On-line debates

My contribution to the Researchgate "Red Queen hypothesis" debate.

(grammar alterations are in italics)

"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 being a process for managing debris (both intra- and extra-cellular) and then presenting this 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 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 at this stage). 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. This remaining pool of selected T-cells have a lower affinity for the locally displayed thymic Mhc molecules. These become naïve V uncommitted V 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 is 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".

My contribution to the Researchgate "Custodial" debate

"I like the metaphor of "integrity". I have well formed views on this subject (easily found). What follows should be viewed as opinion.

The "integrity process" can respond to a whole range of disruptive biotic and abiotic influences or agents. These pathogenic influences can be grouped under the term "pathogens". "Pathogen" is a generic term and its common – specific – restriction to mean only a pathogenic organism is just a lazy abbreviation. Integrity resolves crises and then restores order. "Order" itself is a helpful metaphor and this is most pertinent when applied to an animal or plant's interaction with micro-organisms. I will restrict my comments here to bacteria. Most of these are identifiable by their Microbe Associated Molecular Patterns (MAMPs rather than PAMPs: if I had my way, I would permanently retire the PathogenAMPs acronym). Only a tiny fraction of the extant microbial species act in a primarily pathogenic way. However, a very large proportion of microbial species fulfil the important task of degrading the dead and dying tissues of plants, animals and other organisms. In this way these corpses are recycled. All but the pathogenic organisms are courteous and usually wait their turn until the animal or plant dies or become so sick that it is no longer capable of stemming the tide of entropy. Pathogenic bacteria, however, adopt the strategy of, somehow, damaging healthy host cells to provide themselves (discourteously) with a premature meal. They use a variety of means to do this; the direct injection of toxins; inhibiting the clearance of dying cells; encouraging the host to overreact and so damage its own cells; these are but a few.

Non-pathogenic bacteria do not pose the "integrity process" with much of a challenge. They are disposed of easily when they mix with living flesh. And, in animals, they are easily disposed of with little or no inflammation and do not need to provoke strong adaptive immune responses. Indeed, this would be metabolically wasteful. The simplistic idea that MAMPs (PAMPS if you really must) provoke strong aggressive adaptive immune responses is almost certainly a nonsense. The body’s response to the gut microbiome is a good and emerging example of this. We would simply autodestruct our intestines. So that leaves us with little choice but to accept that some second condition is necessary to augment an aggressive response to the MAMP signal.

So, I suspect, we will begin to realise that it is damage – particularly catastrophic self cell demise – that is the necessary accompaniment to MAMPs that helps trigger strong-adaptive-immune responses to bacteria. And that leads back to a major function of the phagocytic cell system; these cells clear away the corpses of dying self cells. The system prefers self cells that melt away in a pattern of controlled cell shutdown (apoptosis) and subsequent quiet disposal. This disposal of old self cells is the phagocyte population's number one task – it overshadows any other assumed function by a great margin. And, of course, this leads us back to "integrity" and "order".

In this view, strong adaptive immune responses to bacteria are the consequence of them being processed in the vicinity of self cell damage (some degree of uncontrolled shutdown). It is likely that all adaptive immune responses (aggressive or suppressive) evolved to remember pathogenic encounters and then caricaturise and amplify secondary inflammatory responses on any re-encounter. Inflammation thus finds itself armed with a memory – a point that has been very poorly emphasised (and, surprisingly, overlooked).

Again, in this view, any memory provoked "attack" on bacteria is an emergent property of a drive to integrity. But, the way that the discipline of immunology had "grown up" has meant that we have assumed that "bug hunting and killing" are primary purposes. This has biased our questions, our observations and our interpretations so much that we have ignored alternatives. I think that a drive to integrity is the major "purpose" for the system and lymphocyte led attacks on bacteria are, basically, a snapshot of a previous inflammatory encounter (and that encounter is typified by a battery of representative antigens – both self and non-self). So, if your primary purpose is to damage cells to provide yourself with a meal, you will run the risk of getting noticed among the debris."

(Note that integrity and tissue homeostasis are pretty much interchangeable metaphors.)