www.morphostasis.org.uk

(Note, this is the article referred to in "Morphostasis: a revolution?". The versions I submitted lie somewhere between this version and the 12/2002 version. They were serially rejected following at least seven submissions to various journals.  Medical Hypotheses was deliberately not asked to consider this article, in response to David Horrobin's comment that it would be more effective to get published in a mainstream journal, particularly those concerned with immunology. I wonder if this will prove to be a fitting memorial of the blindness of "normal science" to fundamentally different perspectives. The tautologous nature of many of its conclusions show that the components were not in any way novel but the proportions and perspectives attributed to the "immune system" proved to be fundamentally deviant.)

'Nothing in biology makes sense except in the light of evolution' - T. Dobzhansky.

Introduction

The following paragraphs were devised as a brief synopsis of my beliefs. The overview is this. Should it be possible to get a glimpse of the real raison d'être - the grand plan - of the system (morphostatic system for me and immune system for many of you), then we could make some shortcut guesses about what each element has evolved to do. This article attempts to encapsulate four previous papers into a synopsis. Readers must decide for themselves which of these conjectures might be gems and which are garbage.

The evolution of morphostasis.

· Let us look at the sequence of 'shells' that eventually form the mammalian 'immune system' (1,2). All the shells remain fully functional and continue to fulfil their original purposes. None are abandoned. They are layered around each other like the layers of a Russian doll. They are also used in the same sequence - the inner layers first. Each layer will either manage or fail to resolve the problem. Failure to resolve the problem will promote the response to move out to the next shell. These form a barrage of defence lines to counter mess. They only fall back to the next defence when the previous defence has failed.

· In the beginning, heat shock proteins identify - then attempt to repair - protein trash; ubiquitins escort terminally malformed proteins off the premises; endosomes chop them up into short peptides.

· Elective suicide (a forerunner of apoptosis) evolves as a mechanism to limit the spread of rampant disease through a colony. This strategy is also used in colonial bacteria.

· Cell adhesion molecules (CAMs), surface associated molecules and intercellular junctions evolve. These give cells a sense of belonging to the colony and enable them to dock with one other. This is a discrimination of self from non-self. It remains the fundamental root of self/non-self discrimination in mammals.

· Homeotic genes allow cells to adopt alternative (cellular) body plans. When gap junctions evolved (about 700my ago), they (somehow) enabled alternative, homeotic body plans to expand their sphere of influence to cover blocks of cells interconnected by bridges of cytoplasm - so enlarging the body plan.

· A primitive metazoan will require the following of its component cells: when the well being of a cell is compromised it will be expected to detach itself from the colony and it may be extruded from its immediate grouping. It may re-attach provided it fixes the damage. If not, it will be expected to do the decent thing, sanitise its contents (by trashing them) and then invite its own gentle absorption by surrounding cells. Lost cells will be replaced through cell replication. Individual cells are expected to monitor and maintain their own health. If they cannot identify that they are malfunctioning, and so go on to spill their cytoplasms, then they can expect no mercy from the surrounding colonial (self) cells. Such sick cells are potentially dangerous. They will be aggressively attacked by dedicated phagocytes and cleared away together with their spilled contents.

· What has changed in mammals? Nothing - not, at least, as far as the grand plan is concerned; but the system has since been elaborated to enhance the intracellular destruction of suspect cells. (It does so by encouraging those cells that sport a caricature - resembling cells that spilled their contents on a previous occasion - to adopt a lowered threshold to apoptosis.) It does so by encouraging particular cells - those that sport a caricature resembling cells that spilled their contents on a previous occasion - to adopt a lowered threshold to apoptosis.

· Phagocytes pay little attention to cells that are in junctional communication with each other. These cells are stable and healthy. Phagocytes concentrate their attention on the suspicious group that have detached themselves or that were never attached in the first place (interlopers). They use a docking system to attach their uropod to an underlying block of communicating cells. They (probably) feel, with their lamellipod, for cells that are in electrical discontinuity. This docking by the uropod has low specificity. It is able to attach to allogeneic and even xenogeneic cells. Dedicated pathogens may find ways of fooling this surveillance.

· Tnk-like cells evolve as an extension of this low-specificity recognition. Using CAMs already evolved to enhance 'neural' interconnections (probably IgSFs, N-CAM-like), they learn to enhance recognition of detached cells so that this becomes more specific to the individual. By hanging representative peptides off the cell surface, in association with an N-CAM-like molecule (Mhc class I like), local accumulations of these cells can sense when there is a significant deviation away from a healthy-self, Mhc+peptide signature. The pleomorphism of this identity system and its germline receptor mechanism (possibly enhanced by RNA splicing) can gradually expand from two to numerous different specificities. Possession of selfness ensures that a cell will not be attacked; its absence or loss ensures that it will. This system is adept at recognising the internal cell turmoil stirred up by successful Trojan-horse invaders. Should any detached cells still go on to lysis, the next stage will be invoked. Note that Tc cell activity is a functional inversion of this Tnk-like activity.

· Tc-like cells can now evolve. Detached cells that die by apoptosis have proven that they are able to deal with whatever caused their malfunction. ClassII+peptide epitopes hung off the cell's surface allows the respective Tc-cell receptor to get a snapshot of the turmoil that is going on in the cytoplasm of that sick cell. Cells that sport a similar caricature to cells that previously died by apoptosis can be safely left to get on with it by themselves; but cells resembling those that spilled their cytoplasmic contents last time round have proven that they cannot. On any new encounter, they need to be recognised and encouraged into an early apoptosis.

· A key point to grasp is that it matters not one jot whether the Mhc+peptide signature is formed dominantly from peptides derived from self or from some foreign intracellular nasty. A precursor Tc cell that is able to recognise this combinatorial epitope will classify the encounter into tidy (apoptotic) or messy (leaky) death. A previous messy encounter will encourage an aggressive response in the future. Paratopes interacting with Mhc+self-peptide are relatively resistant to an easy promotion into aggression. The staggeringly enormous volume of successful apoptosis that occurs naturally in the body mops most of them up into tolerance. There is also a tendency for younger, precursor Tc cells to be hard to enrol into aggression. Tc cells are designed to kill self-cells. This is their primary role. That is why it is so easy to produce adjuvant arthritis and other experimental autoimmune disorders (note that over-exuberant Th1 aggression is a dominant accompaniment of most of these disorders). They are precipitated when there is a great deal of membrane damage, cytoplasmic spillage and a prolonged stimulation of the aggressive T-cell system but there is an absence (or paucity) of clearly strange antigen to focus attention onto the disordered cells that provoked the mess. By rapidly focusing aggressive attention on the cells that are rupturing (say e.g. due to a viral infection) then the whole process can be brought to a rapid resolution as this selective aggression will be directed preferentially towards the infected cells. Since there will be only a few precursor Tc cells available that are specific to the local tissue (mostly having been mopped up following previous apoptosis) and they are, anyway, young and resistant to recruitment into aggression, the differential expansion of aggressive Tc cell clones strongly favours strange over self epitopes.

· Cells that die suddenly in trauma (e.g. heart attacks, burns) have not been preparing for apoptosis. Cells that die of viral infections or other intracellular nasties have probably moved somewhere along the path towards apoptosis. This means that cells that die by trauma do not spill much Il-1 whereas infected cells do. Spilt Il-1 is a strong contender to be one of the danger signals (eicosanoids, which are released after membrane perturbations, are another). Nevertheless, Dressler's syndrome is the occasional autoimmune sequel to a heart attack - so trauma does increase the risk of autoimmunity. Similarly, in burns and major trauma, autoimmune activity is easy to demonstrate. Indeed, it is the probable precipitant of the phagocytic anergy that precedes multiple organ failure. Any system that allows auto-rejection of normal cells must sport a failsafe cut off device to inhibit the piecemeal destruction of self (6).

· Th1 cells evolve as an elaboration of the Tc cell system. Now, the cellular and cytoplasmic debris of leaking cells can be digested by APCs and then processed so that representative peptides can be presented on the APC's surface. Apoptosis of these APCs will favour tolerance to ClassII+peptide epitopes. But, when these APCs fail to contain the problem and start to rupture, Th1 aggression will be favoured. On any future encounter with a similarly caricatured APC (not of the pathogen nor of its native antigen), the inflammatory response can be quickly ramped up - bringing in copious aggressive phagocytes and Tnk cells. This is designed to give inflammation a memory. The newly immigrant phagocytes still have to sort healthy-self-cells from the rest but they are now stirred up into a frenzy of eagerness to get on with this job.

· Since extensive tissue destruction is undesirable, phagocytes must be inhibited when the Th1 cell amplification process becomes too intense. Phagocyte activity is consequently inhibited (as, e.g. in a boil) and this increases the amount of debris left to be cleaned up; the IgM free antibody system arose to act as a debris mop. (Macrophage derived cells (B-cells) have an immunoglulin receptor that internalises only targeted debris and processes this into peptide+ClassII epitopes. (Then, when a suitable CD4 T-cell receptor encounters this epitope, it triggers the respective B-cell to produce a sea of free IgM.) B-cells (cells that evolve from the macrophage line) have an immunoglulin receptor that internalises only targeted debris and processes this into peptide+ClassII epitopes. Then, when a suitable CD4 T-cell receptor encounters this epitope, it triggers the respective B-cell to differentiate into a plasma cell that then secretes free IgM. This then tags the debris and enhances its clearance. So, progression to Th2 activity is most likely to occur when cell-mediated auto-rejection is inhibited in the interests of inhibiting piecemeal self-destruction. But this inhibits the clean disposal of mess. The release of IgM is an attempt to compensate for this. All the other immunoglobulins have evolved as shells that envelop IgM (e.g. IgG, IgA, IgE).

· Thymic tolerance is probably designed to enhance the tolerance of lymphocytes (perhaps macrophages and epithelial cells too) so that it pre-emptively inhibits their auto-rejection. These cells are expected to migrate to lymph nodes - areas where mess-making agents are likely to be concentrated. This is probably why the thymus turned up in the pharyngeal arch - close to the place where copious seawater (with many mess making contaminants) is passed across the large and convoluted surfaces of the gills.

Synopsis

So, the whole process works through differential rates of cell death. Irremediably dysfunctional cells are expected to do the decent thing and die early by trashing their cytoplasms. In the process, they sanitise their contents. The fact that infection is a frequent cause of intracellular dysfunction is of no interest to the system. Cells don't think 'I am - or you are - infected'. They realise 'I am - or you are - irrecoverably sick'. The corollary is that there is a differential nurturing of healthy-self-cells that are in junctional communication with their neighbours. The adaptive 'immune system' simply remembers some caricature of those cells (or their debris) that failed to do the decent thing last time and it then watches out for similarly caricatured cells (and their debris) the next time round.

The progression of morphostasis

Finally, some thoughts on how the morphostatic response begins at the innermost shell and progressively enrols successive shells until morphostasis is achieved. The heat shock protein system may achieve morphostasis on its own, fixing the problem with minimal disruption. When the volume of malformed protein is too great the next stage is induced (e.g. the dumping of representative peptides on the cell surface in association with Mhc molecules). Intracellular surveillance watches for cell dysfunction and triggers apoptosis where appropriate. Where the mess is dominantly genetic, a healthy p53 gene is required in order to trigger apoptosis. Resident phagocytes (dendritic cells) try to remove the debris of cells or organisms that start making a mess (including p53 mutated cells) - and they are mostly successful. But this can fail. At this point, the agent that precipitated the crisis has probably overcome the system so far. Now there is an increased flow of lymph bringing in phagocytes from the blood. These will ingest the mess then proceed to apoptosis. They may do this locally or after being swept away in the lymph to the local lymph nodes. When this shell fails to resolve the mess, Tnk cells are brought into play. These are more specific about self-identity. They concentrate dominantly on disconnected cells. Nevertheless, some mess makers still lead to the rupture of cytoplasms. By this time the lymph flow has increased to a torrent and both immune and detached sick cells are swept off to the local nodes. Now the Tc cell system is brought into play. This memorises the caricature of cells that ruptured the last time that they were met. Their first encounter with uncommitted T-cells is in the local lymph nodes. The Tc cell system encourages cells - with a caricature that resembles cells that ruptured last time - to do the decent thing next time around. This system provides a clean clearance of the sick cells - while it works. But, even this may be overcome - at which time we are left with a mess of spilled cell debris. This debris is easily recognised and eliminated (by phagocytes). The Th1 system then categorises the resulting ClassII+debris-peptide epitope on the basis of whether or not it has previously been encountered in an inflammatory environment. Aggression (Th1 activity) is favoured when APCs are overcome and begin to rupture. If a Th1 cell meets a similarly caricatured phagocyte (which must already have started to clean up the cell debris to be able to sport this epitope on its cell membrane) then it will bring in a whole army of activated phagocytes to carry out the job more swiftly. But this lays the system open to macrophage anergy. When the going gets too intense, extensive tissue destruction must be aborted by macrophage anergy - and this results in a failure to contain mess by Th1 induced clearance. This anergy leads to a sea of extracellular debris and so to the need to recruit IgM. I am sure that a little thought would allow us to extend into the next rounds (the other Igs) but I will stop here. I have omitted complement here for brevity - that is covered in the other articles (1,2). It is worth noting, though, that complement also fits well with mess/non-mess discrimination.

Thus, for each insult, there is a sequential move from the inner to the outer shells. Now this is rather like the evolutionary steps in forming the mammalian morphostatic system. Remember that ontogeny tends to recapitulate phylogeny. So, is the gradual aging of the 'immune system' the stochastic accumulation of all possible responses to various mess-making insults through these shells? For some insults, the move to the outer shells is early and for others it is late. Could this, superimposed by the gradual genetic divergence of the zygote-derived colony, be the source of the immune changes observed as mammals age?

The finale

Finally, note the following points. An established paradigm can accumulate a large surfeit of apparent anomalies and yet still survive as the valid framework for a majority of minds. A new paradigm must face every apparent anomaly as if it were solid evidence of falsification. To approach omniscience (understanding every facet of how it works and every extrapolation of its function) requires multiple minds and many years of consideration. Any new paradigm should be assessed on its broad - not its focused - applicability as such omniscience will take years and many protagonists to establish.