Further notes about the morphostasis concept – split files

(07) 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:

• Self vs nonself (this is too vaguely defined to have any practical value)
• Self–organism vs non–self–organism
• Eukaryote–cell vs non–eucaryote–cell
• Microorganismic–cell vs non–microorganismic–cell
• Healthy–self–cell vs other–than–healthy–self–cell (and, by this definition, this could include cell/organism debris)
• Self–epitope vs nonself–epitope (this has been the dominant concept in thymic tolerance theories)
• Antigen–typical–of–self vs antigen–strange–to–self (nb, foreign organisms have many Ags shared with the host)
• Epitope–unique–to–cell–surface vs epitope–unique–to–cell–interior
• Dangerous vs non–dangerous
• Extracellular presence of cytoplasmic contents vs extracellular absence of the same
• Pathogen vs nonpathogen (note that a hammer used safely is a nonpathogen but when used without caution it could – retrospectively – qualify as a pathogen)
• PO vs non–PO (note, for example, e.coli is dominantly a non–PO but occasionally it assumes PO status)
• Absence of tissue debris vs presence of tissue debris
• Presence of PAMPs vs absence of PAMPs

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.