune homunculus. The views I find most distant from my own are yours, those of Medzitov and Janaway, Peter Bretscher and, a bit less distant, Coutinho. The main reasons for the difference with the first three is their absolute requirement that self–nonself discrimination by lymphocytes is effectively seen as a concrete reality. With Coutinho's view, the network is king and I feel this would result in a remarkably Rube Goldberg system. The network/homunculus ideas may be rewarded with an observable shift as described but they would, for me, be the passive consequence of morphostasis and not the active cause of discrimination. I think that morphostasis can subsume them all. It will show up the warts of presumption that have driven them up a blind alley and also, so far, prevented their integration.

I am sure that you will want to disagree – at least on first pass. But that is the fun of modeling. We must all accept the potential frailty of our conceptions.

  1. Lo D, Feng L, Li L, Carson, Crowley M, Pauza M, Nguyen A & Reilly CR. "Integrating innate and adaptive immunity in the whole animal." Immunological Reviews, 1999, Vol. 169;225-239. The authors reference a lovely quote about LPS in this article; it is worth reading this.
  2. "Roots of Immunity" by Trisha Gura in the New Scientist (Feb 18th 2000) pp24–28

Nb, anything in non-bold italics in this reproduced e-mail has been added later.

Comments on "danger" vs "stranger" theories:

of lymphocyte activation, 1st December 2003:

adapted from a letter composed in late November 2003)

I feel sure that the immune system (IS) relies on signals generated by unwelcome tissue damage (on the one hand) and that it targets a limited "hit–list" of markers characteristic of micro–oganisms (on the other) and that it recognises them using germ–line encoded receptors . However, it is important to try and gauge how, why and (evolutionarily) when these elements arrived in the armamentarium of the IS, if we are to better understand their "purpose".

One thing that the morphostasis hypothesis predicts (and is not specifically predicted by the other theories of IS function) is the shell like structure of IS functions. Not only are the individual components likely to have evolved in a Russian–Doll–like sequence but there is good reason to believe they might roll out in the same ontogenetic sequence on each new challenge. Note that ontogeny tends to retrace phylogeny. (This means that the extant state of an individual's IS represents a collage of discrete maturation points along this ontogeny; and, this state depends on the various challenges met and the respective shells at which they were resolved.) This gives us important clues as to what the elements (for example, Toll–like receptors) are primarily "designed" (evolved really) to accomplish.

This shell like structure suggests that macrophage functions are likely to share many similarities to those of unicellular amoebocytes. If macrophages are recognising "pathogen" associated structures, they will probably have some counterpart and some "purpose" in unicellulates like amoebae.

Let me digress for a moment around "pathogens". Modern immunology uses the term "pathogen" as if this were synonymous with a foreign organism. But, the term "pathogen" signifies the capacity for harm (from, for example, a hammer through to a living organism). It is a measure of the tissue damage caused (note the past tense). A foreign organism may well have the capacity to lead to damage, but what we are describing, in calling an agent a "pathogen", is a persuant event in that it has inflicted damage. We should, by rights, call these organisms "pathogenic organisms" (forthwith POs). I suspect that shortening this term has led to much woolly headed thinking. There is a trend to consider that the IS discriminates "self from pathogens" (POs intended). But, I suggest, this pairing is illogical nonsense. The only discriminatory pairs that make logical sense are clear opposites. For example, these are admissible:

Any or all of these could, potentially, contribute in the discriminatory function of the IS. But a crossed pair like "self vs pathogen" discrimination is almost meaningless. When the proponents of "self/nonself" discrimination use this, they are effectively scoring an own goal in favour of the proponents of the "danger" theories.

Remember that a pathogen is any agent, living or inert, that provokes tissue damage. So, that should immediately ring alarm bells about any extrapolation of "self/nonself" discrimination into a "purpose" for PAMPs, PRRs and Toll–like–receptors. What is more, it is obvious that PRRs and TLRs have functions to do with development that do not qualify as a self/nonself discrimination. There may be a common theme of recognition if it is recognising microbacterial markers that are released from both obligate intracellular micro–organisms (mitochondrial debris spilled from the cytoplasm) and their free living counterparts.

And so, let's get back to the purpose of Toll–like–receptors in eukaryotic unicellulates. These organisms need to maintain their own order and structure in an environment that is inclined to promote their degradation (eg, by damage, starvation, invasion by other organisms). They do so by consuming fuel of some sort and, for them, bacteria are a major source of this. So, even in the unicellulate ancestors that eventually evolved to construct mammals, there will have been a limited set of germ line pattern recognition receptors that identified suitable organisms for ingestion. One important consequence of this is that POs that rely on their animal host for survival might do a lot worse that to provocatively display "eat me" signals to macrophages – in Trojan horse style. There is increasing evidence that POs, once inside a macrophage or cell, can set off a fresh sequence of activity designed to subvert normal intracellular physiology to their own advantage

It is worth reading what Erwin Schrodinger wrote

"A living organism . . . feeds upon negative entropy . . . Thus the device by which an organism maintains itself stationary at a fairly high level of orderliness (fairly low level of entropy) really consists in continually sucking orderliness from its environment."

Contrast the way that certain gram negative organisms provocatively display LPS (and so heighten inflammation) with the impotence of common commensal organisms to cause any degradative effect until an animal dies Then, these organisms go into a frenzy of feeding and reproduction. So, unicellulates and multicellulates alike have little difficulty in maintaining their own integrity in a sea of non–pathogenic micro–organisms. POs, on the other hand, are highly evolved (often obliged to rely on their chosen host for continued existence; and, they use sophisticated subversion techniques to achieve this). In evolutionary terms, they are always likely to evolve a way around a new defence much faster than a new defence can evolve to counter it. Pathogenicity is always likely to end up as a balance between the successful propagation of the PO and the avoidance of the annihilation of their chosen host.

This quotation is worth heeding:

"The gram negative bacteria .. display LPS endotoxin in their walls, and these macromolecules are read by our tissues as the very worst of bad news. When we sense LPS, we are likely to turn on every defence at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area. All this seems unnecessary, panic–driven. It is, basically, a response to propaganda." (Lewis Thomas, The Lives of a Cell).

Charlie Janeways "stranger" hypothesis was firmly entrenched in the belief that attacking and killing microbes is the primary purpose of the IS. This has always meant that any observed cellular process is interpreted (square peg into round hole fashion) with the assumption that this paradigm is unchallengeable. Thomas Kuhn has a pertinent comment on that:

"Philosophers of science have repeatedly demonstrated that more than one theoretical construction can always be placed upon a given collection of data."

I would like to challenge, absolutely, the security of the 'obviously obvious' assumption that the immune system has evolved to find, kill and eliminate foreign organisms. It is beyond dispute that the system favours the survival of healthy self cells and everything else tends to be degraded. However, look at the evolutionarily old alternative complement system. All biological surfaces get C3b deposited on them. Healthy self (species) cells are protected by the inhibition of the aggressive consequences of this deposition. The system encourages the degradation of ALL biological material unless it is actively protected by complement inhibitors (HS/OTHS discrimination: mess/non–mess discrimination). Antibodies simply amplify complement deposition on those biological surfaces that have previously been associated with disorder (as judged by APCs, particularly dendritic cells). Inhibitor protection for self cells still applies but it is now harder to assert. So that sheds a different light on the specific attack on foreign organisms. The same can be said of Tc and Th1 activation. The first identifies self cells that have an MHC/peptide signature (Class I) that was previously (closely) associated with uncontrolled cell shutdown (or death). Similarly, Th1 activity just amplifies and accelerates the accumulation of phagocytes at the site of APCs displaying MHC/peptide signatures (Class II) that were previously encountered in an inflammatory context. Again, there is no direct attack on the foreign organisms by Th1 cells. However, they do encourage an inhospitable, local, inflammatory milieu.

Now, there is a naïve (to my way of thinking) belief that a mammal needs a sophisticated IS to fight infective organisms. But this flies in the face of what we know. Free living amoebae, hydra, jellyfish, sponges, insects and protean other invertebrates maintain their structural identity until they die. Then, like all other life forms, they are rapidly degraded by the plethora of organisms populating our environment. Next time you pass an aquarium, observe and wonder at the pristine structure of its resident sponges. Are these highly susceptible to infection and degradation because they don't have a cognate (anamnestic) IS?

Whatever the "purpose" was in evolving a mammalian cognate IS it can only have led to relatively focused advantages in combating invasion rather than in the common, general principles of protection. A corollary of this is that, whatever shells of IS–function an invertebrate possesses, each shell is fulfilling its appointed task efficiently. Remember that micro–organisms can evolve advantageous mutations in days (if not a lot shorter), and certainly far faster than can a colony of amoebae; mammals are stuck with trying out a new mutation much more slowly (for full testing, 15 or so years minimum for humans where there is but one child per family; sperm and ovum can be tested at single cell rates but this probably cannot test out multicellular properties). Now, this may well be one reason why mammals have multiple, tiered defence lines. They have to be less susceptible to advantageous PO mutations. Another might be related to the relative inability of certain tissues to tolerate regeneration (eg, the brain). But multiple tiered defence lines also increase the number of potential Achilles heels that POs can learn to exploit. And, I propose, the vast majority of POs that invade mammals are focused on one or more of these Achilles heels – ie, they are highly specialised and dedicated invaders.

In looking for a "general" (common to most animals) property that enables an animal to keep itself in order (against the gradient imposed by all the potential invaders that could use it for its fuel) we should be focusing on why the defence of potential hosts against commensal organisms is so overwhelmingly efficient. Forget, for now, the POs; with these we should be looking in detail at which Achilles heels are being exploited.

There are so many observations that fit better by looking at IS function as an order/disorder discriminating system that, I contend, it at least shows up the potential frailty of the "self/nonself" perspective. Further, it may help us to focus better on the important issues that will bring better understanding and, in consequence, lead to a more precise manipulation of the system.

Marrow derived stem cells and cancers

Timothy Wang's group (Massachusetts Medical School) and other workers have recently reported some interesting findings that could have far reaching implications – especially for morphostasis. Bone marrow derived cells can infiltrate a wound and take on the form of local tissue cells. Cancerous cells expressing a local cell phenotype (gastric carcinoma) were shown to be descended from a bone marrow cell line rather than from a de–differentiated and malignant local cell line. The implications for tissue homeostasis (morphostasis) are, potentially, enormous. Not only would bone marrow derived cells (monocytoid cells) infiltrate areas where tissue homeostasis is disrupted but they might also, at some stage in the "resolving" process attempt local tissue regeneration. It is becoming increasingly clear that locally persistent chronic inflammation is often the prelude to the onset of cancer and that, as inflammation subsides, the immigrant inflammatory cells go on to promote resolution and regeneration. It is tempting to speculate that cancer may be, in many cases, the occasional product of a physiological repair (homeostasis restoring) mechanism that has gone wrong. This behaviour would be consistent with the idea that macrophages are closer to free amoeboid cells in their state of differentiation than tissue resident (building block) cells. Thus, free roaming amoebocytes occupy a central "shell" in the morphostatic response. (Science Daily summary original article in Science ).

One thing that has to be dealt with, should more cancers be found to be derived from immigrant myeloid cells, is the relevance of mutations and the long antecedent history of local tissue exposure. Clearly these mutations are of importance but we may have jumped to conclusions about the exact way in which they give rise to a cancerous growth.

This leads nicely into a perspective of cancer that sees it as "distorted regeneration". Inherent in the process of morphostasis is the damage –> inflammation –> debris clearance –> regeneration sequence. To free cells of any restriction to growth (division and multiplication) it is necessary/desirable to temporarily abandon intercellular communication. To bring growth back under control and to coordinate healthy, co–ordinated differentiation amongst a group of cells, it is probably necessary/desirable to re–establish gap junctional intercellular communication. It is in the process of normal regeneration that carcinogens might facilitate this distortion. The drive to regenerate might be continuing without the system being able to "close out" (a chronic inflammatory process might be sufficient).

Once again, the morphostasis perspective opens out a view that becomes almost tautologous (inherent of the system and therefore no need to state it) whereas the old view does not inherently encapsulate it.

Grandics P. also develops a parallel concept of "The cancer stem cell: evidence for its origin as an injured autoreactive T Cell." in Mol Cancer. 2006 Feb 14;5:6.

Autophagy and defence

Just as apoptosis may act as a defence mechanism to "globally" mulch (sanitize) the contents of a compromised cell, so autophagy (the intracellular destruction and re–absorption of a part of a cell without destroying the whole) is now emerging as an effective defence mechanism. See these articles:

This emphasises another important point about morphostasis. It is important to re–assimilate the material that is dismantled in apoptosis and autophagy. Leaving it unused invites "predatorial" species to use the material for their own gain. It would also be a serious increase in the total entropy of the host animal. It needs to be rapidly reutilised and recycled into entropy resistant self cells.

And, a last point about autophagy: there are reports that suggests that this is an important mechanism in peptide cross–presentation (Class I – endoplasmic reticulum resident peptide – to Class II – phagosome resident peptide) and it is a logical consequence of autophagy. Search "autophagy" and "cross presentation" in something like Google Scholar .

Cancer and morphostasis

Here are a few thoughts on where we might be heading in the future.

More thoughts on the "battle" with micro–organisms

"One litre of pond water include members from all domains of life (virus, bacteria, archaea, eukarya) and contain up to 2 billion bacteria and 1012 viruses."

Here are some extra thoughts generated whilst reading current articles

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

The backdrop for morphostasis

Morphostasis is "painted" on a (very) "fluid" backdrop that allows the persistence of patterns and their form whilst more fundamental elements, that "create" this form, "flow" through it.

  1. Blank
  2. Blank
  3. Cells survive longer than their constituent internal components (autophagy).
  4. Animals survive longer than than their individual, constituent cells (apoptosis, necrosis, regeneration – what I have called morphostasis).
  5. Species survive longer than their individual, constituent animals ("death and taxes are the only certainties in life").
  6. Life survives longer than its individual, constituent species (species extinction).
  7. Blank

I have deliberately left (1), (2) and (7) "Blank" because we can add some conjectural extras at these points:

(1) The standing waves that constitute individual particles that make up matter, planets and the biosphere "persist" longer than the evanescent electromagnetic waves that are passing through them. They create an illusion of directional time and considerable permanence

(2) Internal cell components persist (in a formed construction or organelles and cytoplasm) longer than the atoms that pass through these intracellular constructs.

(7) Information and organisation (order) could, potentially, outlive life (as we know it) and persist longer than the collective intelligences that have nurtured them into existence (an emergent phenomenon).

The backdrop for self/non–self

It is worth re–emphasising how the idea of self/non–self discrimination emerged; it was "born" as a simplistic concept based on the categorisation of epitopes into self or non–self (epitopes are roughly equivalent to antigens). For a very long time (and it continues for many) self and non–self was believed to be established epitope by epitope: each epitope is apportioned to either self or non–self.

Now if we abandon this simplistic assumption (reject it), we can now reform the whole concept on the basis of healthy–self/other–than–healthy–self whole–cells; this is a cell–identity based system. This means we have to abandon the idea that lymphocytes and antibodies classify epitopes into self and non–self; we will need an alternative explanation of what they are differentiating (for they do end up "differentiating" and it does tend to approximate to self/nonself epitopes). In this shift, every cell expresses an identity on the basis of its "I am OK" communication with its neighbours. This healthy–self identity could be simple or complex (e.g., one ligand–receptor interaction or multiple ligand–receptor interactions together with chemokine messages, unhealthy–self markers, cellular junctions and others). It is more likely that self/non–self recognition arose in this way because antibodies are late comers in phylogeny. Epitope by epitope would be a hopeless strategy in hydra. And, it also suggests a totally de novo emergence – not rooted in any pre–existing process (it is generally assumed that RAG genes are the things that allowed this).

The alternative explanation of antibody/T–cell reactivity is that it classifies epitopes (roughly) into inflammatory or non–inflammatory encounters: and these epitopes need not be expected to remain rigidly committed to one or other compartment (as they are with the self/non–self epitope concept).

Atherosclerosis

There is much literature, now, on the involvement of inflammation and inflammasomes in the pathogenesis of atheromatous disease (often called atherosclerosis now; my pathology teachers were keen to retain arterioslerosis for hypertension associated vessel changes and insisted on atheroma rather than atherosclerosis). The one thing that I have not come across in the few articles I have read is the possible importance of the shift in the egress of inflammatory cells from a predominantly venous to a markedly arteriolar/arterial pattern as occurs with increasingly ramped up inflammatory processes. Examples include Behçet's syndrome (see the neuro–BS article in the unpublished section), graft rejection, hyper–acute EAE, tuberculosis and syphilis. Ideally, in the luckiest of animals, the inflammatory intensities will probably stay dominantly with a predominantly venular egress of inflammatory cells and avoid long term and cumulative damage to arterioles and large arteries. Atheromatous disease may follow a prolonged shift in emphasis from perivenous to periarteriolar inflammatory egress.

Assumed purpose of the adaptive immune system

Almost "to a man" articles consider the purpose of T–cells, B–cells and antibodies to be the specific recognisers of pathogenic agents (usually microorganisms of one sort or another – commonly referred to as "pathogens"). However, the evolutionary emergence of the adaptive immune system was likely (I would say certainly – 99% surity for me) to be for the memorising of patterns of excessively stressed tissues and, in particular, to act as a memory for inflammatory responses (provoked by pathogenic stimuli). Now, whilst individual epitope/paratope interactions are the final "quantal" components that add up to provoke this response (specific micro–organismal antigens are favoured because they were associated with the pathogenic stimulus) it is very likely that the system is geared to respond, most vigorously' to a pattern of epitope association rather than to individual epitopes on their own. So – and this is a very testable point – a characteristic pattern of different epitopes will reveal the re–occurrence of a previously encountered pathological stimulus. We should be able to take a pathological stimulus, analyse the epitopes (and immune response class) that lead to inflammatory amplification then provoke an animal immune response to one, then two, then three (and etc) of these epitopes and then measure the levels of the response. I would like to think that the progressive recruitment of an expanding paratopic repertoire will escalate the response – perhaps exponentially. Not all of these epitopes will be restricted to micro–organismal epitopes. Many of them will also characterise the associated self tissue damage. We already know that the immune response often retains a memory of the tissue location. It is like telling the police about a crime. "It was a robbery, a small disorganised gang were involved. They carried out the crime by breaking into the back of the building that was a small post office." Various other characteristics of the event and a description of various characteristics of the individuals who carried out the attack are noted. The police then compile a dossier of the event, look for patterns and can respond much more effectively at any repetition of a similar crime. Current "just–splat–the–bug" perceptions are very much biased towards a "one organism / one epitope" perspective and, particularly, do not differentiate a pathogenic from an incidental/commensal encounter.

One more point to emphasise is that "kill–the–bug" (splat–the–bug) perspectives ignore the feature that, I believe, is nearest to a "purpose" of the system. A bit of "me" (the zygote derived conlony) was damaged in a previous encounter. I will be on the alert for a similar future event and do what I can to limit any damage and encourage a rapid resolution to reasonable function if it does occur.

Pathogen (Microbe) Associated Molecular Patterns (PAMPS or MAMPS)

I have been ruminating on this for some time now.

PAMPs (or, better, MAMPs) interact with Toll Like Receptors (TLRs) and this seems to bring the attention of host cells to the presence of micro–organisms. The simplistic view taken so far is that this is part of a "bug hunting and disposal process". However, this may be far too simplistic. In this section I will concentrate solely on those molecules that bacteria display and that alert sentinel cells (of whatever lineage they belong to) to the presence of "invaders". I have already emphasised that the vast mass of heterotrophic bacteria are "polite". They wait for the death of living organisms before they use them as a their nutritional source. (Heterotrophs are other–seekers or more specifically, those that eat other organisms – alive or dead).

From here on, I am going to abandon the generally popular term PAMPs in favour of MAMPs.

I can, as yet, not find easy access to information on the (bacterial) species distribution of MAMPs – like eg, LPS (lipopolysaccharide). The question is, do chemio–autotrophs display MAMPs in the same way?

An important question to raise is this. Do MAMPs have an important role to play in the identification of sick and dying cells? (This could explain their involvement in development and their close relationship to DAMPs. (DAMPs are danger associated molecular patterns – although I would prefer to rename them as "debris associated molecular patterns.) Do these molecules help the zygote derived colony to re–assimilate organic building blocks? And do they help to identify suitable nutrition for heterotrophs? Could they be giving dedicated necrotrophs (dead flesh "eaters") an "early foothold" or "head start" in the colonisation of dying tissues? If this is a valid conjecture, then – in one stroke – it would help to make better sense of the "duality" of MAMPs that has become apparent in the literature. It has become increasingly clear that TLRs (cell receptors that recognise MAMPs) can be triggered by damaged tissues. If this view is valid, TLRs themselves might be a manifestation of DAMPs – developmental cellular debris that needs clearance and re–assimilation. It is fairly obvious that sick and dying cells – like those extensively harvested everyday after apoptosis – should be dominantly shepherded away by the body's phagocytic system so that they can be used as fuel for regeneration and, also, be sequestered away from competing micro–organisms. However, once the phagocytic clearance system fails (on the death of the whole organism) this debris becomes more freely available for environmentally ubiquitous heterotrophic bacteria (and other heterotrophs, like amoeboid cells and fungi). So the MAMPs of bacteria may be dominantly displayed as receptors for TLR "ligands" that then tap into a nutritional resource that is normally commandeered and shepherded away by host cells. So, an equally valid – if not better – perspective, is that bacteria use a similar system that animal cells have integrated a new pathway – developed anciently in heterotrophic bacteria – and refined it for its own management of sick and dying cells. Now that has an immediate resonance with the centrality of mitochondria (obligate microbial symbionts in animal cells) that are intimately involved in the mechanism of apoptosis.

I am guessing that this conjecture might well be worth pursuit. The first step would be to analyse the distribution of MAMPs in all bacteria – from those that populate the vicinity of deep ocean vents to dedicated pathogenic species. So far, I have not found articles that discuss the particular distribution of MAMPs in non–heterotrophs.

A further thought: it is possible that microbes deliberately display MAMPs to saturate the Toll–receptors of debris clearing cells. In the process, although they might sacrifice a proportion of their population, they would ensure an increased persistence of self cell debris for the survivors to proliferate. This might be worthy of investigation.

Silent paradigm shifts

Thomas Kuhn observed that the shift of a discipline to a new major paradigm is "silent". What he meant was that extant researchers experience no major shifts, no sudden gestalt events, the scales do not suddenly fall from their eyes in a sudden realisation, Saul does not suddenly become Paul. It is only in retrospect, in reading and comparing text books from different eras, that these major shifts become glaringly apparent to historians. I would like to suggest that the more tautological a shift proves to be, the more that the extant discipline is blind to the shift. By tautological I mean "how could I ever have thought otherwise" – it was already "obvious" in the evidence. This sort of realisation, where nearly all the "nuts and bolts" are already present but less organised before the shift, becomes second nature and simple common sense. Workers in the discipline absorb the actual changes without being aware that a seismic shift is occurring in its perception. This is now looking pretty certain for a "tissue homeostatic" approach to immunology – regardless, again, of any attribution of "ownership". Indeed, this sort of shift can have no "ownership"; for it comes to be what we have all always known but never quite (previously) verbalised.

Leverage – as a verb

I know this comment is "ectopic" but I hate this modern use of leverage so much that I want to draw attention to it here. The use of this word now seems to be taking over the scientific literature.

Leverage is NOT a Verb!

Leverage is the process of being levered. Lever is the relevant verb from which leverage is derived. So, when authors use leverage as a verb, they are not using their language as the precise logical tool that it should be. It is, at best, a metaphorical tool with loose meaning and, at worst, grammatically hideous.

Or, as Wictionary points out, would you remark that "you are wastaging my time" ?

Oddments

"The role of the inflammatory response is to combat tissue injury and infection."

This appeared in the opening statement of a recent article. I would like to take this point of view to task and reword it as "the role of the inflammatory response is to combat (or, better, respond to and resolve) tissue injury." Adding the infection bit is, I contend, completely redundant. ALL cells are capable of responding to the presence of (non–pathogenic) microbes and dealing with them effectively. Phagocytes do carry out the process well BUT their presence, to be able to take over the lion's share of this process, is – I contend – the consequence of a response to messages released by damaged cells. This damage may be primarily trauma or secondarily damage inflicted by pathogenic organisms as they seek to prepare body cells into a suitable state for their feasting. For bacteria, that usually – if not ALWAYS – means damaging cells (the pathogen bit) so that parts of the host's flesh has properties similar to a dead corpse. There is a major trend into shifting viewpoints so that "tissue injury" is now a prominent part of the event. BUT, authors are still very reluctant to dump "combating infection" as the/a prime mover. I challenge you to dump it: I predict that no conceptual damage will ensue.

The origin (and "reason") for the emergence of the adaptive immune system

There is a growing tendency to attribute the origin of the adaptive IS to the need to manage our gut microbiome. However, attributing it this "raison d'etre" ignores the fact that many invertebrates, that have no adaptive immune system, also encourage a symbiotic colonisation by bacteria within their guts. Whilst the adaptive IS may enhance the management of gut colonies, it can hardly be said that it is necessary for this purpose. Should my interpretation of the system prove to be "on the right track" then the adaptive IS is dominantly about damage management. What critical aspect of damage management becomes so important in mammals? I think this may turn out to be complex eye and brain structures that are adaptive rather than hard wired (a calf's ability to walk soon after birth is, for example, endowed with a substantial element of hard wiring). I suspect that the need for increased complexity in damage management was driven by brain and eye function. This would help to explain the parallel and mutually dependent emergence of complex nervous and immune systems.

Evolution (and emergence)

When we think of evolution, we tend to conjure up metaphorical "trees" of somewhat related organisms, plants and animals. We imagine how a primitive ape diverged into chimpanzees, gorillas, orang–utans and humans. We imagine how primitive fish started to occupy a partially terrestrial habitat. We imagine how various insects emerged from some segmented predecessor (and that in turn from an unsegmented ancestor). And we imagine how these various forms have intermediates that show a gradual and incremental divergence such that the evolutionary steps required are sufficiently incremental to occur within the available timeframe.

However, step back a little and think instead of how evolution is a tendency to an increasing complexity that is then edited by a process of survivor concentration. So, this can go right back to molecules and atoms. Galaxy formations are evolvent structures. Complex organic molecules are emergent structures. The universe is constructed out of a boiling turmoil of "virtual" particles that occasionally hit upon a sufficient complexity of interaction that leaves some parts more persistent. (Indeed, the very fabric of our atomic anatomy relies on a quantum generation of virtual particles with which our own "real" particles are "exchanged" in a sort of standing wave fashion.) This complexity slowly emerges into gas clouds, suns, planets, primitive organic matter and, ultimately, intelligent machines (biological or otherwise). The whole process is a demonstration of how entropy (and borrowing more energy than "you" are prepared to repay) can be encouraged to accelerate part of our environment into a faster homogenisation so that the other part is able to indulge in this complexity and establish, at least briefly, an increasing order. This complexity does not, automatically, dictate, more and more "cogs and wheels"; redundant "complexities" can be lost as well as gained if these chancy loss events prove viable. However, even these add to the overall complexity of variety and the complexity of the ecosystem.

Tolerance of gut microbes (nurturing? cultivation?)

It is no longer a question of whether this happens. However, the perspectives paraded in discussing it are still often coloured by the assumption that the IS should normally attack bacteria/foreigners because they are the "bad guys". However (and this is my opinion), the vast majority of bacterial species are benign when in contact with, or even introduced into, an uninjured human body. The pathogenic species must injure body cells to carry out their dastardly deeds. Once an immune response has been provoked by damage caused by one of the "nasty guys", the system then lies in wait until it senses a nibble from a new attack. At the slightest provocation (the sensing of the slightest new damage) the inflammation memory system (the adaptive IS) swings into action and encourages the more primitive shells of the innate system to focus on "swatting the wee beasties" – rather like you might feel a mosquito in action on your skin and splat it quickly, willingly sacrificing a few healthy skin cells in the swatting process. It is the fresh encounter with a particular damage pattern that is recognised (that, of course, includes epitopes typical of the provoking bacterial agent) rather than identifying it as "a foreigner".

Prelude to thymic tolerance (next section)

There is a devastating "hidden" assumption in the formulation of the science of immunology that still pervades much accepted dogma. When we approach immunology from the point of view that "it is battling, aggressive system" that seeks out and destroys "invaders (pathogens)" then we miss the lion's share of what it is really concerning itself with.

There is a vast "tsunami" of dying self cells that are tidied away by the extended immune system (that includes innate immunity, inflammation and various phagocytes). The volume of this debris is enormous but it is silently removed because our immune system tolerates and encourages this form of disposal. This provokes adaptive immunity just as potently as foreign organisms but the actions taken on re–encounter are quite contrary to the accepted dogma of an immune system dominated by aggression – or, worse, one that is exclusively aggressive. In fact, there is good reason to suspect that the immune system is dominated by tolerant responses. The aggressive responses are clearly apparent to us but probably represent an iceberg tip of immune activity. The "iceberg base" (the majority) is "under water" and it consists of tolerant responses.

The insistence that the immune system is dominantly (even exclusively) a defence system colours all our subsequent interpretations of what the system concerns itself about.

Thymic tolerance

The following is adapted (very slightly) from a response I recently submitted to a discussion in ResearchGate .

Start: It is important to keep the initial subject of this discussion group clearly in mind and anything I write, now, must have a clear bearing on it. Metaphorically, the Red Queen hypothesis implies that we are running simply to stay still. When this is applied to species vs species competition it is all too easy to assume that the primary goal is to learn, on the one hand, new methods to recognise and kill the opposition and, on the other, to devise new means of better cloaking your activity. However, you can win a war by starving your opponents out of resources; and of all strategies, this would be the best basis on which to start. Other mechanisms can then be bolted on as adjuncts. To me, the real Red Queen process lies with entropy; an animal looks very stable and organised but the gradient of entropy strongly favours disorganisation unless integrity is actively maintained. This is very much a process of continually running simply to stay still. To maintain order in a world where entropy favours disorder, we must continuously find energy sources, building materials (that themselves have a tendency to disperse evenly throughout the wider environment) and a niche environment where this can be achieved. So, a major problem arises once more than one species competes for the available resources whenever they occupy an overlapping niche. All subsequent evolution (unless extinction comes to one of the parties involved) becomes a compromising trade off and a continual vying with opponents for these resources. Resources are absolutely central; the management and the protection of them is a major goal of every organism that has ever existed since life began.

Now, the extant view, pre–1994 was, for almost every immunologist, that the immune system discriminated self from non–self. Self was learnt in utero by the elimination of all self reactive T–cells (and B–cells/antibodies) and the thymic system generated a population of immune cells that were ready and able to zap the rest. QED – immunity's overarching mechanism and purpose was explained.

Why do I think that the thymic processing of T–cells is relevant to the Red Queen hypothesis? What justifies many words – here – on this subject? Well, an alternative and newer view of immune function is that it is driven by the phagocytic/inflammatory processes in an animal. Inflammation identifies all sorts of debris. It listens out for the cries of distressed static tissues and responds vigorously. First, it delivers a deluge of phagocytic cells that look for anything that has the signature of debris, represents openly available energy or contains useful resources (micro–organisms included here as they represent the amoebocyte's primeval banquet). Included in this debris are membrane intact globules of apoptotic debris and spilt cytoplasmic debris (a nice meal for bacteria). It is important to mop them up, re–assimilate them, deny interlopers access to them and then, in the resolution phase, to restore order.

All the evidence, for me, points towards the Mhc system as a process for managing debris (both intra– and extra–cellular) and then presenting this debris as peptide fragments attached to Mhc molecules at the cell surface. The NK cell system probably uses the same process. I suspect it learns to recognise self Mhc associated with some pretty standard physiologically usual intracellular turnover products that are typical of healthy self cells. And it is on the alert for a sudden change from this pattern (frequently such a change is an indication of a viral invasion). So new viral peptide debris may suddenly populate the peptide grooves and this robs the cell of its "healthy self" identity. Interestingly, the second "cull" of T–cells in the thymus is of a population of cells very similar to this NK specificity and it is remotely possible that some of these are promoted into an NK like activity rather than being totally (clonally) eliminated. Whatever, this second filtering (culling or diversion into an alternative activity or disabling) is of T–cells strongly reactive with an Mhc+healthy–self peptide signature – of this "healthy" sort.

The first filtering in the thymus – and this filters out the large majority of incident precursor T–cells – is of those cells that have no affinity for self Mhc. I guess that this first filtering is NOT preoccupying itself with the Mhc groove. These cells – 95% or more of the incoming precursor T–cells, die by neglect and produce a veritable mountain of apoptotic debris that is efficiently and silently (no inflammation) cleared and re–assimilated.

However, it is becoming eminently clear that naïve T–cells (those that have escaped thymic filtering) do not come armed with a preformed intention to "zap" nonself. They remain naïve and available to be committed to tolerance (T–reg) or aggression (cells like Tc and Th); but this commitment is made in the context of the inflammatory environment in which they are encountered in the periphery. Precursor T–cells (fresh from the marrow and so far not filtered in the thymus) continue to be produced throughout life.

What this all means is that precursor T–cells are selected for self Mhc reactivity (perhaps excluding the peptide groove). The majority (no affinity) are redundant and die of neglect through apoptosis. Of the remainder, those that respond strongly to locally presented Mhc molecules (presumably loaded with healthy self / physiologically normal and common peptides) are in some way rejected from the pool of final responders. The remaining pool of selected T–cells have a lower affinity for the locally displayed thymic Mhc molecules. These become naïve – uncommitted – T–cells. The massive apoptosis that occurs regularly in the thymus probably leads to a substantial proportion of these naïve T–cells being committed, in the thymus, into T–reg cells and these actively suppress "self" reactivity once released into the circulation. The remaining naïve T–cells that escape the thymus circulate and are ready to be committed – on the basis of messy or tidy debris – into T–aggressor or T–suppressor cells. So thymic tolerance may well be pretty much the same process as peripheral tolerance.

See DOI : 10.1038/nri3155 for a good summary of thymic processing and the involvement of T–reg cells.

The upshot is that there is a strong argument for saying that the system is a debris management system. "Foreign" does not guarantee aggression – as many pathogenic organisms have discovered for they encourage apoptosis to get themselves tolerated. And it is fortunate that this is possible in our guts. Likewise "self" does not guarantee tolerance. When "the mess keeps coming" a persistent and substantial provocation is eventually able to overcome the T–reg down regulation of inflammation. Both thymic and peripheral tolerance may be overcome – but it is hard to provoke this. Adjuvant arthritis, however, shows how potentially easy it is to overcome it with a concerted attack of "mess". End.

The dominant, extant, view of thymic processing is that self reactive T–cells die by neglect. Is this view a true fact (a confirmed observation) or an assumption? Many precursor T–cells do die in the thymus as evidenced by their massive apoptosis in that organ. But, are these all self reactive T–cells? Or are they T–cells with no reactivity to unloaded or loaded self Mhc molecules (Mhc groove loaded with peptides)? The simplest explanation would be that precursor T–cells that "recognise" Mhc molecules (with low affinity) may lead on to the production of a population of naïve T–cells that are then ready to be committed to suppression or aggression when they encounter their appropriate Mhc/peptide epitopes in an appropriate melieu. One might anticipate that high affinity precursor lymphocytes are enrolled into a T–nk like activity rather than being deleted. These are points to be firmly established but the early evidence is favourable to at least some of these proposals. My guess is that the first filtering is to eliminate precursor T–cells that have no affinity for unloaded self Mhc molecules. The second filter is to divert those with high affinity for self Mhc and common degraded self peptide into an NK or T–nk profile. The last filtering is to select for the rest, those with lower affinity for self Mhc molecules (whose affinity may increase on peptide loading). Now, all the apoptotic debris in the thymus can commit appropriately reactive naïve T–cells into tolerance and then release this mix of regulatory (tolerant) T–cells and continuing naïve T–cells into the blood stream and thus the periphery. This makes much more sense and leaves central and peripheral tolerance as similar processes. These conjectures are "suddenly" allowed by adopting an alternative perspective to the microbe killing and immunologically aggressive system that older views have assumed.

Self/nonself discrimination

An early problem that immunology became encumbered with was a concept on self/nonself discrimination based on individual epitopes. This was formulated in the days when the immune system was regarded, exclusively, as a system of circulating antibodies. However, in retrospect, it was naïve to formulate this discrimination around a classification of epitopes into self or non–self. All self epitopes were believed to be learnt in utero and all new (stranger) epitopes then became the basis of an attack on foreign matter. This early assumption is understandable. However, it is astounding that this simplistic formulation is still barely acknowledged and remains largely unchallenged.

The regulation of effector class

There has been considerable discussion on the regulation of effector class in immune responses. For example, what provokes Tc responses or Th1 responses or Th2 responses or T–reg responses etc.. This can be extended to IgM, IgG, IgA and IgE responses. The solution to this conundrum might be more easily appreciated if we remember that inflammation acquires a memory by enlisting the help of adaptive immune responses. Now, innate inflammation has many facets and many specialised cells are involved; there are dendritic cells, Langerhans cells, M1 and M2 macrophages, polymorphs, eosinophils, basophils to name a few. It might be that the innate response that is evoked provokes a corresponding effector–class–response that amplifies this innate pattern on any subsequent encounter with a similar provocation. Should this be a valid interpretation then it could greatly simplify the investigation and understanding of the regulation of effector class.

Trying to usurp the hegemony of extant, perceived wisdom

I will progressively expand this section so these are early thoughts. Thomas Kuhn talked of "tautologies"; the emergence of perceptions that, in retrospect, become so obvious that it is hard to see they were ever regarded differently.

The greatest mis–conceptual skyscraper that I believe we need to topple is the conviction that the immune system is a pathogen hunting and killing system. The immune system – for many immunologists – hunts, identifies, chases and destroys invaders (pathogens). The exponents of this perspective generally see the word pathogen as a synonym for a potentially pathogenic micro–organism (potential here reflecting a tendency to cause disease in at least some of the multi–cellular creatures that are exposed to it). But, as the examples quoted in the introduction to "A proliferation of pathogens ..." article demonstrate, those that use this interpretation lose sight of the perspective that pathogen–equates–to–damage and start to use the word interchangeably with a "micro–organism–in–general". And they do so in a vacillating interpretation that they seem to remain unaware of.

There is no question, whatsoever in my mind, that a failing immune system does render us susceptible to infections. However, it is the failure to respond to and contain damage that leads to immune responses that we then interpret as specific adaptive responses against the infecting organisms. Epitopes of damaging micro–organisms will tend to be both novel (not previously tolerised following controlled–cell–shutdown then tidy–disposal) and exposed at the sites of cell damage. These epitopes will "favour" aggressive responses; but not because "they are foreigners and need to be zapped". Immune cells (inflammatory to adaptive) are rather like caretakers of a public building who will tolerate visitors provided they do not stray too much or start breaking up bits of the building. And these caretakers won't leave free lunches lying around that invite all and sundry to come along to enjoy the party. They will ensure that these visitors seek their sustenance elsewhere (except for those who are welcomed because they help).

The innate immune response is generally regarded as a rather primitive system that, on its own, can retain no significant memory of a past encounter with a specific "pathogen". This view is beginning to change as various papers surface suggesting that innate immune responses can be "trained" (for example look at Eur J Clin Invest 2013; 43 (8): 881–884 then locate it in PubMed for a list of related articles ). There are a few other articles describing invertebrate immunity where immune responses appear to be adaptive. This observation would have been regarded as heresy by past generations of immunologists. But, what all these articles fail to shout, from the rooftops, is that the adaptive arm of the vertebrate immune system is managed by the innate immune system (at both initiation and execution points) so that it acts as a memory for past pathogenic stimuli. The inflammatory response is thus quicker, more focused and more aggressive on re–encountering a similar pathogenic stimulus; and it can also be dampened down when not needed (tolerance). My guess is that the immune system has, throughout evolution, explored mechanisms for producing a "trained innate immunity". The so called "big bang" in immunity, set off by the incorporation of RAG genes, was probably a dramatic jump in this quest.

Injury and infection

Nature Immunology, this month (Oct 2013), has a series on tissue resident leukocytes. In the introductory article they say "Immune cells are found in diverse nonlymphoid tissues where they patrol against infection and injury and help to maintain homeostasis." because pathogenic organisms require injury to conjure up their repast, the statement can be contracted to "Immune cells are found in diverse nonlymphoid tissues where they patrol against injury and help to maintain homeostasis." When pathogenic organisms are recognised by adaptive immune cells it is because they have, in the past, been closely associated with some injury (damage). The big question is this: Is it now time to ditch this conviction that the adaptive immune system is primarily interested in infection? Are all such apparent "pathogen specific adaptive immune responses" just a manifestation of remembering the pattern of debris associated with damage?

Here's another: "Inflammation is an innate immune response to infection or tissue damage." Micro–organisms have nothing to "eat" unless there is damage and debris. "Inflammation is an innate immune response to tissue damage [full stop]." We don't need more.

A great number of different cells can (very likely) recognise, ingest, digest and assimilate micro–organisms. If they don't, then they have suppressed this ancient capacity for some "loss of old function"/"gain of new function" strategy. They may not do it as aggressively as phagocytes but they, quite likely, retain some amateur capacity to do this. Phagocytes do it more aggressively and efficiently: and with the vast proportion of microbes they do it without any need to go on to aggravate adaptive immune memory. Indeed, this would be metabolically wasteful. The ones that do aggravate adaptive immunity are the "damagers": these have strategies to macerate host cells in order to provide a repast (or they capitalise on coincident damage). This is the big point. Current perceptions, at least until recently, regard the response to microbial presence as an inevitable provoker of aggressive adaptive immunity. But, I propose, it is damage that is the inevitable provoker of aggressive adaptive immunity.

More on microbes and the immune system

The dominant current paradigm about infection is that the immune system (whether innate or adaptive) is needed to deal with microbial (pathogenic) invasions. Back in the 1870s and 1980s the adaptive immune system would have been considered the essential and dominant force; now it is the innate immune system. However, my bet is that virtually all cells derived from the fertilised zygote will retain some (effective) capacity to manage low grade infection (the presence of microbes – whether viral or bacterial) using bactericidal peptides and limited phagocytosis of and digestion of microbes. It is fulminating infection (a rapidly growing population of pathogenic microbes) that this low level immunity is unable to contain on its own. Fulminating infections need to generate suitable resources to fuel their proliferation. The intrusion of most microbes species into the host's tissues are probably dealt with effectively by the local population of cells before the microbes are able to proliferate. It is the pathogenic micro–organisms (the debris generating damagers) that manage to overpower this basic response and so trigger an inflammatory response.

Conception blinkers

The bug hunting, chasing and killing – war like – metaphor arms us with a set of blinkers that makes it almost impossible to escape this perspective and perceive anything else. Here is a very recent commentary on innate immunity.

"Innate immunity is activated by the recognition of a set of molecules that are found only on invading substances rather than on cells of the body. Any sign of things such as bacterial lipopolysaccharide, double–stranded RNA and bacterial flagellin will trigger an inflammatory response."

Well, no: this is not right. We already know that these TLR stimulants, associated with friendly gut bacteria, lead to tolerance. Otherwise we would destroy our intestines. Yes: (in my opinion) they do lead on to the activation of an adaptive immune response but the decision to provoke an aggressive or a tolerant response still depends upon an association with, or absence of, priming damage. In fact, lymphocytes are charged to reproduce the priming inflammatory (or non–inflammatory) milieu that was originally encountered in association with these TLR triggers. The commentary goes on:

"White blood cells, called dendritic cells, will engulf pieces of the invading organism and ferry them to the adaptive immune system command centres in the lymph nodes. It is here that the body plans the most successful and impressive attack on pathogens; producing tailor–made molecules to hunt down and destroy the attacker."

Well, no, again, in my opinion. They engulf all debris they encounter and it is particularly attracted to ingest debris that triggers TLRs. Indeed, the debris is a metabolic resource (including bacteria that are an anciently recognised food source for amoebocytes). For Tc and Th immune responses to occur, this debris is chopped up into peptide chunks by the antigen presenting cell's protein degradation system. Dendritic cells present representative peptides of this debris to the adaptive immune system so that an appropriate tolerant (inflammation suppressing) or aggressive (inflammation amplifying) immune response will be activated and reproduced on re–encountering this debris – when in its original stimulating form (eg, peptide displayed as an Mhc/peptide membrane "flag": it is tempting to regard this recognition as just the recognition of diverse allo–Mhc ligands). It is, of course, correct that it can favour the ultimate destruction of pathogenic (damage causing) organisms. But, it is only ramping up an inflammatory response when it recognises the memorised debris, presented on self self cells by self–Mhc/peptide molecules because it was previously associated with damage (Th recognition); OR, it is encouraging apoptosis of cells that previously died in an uncontrolled fashion (Tc recognition). Tc and Th cells do not recognise "pathogens". The apparent attack on micro–organisms is a "sideways" response; it occurs because peptide debris representative of the pathogenic stimulus (that may well include micro–organism debris) is either presented in an inflammatory milieu that provokes an aggressive inflammatory response or it encourages cells that display appropriate Mhc/peptide "flags" to commit suicide. Any microbe "killing" is a bystander effect of the adaptive immune acceleration of inflammation or it is effected by the apoptosis (and internal sanitisation) of infected cells.

Think about it !! Examine – every time it is paraded – the use of the term pathogen as a synonym for a pathogen micro–organism. Does this interpretation effectively put perceptual blinkers around the minds of the writers?

Immunological Reviews has just published an edition concerned with immunological tolerance. In its introductory paper it states, "The adaptive immune system endows vertebrates with the ability to identify and target pathogens for elimination during primary infections and to form memory cells that provide accelerated responses and/or protection upon subsequent encounters with that pathogen." Well let's rephrase that: "During primary infections, the innate immune system endows vertebrates with an ability to process the debris generated in the wake of infection by the respective pathogenic organisms. The adaptive immune system can then be triggered to encourage an accelerated inflammatory response (that enhances protection) upon any subsequent encounter with debris characteristically generated by that pathogenic organism." This is particularly true of cytotoxic and helper T–cells that recognise Mhc/debris combinations and these must be encountered in the same form to be able to trigger subsequent recognition (ie, processed debris – short peptides cradled in Mhc grooves). It is not the native "pathogen" that is recognised and attacked.

Antibodies are different. However, we can view B–cells as "targeting phagocytes". A B–cell only ingests debris that displays, somewhere on its structure, an epitope that is "grasped" by the immunoglobulin cell surface receptor that is then gathered in for ingestion; this debris is then processed by the B–cell into representative peptides that are then presented as Mhc/peptide membrane "flags" that can be "recognised by T–helper cells. These T–helpers enable the clonal proliferation of respective B–cells and then their clonal expansion into plasma cell "antibody factories". Now, on fresh encounters of the same B–cell Mhc/peptide (processed) peptide debris, respective B–cells can be clonally expanded, very rapidly. This requires the same conditional presentation in the Mhc molecule's peptide groove and then recognition by the previously primed T helper cells. Effectively, the B–cell – by enabling the release of freely circulating antibodies – is endowing all the innate immune system with an ability to capitalise upon this same specialised way of recognising specific, targeted debris. Antibodies simply amplify the ingestion and subsequent peptide–fragment–presentation of the antibody–tagged debris.

In Janeway's Immunobiology (8th Edition) there is a header that reads "Pathogens can damage tissues .... ". Whoops. This should read "Pathogens damage tissues .... ". Even if it were written as "Pathogenic organisms" the same would apply. We should be referring to the damaging property when we call an organism a pathogen.

Class control

I am not sure if I have addressed this before (a quick search for class + control suggests not). This has become a topical subject for some theorists. My two–penn'orth on this is that we need to keep in mind the "purpose" that seems to have emerged on the reason for employing an adaptive immune system. It acts as a memory for inflammatory stimuli; the initiation and control of the adaptive immune system is "inflammocentric": inflammation triggers it into remembering the inflammatory or non–inflammatory milieu of previous peptide debris encounters (even the B–cell system requires Mhc+peptide permission to turn into plasma cell antibody factories). This acts as a memory and (contrast) amplifier for inflammation: damaging or safe is turned from shades of grey towards exaggerated "black or white". So, the obvious conclusion is this: it is inflammation that triggers the adaptive system into reproducing and amplifying its preferred initial (innate) response – inflammation retains command and control. Class control is handed down as an amplification of the appropriate class of innate response.

Wound induced polyploidy

Her is an interesting point. In this article the authors discuss the "use" of polyploidy as an initial mechanism to restore tissue structure. Local cells swell and become polyploid in a first pass (?) technique to restructure tissues. So, there seems to be a positive reason for these apparently miscreant cells and – of course – they are very characteristic of tumour tissues.

The immune (or morphostatic) system may have evolved from an allo–competetive system

In case you are wondering, allo– infers "from a related zygote derived colony" from the same species. This contrasts with iso– that infers "from an identical zygote derived colony" (eg, monozygotic twins where transplantation between individuals mostly succeed because they are iso–grafts). When we look at the T–cell system (including natural killer T–cells) we can see that the system is preoccupied in paying attention to allo–specificities. Foetal conditioning in the thymus selects for T–cells that can recognise iso–specific elements of the Mhc molecules and then selects, from this pool, those that can be subtly altered, by a single short peptide chain, to look like allo–specificities. In this way, debris within the cell can then redeploy this ancient allo–recognition (often competetive) system as an "altered self" alerting system. Not all "altered self" needs destroying – quite the contrary; only those that are presented along with cell damage need to provoke an aggressive response.

There is a nice – readable – article in "Reefkeeping" magazine that acts as a good introduction and gives references to appropriate research articles .

Aging

Science daily has just published a bit on the immune system and aging . It gave the illusion that we could alter the intrinsic longevity limit. This prompted me to add this bit. We are (almost certainly) genetically programmed to die in a (roughly) bell shaped normal distribution (perhaps with a tail) around 92 for males and 95 for females. There are a lot of epigenetic things that we can do to improve our longevity (as attested by modern survival rates). However, short of substantial alterations to our genetic code, all we can do is to drag out our longevity rectangle to get ever closer to a square shape before it will drop off vertically around this 92–95 year limit. Those that survive to 110 (or more) are probably (genetically) many standard deviations out along the normal distribution around this 92–95 limit. The figure here illustrates this. It shows the improving life expectancy distributions from past centuries (lower left curve) towards our current expectation and beyond (upper right curve). Better birth management, child care, immunisation, diet, avoidance of smoking, low alcohol intake, lots of exercise, limited calorific intake, loads of live plant food, good housing conditions, antibiotics (given sparingly and in real need), medicines, surgery, seat belts, cocooned cars vs open motorbikes, speed limits, avoiding fighting/war/trauma, health and safety at work (and etc) will all help to drag the life expectancy curves out towards the top right hand corner. But, once you are into your early to mid 90s, whatever you do, your genes are going to get the better of you and any slight pathogenic stimulus is going to tip you across your limit. This is well illustrated by vO2 max (cardiovascular fitness) assessments. They can be dragged out in the same "fill up the oblong" fashion with appropriate vigorous exercise. However, come the mid/late 80s, whatever you do, your vO2 max will start to fall precipitously.

Specific and non–specific pathogenic stimuli

I have suggested that the adaptive immune system, rather than remembering a specific pathogen, is remembering the signature of a specific pathogenic stimulus. This signature is likely to be made up of a suite of epitopes that are encountered when a certain pathogen (pathogenic agent) provokes its disease. The biotic or abiotic nature of the pathogen is not yet assumed; it could, for example, be abiotic (like asbestos fibres) or biotic (like measles virus). Non–specific pathogens, like trauma, do not expose or present strange epitopes to the adaptive immune system. All they present, unless there is wound contamination, is damaged self tissues. Specific pathogenic stimuli are those suites of epitopes that include a number of unusual molecules that have not been previously encountered as part of tidy apoptotic debris (this latter is the suite of epitopes that induce adaptive immune system tolerance). These strange epitopes will be presented along with non–specific epitopes (damaged self) and the "job lot" provokes an adaptive immune response. This is why we are left with the illusion that microbes are actively "hunted and killed", because strange epitopes provoke specific antigenic responses. Micro–organisms regularly (but not inevitably) present strange epitopes that can than be utilised as the dominant pegs upon which to hang a focalised and very aggressive inflammatory response.

Tissue homeostasis (summary)

(This is adapted/personalised from something I read elsewhere – I have lost the source)

Homeostatic equilibrium is achieved by:

"The origin of immunity is in the management of the microbiome"

This theme is becoming increasingly popular. By this view, the primary "purpose" of the primordial immune system is to manage the microbiome. Managing pathogenic organisms, by this view, came later. Now, I can appreciate that the proportion of non–pathogenic microbe to pathogenic microbe species is very heavily weighted towards non–pathogenic species. In consequence, the activation of adaptive immune responses are, equally, heavily weighted towards responding to non–pathogenic commensals/symbionts (effectively, the microbiome). However, this can be equally viewed as "how to respond to micro–organisms" in general based on

Now we can see that tolerance can be enrolled to respond to non–damagers and aggression can be enrolled to respond to damagers. Equally, non–damagers that regularly get presented alongside some repeated but unrelated damage signal will probably provoke a similar aggressive adaptive immune response. And the corollary to this (tolerance induction) may be favoured when presentation is associated with a coincident but unrelated tolerance inducing circumstance. If this observation is valid then "the origin of immunity" rests with tissue homeostasis/integrity; the microbiome must favour homeostasis if it is to be tolerated.

Critically, this "management of the microbiome" view has, once again, pegged "the purpose of the immune system" to the management of microbes. This is reminiscent of the original "splat the bug" conceptions of the immune system. Here, the management of pathogenic organisms was universally regarded as its overriding purpose (lasting from the early realisation that the immune system is active during infection through until at least the early 1990s). This ignores any role the immune system may have in all other pathological processes (eg, damage management – particularly response to cell death, cancer, neoplasia in general, regeneration, the metamorphosis of form from infants to nonagenerians, in metabolic homeostasis and so on).

More on "pathogens"

Today (21st Oct 14) Science daily posted this comment "The house fly genome has been sequenced for the first time, revealing robust immune genes, as one might expect from an insect that thrives in pathogen–rich dung piles and garbage heaps." What this should have read is "The house fly genome has been sequenced for the first time, revealing robust immune genes, as one might expect from an insect that thrives in micro–organism–rich dung piles and garbage heaps." A few of these micro–organisms might, indeed, be capable of pathogenesis but this highlights the interchangeable (and incorrect) use of pathogen to mean micro–organism.

And still more on "pathogens"

Science has just presented an article in which it says this, "Human skin, the body's largest organ, functions as a physical barrier to bar the entry of foreign pathogens, while concomitantly providing a home to myriad commensals." (The emphasis is entirely mine.) So what is a "foreign pathogen"? This seems to me to be a strange mish–mash of confused perceptions. It encompasses "the skin (and immune system?) responds to foreigners"; it encompasses "pathogens are microbes"; it seems to imply that "commensals are not foreigners" (or for that matter capable of being pathogens). To me, this simple phrase immediately confuses the issue of what is really happening.

This all points back to the point, "Show me how the cellular adaptive immune system (vs antibodies) directly attacks micro–organisms (M–Os)." My challenge is that you cannot. It can encourage (self) cells (displaying a peptide/Mhc_Class_I signature that was created from the debris of a M–O) to go into premature apoptosis. It can amplify an inflammatory reaction in the vicinity of a peptide/Mhc_Class_II signature and this makes life uncomfortable for proximal M–Os. However, there is NO direct attack on the M–O. Antibodies, also, tend to prepare their target for enhanced inflammatory (phagocytic) clearance. The only exception is where a M–O may be sickened by strong C8/C9 complement deposition on its membrane. They can also disable the M–O's pathogenic mechanism to make the M–O impotent in attack. Otherwise, the antibody/complement interaction opsonises the M–O ready for inflammatory (phagocytic) attack. Why do immunologists persist in insisting that the M–O is directly attacked by adaptive immunity? Without an inflammatory effector mechanism, the adaptive immune system is impotent (even apoptosis encouraged by Tc cells needs phagocytic clearance).

More on perspective distortion

Cell have recently published an article on apoptosis and how it is "hidden" from the immune system. The article abstract states ". . . (this) has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production . . .//. . . Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent." This is how Science Daily reported it: "The research answers a decades–old mystery about the death of cells, which in some situations can alert the immune system to potential danger, but in other circumstances occurs 'silently', unnoticed by immune cells. /p/ Silent cell death, or apoptosis, is a controlled way for the body to eliminate cells that may be damaged, old, or surplus to the body's requirements, without causing collateral damage. This 'normal' cell death process is ignored by the immune system. In contrast, the death of cells at sites of infection or damage can alert the immune system to be on the lookout for danger."

So, apoptotic cell death does not trigger an immune response then!! This, surely, just continues the fuzzy thinking that is inherited from traditional perspectives of the immune system acquired from the perception that it is "a bug hunting and killing system". I will bet heavily on the following. ALL debris is processed by amateur and professional phagocytes. Dendritic cells are specialised phagocytes that efficiently process such debris for the attention of the adaptive immune system. ALL debris provokes an adaptive immune activation of some sort if appropriate paratopes can be activated. It is the balance of tolerance to aggression that is skewed by apoptosis; not the presence or absence of a response. To say that apoptosis is hidden from the adaptive immune system is – I contend – almost certainly WRONG, WRONG, WRONG.

Most cancers are just 'bad luck'

There is currently (new year 2015) a great deal of discussion around a study published in Science that is titled "Variation in cancer risk among tissues can be explained by the number of stem cell divisions." The authors reach the following conclusion, "These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to 'bad luck', that is, random mutations arising during DNA replication in normal, non–cancerous stem cells." This was in the editor's summary, "Remarkably, this 'bad luck' component explains a far greater number of cancers than do hereditary and environmental factors."

This has led to a welter of comments including:

[BBC] "Most types of cancer can be put down to bad luck rather than risk factors such as smoking, a study has suggested. ..//..The results, in the journal Science, showed two thirds of the cancer types analysed were caused just by chance mutations rather than lifestyle. ..//. . The study shows that two thirds of cancer types are simply chance. But the remaining third are still heavily influenced by the choices we make."

The science reporter goes on, " .. old tired cells in the body are constantly being replaced with new ones made by dividing stem cells. But with each division comes the risk of a dangerous mutation that moves the stem cell one step closer to being cancerous."

Now, this is all very strange and there is (in my opinion) something wrong with the interpretation. Let me quote two passages from my unpublished papers.

From Morphostasis and immunity 1984: "Cancer is characterised by disturbed growth control and a reversion to an embryonic cell behaviour (retrodifferentiation). These conditions seem most likely to occur when regeneration and/or proliferation (eg, T–cells in 1ymphomas) are exuberant. There is an inverse relationship between, regenerative capacity and cancer in the animal kingdom and it is worth noting that carcinogens may induce supernumerary structures (eg, limbs) in lower phylae. Note that lymphomas will be relatively common in the years in which auto–rejection can become intense (16–45yrs) and also note that lymphomas will predominate over other cancers in granulomatous disorders because local regeneration is impaired."

From Clinical Morphostasis: "In mammals, this impairment of surveillance should occur either at the extremes of life or following prolonged focal auto–rejection and its consequent anergy. In the elderly, the increasing impairment of immunity coupled with the heightened susceptibility of epithelium to various noxiae (and thus auto–rejection) may predispose to a high incidence of carcinomas. Focal anergy on its own (consequent upon intense auto–rejection) may be a major cause of the predilection that certain cancers have to strike young adult to middle aged patients (eg, lymphomas, focal cancers like colonic cancer in ulcerative colitis and testicular tumours following mumps). In the very young there is a relative incapacity to reject tissue. It is worth noting, then, that the predisposition for epithelial cancers found in the elderly is not mirrored in the young. Cancers are relatively common in the very young and there is evidence to suggest that many regress before they reach clinical significance. Note that carcinoma–in–situ occurs more often than overt cancer, the abnormal cells tend either to be kept in check or are eliminated by lympho–monocytic cells."

This predominance of cancer in the tissues most exposed to high regeneration never tempted me into the same conclusions aired above (that the majority cause of cancer is just 'bad luck'). And this despite the prediction that highly regenerating tissue would be more susceptible. So why? It has taken me a while to escape my perceptions of the process in order to appreciate why the authors stated, "These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions." I think we need to take a step back and examine the paradigm that governs the interpretation of these observations. The traditional view of cancer is that it is a genetic disease caused by mutations. Traditionally, the acid test for carcinogenicity has been whether an environmental agent can cause genetic mutations in exposed cells (bacteria are usually used). There is no place in this paradigm for non–genetic causes. Every time a suitable set of cancer favouring mutations arise, they go on to produce a full blown clinical cancer. End of story.

This study appears to support the notion that particular tissues within the body are increasingly susceptible to the emergence of cancer as the level of regenerative activity increases ("appears" because I can't read the full original without buying it at a silly price). In dismissing environmental "triggers" as the dominant cause of cancers and substituting the frequency of stem cell divisions it conveniently ignores the point that such enhanced stem cell activity has either immediate (noxious) triggers or is an evolved adaptive and pre–emptive response to this noxious threat (shedding epithelium rapidly will enhance the clearance of noxiae). The underlying result is an enhanced auto–rejection and then replacement of damaged cells. This exposes the system to a heeightened prevalence of mutations.

The authors talk freely about "tissue homeostasis". Now, I think it is around this that the conclusions that many folk are reaching have been blown out of proportion. The majority of the stem cells that develop a mutation, that could lead on to cancer, are dealt with by a sophisticated tissue homeostatic process with its intrinsic surveillance for miscreant cells. Only a tiny fraction of these miscreant cells go on to turn into full blown cancers and the circumstances under which this happens is heavily influenced by age, inherited predispositions, concomitant disease, environmental factors and epigenetic factors. The original mutation, though generally necessary, is not sufficient to lead on to a clinical cancer. The failure of tissue homeostasis is the final arbiter on the emergence of clinical cancer. (Note how the individual cells from some teratomas can be cloned to produce normal embryos – hence I have qualified the statement by "generally" necessary). This paper from Rozhok and DeGregori is highly relevant to this point.

The short section on cancer and stem cells ""The danger theory: 21 years later" (unpublished section) makes all this a little clearer I think.

The BBC World Service have a nice little audio snippet about this. And, interestingly, this has just turned up in Cancer Research . Also, Researchgate currently (Jan–15) has a discussion on this Science paper to which I have also contributed . You may find more insights there.

Entropy, evolution and life

There is a fairly persistent point of view that alleges that entropy runs counter to the spontaneous emergence and evolution of life. This alleged incompatibility is frequently paraded by the more fundamental religious groups to prop up their assertion that life must have been created, in genesis fashion, by a deity. However, this assumption is based on the premise that entropy is synonymous with disorder; and that is wrong. States of low entropy have a natural tendency to flow to states of high entropy. What does this really mean? We can restate it simply by saying that concentrations of high energy (equivalent to highly improbable states that want to "flow" to more probable states) are unstable and will redistribute to a state of homogenous distribution – unless they are maintained. So, for example, if we stuff all the air molecules in an airtight box into the top right hand corner – and then release them – the molecules will redistribute themselves so that there is virtually no potential (pressure) difference in any macro– or micro–scopic part of the box ("virtual" because at anything above absolute zero temperature there are always microscopic peaks and troughs, viz, Brownian movement). We are now no longer able to devise an engine to extract work from the system. Order is something that is highly coloured by our anthropocentric perspectives. We make a motor car and marvel at its order then get upset when it starts to rust, gets damaged or breaks down. Entropy, itself, treats our man made order as something that will eventually disperse into bland homogeneity (for example, a sandstone city into sand). We are only able to stop it if we borrow from some available energy source to repair the disorder that is the consequence of this slide into macro– and micro–scopic homogenisation. Now, wherever energy flows from a concentrated focus to a diffuse homogenised state, it rarely does so in a smooth and bland manner. The energy flow induces eddies that, from our human perspective, take on the perspective of order. For example, look at a mountain river flowing down through a cavern. Here, there are lots of whirlpools, eddies, and standing waves. An attractive order emerges in this hectic flux of energy as it goes from high to low potentials. It only disappears when the flow ceases. The big focal energy concentration, for us on Earth, is our Sun. Without it, all energy flux from the sun (that flows into our ecosystem and is then radiated out into deep intergalactic space) would come to a virtual standstill and all the fractal vortices (of which mammalian form is just one complex example) would cease to be "fuelled"; and they will homogenise. Our animal form is just a complex, fractal based, series of eddies that owe their existence to differential energy fluxes. We will eventually go (ashes to ashes and dust to dust) the same way but by using a slingshot technique, we can send some bits to their homogenised "doom" earlier than others and create the illusion of some permanence. Genes are the very epitome of this process. They are like standing waves that claw themselves, in a counter–current of semi–permanence, though this hectic flow of energy and form.

Direct "pathogen"/microbe killing by the adaptive immune system

I know that this is repetitious but only constant repetition will eventually encourage people to pay attention.

The opinion – that the adaptive immune system directly attacks "pathogens" – sticks like a limpet.

Think about it.

Can lymphocytes or antibodies directly kill or eliminate anything without enlisting the co–operation of more primitive (innate) immune mechanisms?

Cytotoxic T–cells encourage cells to commit suicide when they display the Mhc/peptide debris–products derived from the processing of internal pathogenic micro–organisms (or abiotic pathogens). These cells are encouraged to sanitize their contents (a very primitive innate immune mechanism). This is NOT a direct attack on the "pathogen". Helper T–cells recognise the Mhc/peptide debris–products that APCs (phagocytes) have ingested and processed. They cannot recognise and respond directly to the "pathogen"; it MUST be processed first. When it does recognise this Mhc/peptide–debris it ramps up the local innate immune activity. The latter is what "kills" the "pathogens" (and gives local self cells a hard time too). I suspect that B–cells are specialised (targeting) phagocytes that are, probably, originally intended to target specific developmental tissue debris (eg, resorbed stuff like finger webs). This system has been "licensed" to other, more extrinsic, debris by enabling the B–cell (as an APC) to stimulate helper T–cells. Once again, what is recognised on re–encounter is the processed debris that the B–cell has ingested and then presented in the Mhc groove. It is the presence of locally processed debris, processed by an APC, that encourages a ramping up of local innate immune aggression. Again, there is no direct attack on the "pathogen". The closest we come to a direct attack is by the immunoglobulin led "opsonisation" of directly recognised "pathogen" epitopes. BUT – this simply leads to an enhanced, focalised, ramping–up of the complement (primitive innate immune) system that will still avoid excessive damage to healthy self cells (through complement inhibitors).

T-cells and antibodies do not directly attack "pathogens". They generate a large repertoire of receptors that are able to recognise cell(Mhc class I)/phagocyte(Mhc class II) processed biological debris. This processed debris is then assigned either an aggressive or a tolerant association. These can then be used to reproduce a caricatured (aggressive) inflammatory or a (tolerant) non–inflammatory milieu on any reencounter.

Isn't this incontravertible?

A useful way of regarding this is to realise that T cell receptors are predilectively focused on allo-mhc ligands (a clue that the vertebrate immune system evolved from ancient mechanisms of colony interaction – not necessarily or inevitably competition). In practice, debris is processed and presented in the peptide groove of self–mhc ligands. This produces peptide–modified–self–mhc ligands. These modified self ligands have the properties of allo-mhc ligands. It is always modified self ligands that are generated as a consequence debris processing. There is no direct T–cell attack on foreign antigens.

Innate immune memory

This month's Nature Immunology (August 2015) has an article on "Innate immune memory: a paradigm shift in understanding host defense" . This commentary presents some clues as to why the obvious may have been missed; the obvious, here, being that the adaptive immune system acts as a memory for past inflammatory encounters, rather than it being a system that memorises invading (micro–)organisms (generally referred to as "pathogens" but what I prefer to call "pathogerms").

They state: "The consensus until recently was that [innate immune cells] mount nonspecific responses and they are not able to confer immunological memory on their own. In contrast, the adaptive T cell– or B cell–dependent immune responses are antigen specific and they often provide lifelong protection against re–infection." Implicit in this statement is the continuing assumption that adaptive immunity targets and attacks micro–organisms ("pathogens") directly. It ignores the point that it is damage–associated–then–processed–debris that initiates aggressive immune responses. If the "debris" is dominantly from apoptotic bodies (with some excess of panic [damage] signalling) then Class I (CD8) responses are invoked. If it is dominantly phagocyte–ingested–spilt–cytoplasmic–debris, then Class II (CD4) responses are invoked. The effect of the CD8 response is to encourage an expeditious apoptosis of similarly tagged self cells. The effect of CD4 responses is to ramp up the innate immune response (inflammation) in the vicinity of phagocytes that display processed and memorised peptide fragments on the cell exterior, within the peptide grooves of Class II Mhc molecules. What is recognised is self phagocytes displaying (phagocyte) processed debris that the phagocyte had earlier ingested as debris and that was associated with spilt and damaged cytoplasmic contents.

Note that the free antibody response (plasma cell derived circulating antibodies) is more complex and more apparently a direct attack on "pathogens" ("pathogerms"). However, for all but IgM responses, the licencing of plasma cells (to produce antibody) involves CD4/B-cell co-operation and is similarly restricted to peptide–in–self–Mhc–class–II presentation.

I can only access the first page of this article so I do not know if they have addressed this aspect of adaptive immunity (a memory for pathogenic events – assuming that the word pathogen means any damaging agent whether biotic or abiotic). However, I suspect, from the abstract and introduction, that this is not discussed.

Fibrotic repair.

It has been an ongoing puzzle to me as to why the repair of so much human tissue–damage leads to fibrosis. This reaches a zenith of intensity in burns. I have long suspected that it is a "panic driven" response. I now wonder if I have had some insight into this. It was an expeditious exchange on a Researchgate discussion forum that focused my attention on a recent article in the EMBO jornal . In an earlier response, Andrey Luchnik had asserted that wounds never heal from stem cells; he insisted that this was always from fibroblasts. "Always" is a alerting word in science and particularly bio-medicine. You can bet your bottom dollar that you are missing something (eg, cartilage never repairs/regenerates; it might not be good at it but we would all be seriously arthritic by our teens is this was absolutely true). So, armed with this paper on cancer (below) and wounding in zebrafish, it occurred to me that the inflammatory response is looking around for cells that show promise for regeneration. Where there is a struggle for dominance in some ecological arena, it is important to assert a clonal population dominance. The early stimulation of a suitable cell proliferation can help assert this dominance in the altered ecosystem of the wound. Suitable cells probably display at least some degree of stemness (less committed differentiation). In panic, neutrophils (the cells identified in the papers above) will choose the most available; these include fibroblasts and other mesenchymal stem cell related populations. These may have varyious degrees of differentiation. As this EMBO paper shows, they will also stimulate appropriately mutated, pre-cancerous cells. (A recent study shows just how common these pre-cancerous cells are .) With less panic, the best source, the dedicated tissue stem cell niches, could be enrolled into a scarless regeneration. Our bowels are well equipped to – scarlessly – replenish the intestinal epithelium. So, by stimulating fibroblasts in panic, we are probably forfeiting the opportunity for faultless repairs (which various observations indicate are possible). A number of stem cell niches are well recognised; the basal layer of the epidermis, the base of the hair follicle, intestinal crypts, at least a proportion of blood vessel pericytes and other niches in many other organs.

Immature immune systems

A recent article in Trends in Immunology writes this in the abstract (I cannot access the full text): "Exiting from the largely sterile environment of the womb, the neonatal immune system is not fully mature, and thus neonatal immune cells must simultaneously mount responses against environmental stimuli while maturing." They continue: " . . . shed light on the mechanisms by which they drive immune maturation." I have bone to pick with the metaphor "mature" and "maturation". These have an emotional baggage that suggests that they are "not ready" in some way or that they are ill-adapted to the new environment. The liklihood is – for me – that the infant immune system is very well adapted to its needs. It is very likely that a "mature" immune system would stunt growth and scatter unwanted scar tissue in gay abandon. I would reword this as: " . . . the infant immune system is optimised to encourage rapid growth and development and this limits the allowable intensity of auto-aggressive defence strategies. It is only as the animal reaches its fully grown state that the animal can allow piecemeal destruction of suspect self tissues as a defence mechanism." The original statement perpetuates the "fight the microbes" purpose/perspective of immune function whereas optimal "tissue homeostasis" may be its real role. In growing animals this "tissue homeostasis" must also accomodate the need for continuing development and growth of the individual into "maturity" (effectively – optimal reproductive capacity).

What is the "immune system's" response to non-damaging micro-organisms?

I keep reading comments similar to the following statement and wonder how apposite they are: "Inflammation is a key host defense response to infection and injury, the aim of which is host protection against pathogens, regeneration of injured tissues, and re–establishment of tissue homeostasis." What if a potentially infective organism gets into body tissues and causes little or no harm? If it were to cause harm, then the cascade of subsequent events may have far more to do with the harm inflicted than the mere presence of the organism. This is one of those situations where observation is likely to conform to hypothesis. The consequent events will be attributed to "inflammation is a response to "pathogens" where "pathogen" is a loose term for micro–organisms. Should we have said pathogenic micro–organisms we could then have held in view the point that the inflammation cascade is a consequence of damage and its intensity consequent upon the degree of damage. If all cells have some capacity to ingest micro–organisms (a throwback to their primordial amoeboid origin) and resident sentinel phagocytes (eg, dendritic cells) are also ready to eat these micro–organisms, then the capacity for these organisms to proliferate will be limited. The first, obvious, cause of tissue damage – before the micro–organism releases any of its pathogenic armamentaria, if it has any – is its insinuation between host cells and the disruption of their junctions (I would interpret this as "damage"). And that depends upon them finding suitable nutrients. Without pathogenic mechanisms or collateral damage, it is probably going to be very hard to find such nutrients. I think that we can reword the whole scenario like this: "micro–organisms are usually phagocytosed (by amateur or professional phagocytes) once they are encountered and do not, generally, lead to significant tissue damage. Pathogenic organisms need to generate damage whilst opportunistic micro–organisms need to rely upon collateral damage. Neither of them are able to proliferate in the tissues of a host without the presence of significant damage." This tendency to ignore the importance of damage leads to the idea that a function of inflammation is to actively eliiminate "pathogens" (micro–organisms meant here); inflammation suppresses infection – it does not aim to eliminate it. This suppression often leads to the apparent elimination of the micro–organisms but only becaue it gives them a hard time or they are treated as suitable "food" by just about every cell in the body; not just by inflammatory cells.

Our immune system evolved to . . . .

These are typical and extant statements:

I am going to suggest a rewording that makes things clearer – I think.

Our adaptive immune system evolved as a debris classification system. This debris has been processed within a cell and broken down into short peptides. It is processed either in the cytoplasm of any cell (Class I / CD8 processing) or within the phagosomes of an antigen presenting cell (Class II / CD4 processing). These peptides are displayed on the cell surface attached to self Mhc molecules. The appropriate T-cell receptor recognises these Mhc/peptide complexes NOT as "pathogens" (micro–organisms) but as self cells, identified by self Mhc, subtly modified to act rather like an allo–Mhc ligand (altered self). The "pathogen" (micro–organism) is never recognised by T–cells in its native state; what is recognised is the debris that its earlier demise has generated within a cell. This cell has (necessarily) broken down the organism and "trashed it" into short peptides to display these (in an Mhc groove), on the cell membrane, as a signature of the internal "turmoil" that it is experiencing. The micro–organism must have already died and been disposed of for it to have rendered this peptide available for loading into the Mhc groove. Naive T–cells that interact with an appropriately specific Mhc/peptide (which can now be regarded as an epitope) can be committed to tolerance or aggression. This is done according to the usual inflammatory/non-inflammatory milieu in which this epitope is encountered so that this milieu can be rapidly exaggerated on reencounter. To repeat, this debris is recognised by T-lymphocytes but only as processed peptides resting in the peptide groove of Mhc molecules. This means that the parent protein has already been processed and degraded within a cell then "hung out" for display. It is not the parent protein that is recognised; it is the processed protein – broken down to a peptide – that is recognised. All subsequent "actions" lead to an exaggerated reproduction of the inflammatory/non-inflammatory milieu typical of its triggering encounter. Effectively, this provides the inflammatory process with a memory. T–cells DO NOT recognise and interact with the native "pathogens" (micro–organisms).

"There is – arguably – no such thing as an immune system . . . .

I think I need to make it clear what I meant in this statement as several groups seem to have seized on this to support their personal viewpoints without clearly grasping my meaning. The conventional view of the immune system (and especially the adaptive immune system) is that it is a dedicated microbe hunting and killing system. My opinion is that the immune system is overwhelmingly dedicated to noticing and responding to pathogenic stimuli (tissue disruptions). If you are an animal that predates on another animal that you use for food (nutritional and energy resources) then it is hard to imagine how this predation can be carried out without you damaging the animal that you are eating. The damage is pretty obvious. Most bacteria living around animal bodies are opportunistic heterotrophs – they feast on dead/dying/decaying organic matter; they are detritophiles. Most are polite and wait their turn; and they do an important and essential job in keeping the local (and cycling) ecosystem healthy. A small group of bacteria, however, will not patiently wait their turn. They create foci of damage and premature decay within their targeted host. They are pathogens; this word means nothing BUT that they are agents that damage tissues. Impact injuries, radiation injuries, pathogenic microorganism injuries, asbestos provoked inflammation and many more are all pathogenic stimuli. When particular agents can be identified as the cause of the damage, these can all be regarded as pathogens. Pathogen says nothing about the living state or microorganismal properties of the agent. It simply reflects the point that it has damaged tissues. Our "immune system" is really a morphostatic/tissue homeostatic/integrity protecting system. It is constantly identifying the debris provoked by pathogenic (and not so pathogenic) stimuli and processing this ready for presentation to anamnestic ("memorising") immune cells. The context of the presentation of this debris is thus remembered so that the intensity of the response can be ramped up (if the previous encounter was "messy") whenever it is re–encountered. The "attack" is a mindless ramping up of the inflammatory response in the vicinity of this re–encounter of previously classified debris. The conventional view is completely blinkered by the belief that it mounts purposeful attacks on micro–organisms. It simply classifies what was previously damaging as probably dangerous and in need of extra aggressive attention. The capacity of various cells to "eat" micro–organisms (as a nutritional resource) is an anciently aquired one that is simply exaggerated in various phagocytes. "No such thing as an immune system" is simply a provocative statement to emphasise that the adaptive immune system does not remember micro–organisms: it just remembers debris patterns found in damaged tissues.

 

More to follow ......?