(Phlogiston version March 1998)
The evolution of morphostasis.
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 most if not all of you), then we could make some shortcut decisions about what each element has evolved to do. This summary attempts to encapsulate three articles into a brief summary. It is my opinion.
- "Nothing in biology makes sense except in the light of evolution" – Dobzhansky.
- 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.
- 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 in colonial bacteria as a mechanism to limit the spread of rampant disease through the colony.
- CAMs (cell adhesion molecules), SAMs (surface associated molecules) and ICJs (intercellular junctions) evolve. These give cells a sense of "belonging" (to a colony) and enable them to dock with one other. This is a discrimination of self from non–self. It remains the fundamental root of S/NS discrimination in mammals.
- Homeotic genes allow cells to adopt alternative (cellular) body plans. When gap junctions evolved (c700my ago), they enabled alternative, homeotic body plans to expand their sphere of influence to cover blocks of cytoplasmically interconnected cells – so enlarging the body plan.
- A primitive metazoan will require the following of its component cells: when a cell's well–being is compromised it will be expected to detach itself from the colony and may be extruded from this immediate grouping. It can re–attach provided it fixes the damage. If not, it will be expected to do the decent thing, sanitize its contents by trashing them and then encourage its own gentle absorption by surrounding cells. Any cell gaps will be filled by replicating adjacent cells. Individual cells are entirely responsible for monitoring and maintaining their own health. If they cannot identify that they are malfunctioning, and so go on to spill their cytoplasmic contents, they can expect no mercy from the surrounding colonial (self) cells. Such sick cells are potentially dangerous and will be aggressively attacked by dedicated phagocytes and cleared away together with any of 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 by promoting apoptosis to those cells that sport a caricature resembling cells that spilled their contents on a previous occasion (more later).
- Phagocytes pay minimal 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 were never attached in the first place (interlopers). They use a basic and fairly non–specific 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 is not too specific, and it is clearly able to attach to allogeneic and even xenogeneic cells. Cells dedicated to being pathogens may find ways of fooling this surveillance.
- Tnk like cells evolve as an extension of this non–specific recognition by phagocytes. Using CAMs already evolved to enhance neural interconnections (IgSFs; N–CAM–like), they learn to enhance recognition of detached cells so that this recognition 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 (probably effected by RNA splicing), can gradually expand from 2 to numerous different specificities. Possession of selfness ensures that a cell will not be attacked; its absence or loss of it ensures that it will. Tc cell activity is a functional inversion of this Tnk–like activity. Should any of these detached cells still go on to lysis, the next stage is invoked.
- 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. Mhc+peptide hung off the cell surface gives the respective Tc cell receptor a snapshot of the stress response that is going on inside the sick cell. Cells sporting 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 have proven that they cannot. On any new encounter, they need to be recognised and encouraged into an early apoptosis.
- The major 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 resistent to an easy promotion into aggression. The huge volume of successful apoptosis that occurs naturally in the body mops most of these paratopes up into tolerance and there is also a tendency for younger, precursor Tc cells to be harder 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, however, that overhuberant Th1 aggression is a dominant driving force in these disorders). These disorders are precipitated when there is a great deal of membrane damage, cytoplasmic spillage and a prolonged stimulation of the aggressive T–cell system in the absence (or paucity) of clearly strange antigen that will focus attention on the provoking disordered cells. If you can rapidly focus aggressive attention on the cells that are rupturing due (say) to viral infection, then the whole process can be brought to a rapid resolution by a selective aggression directed preferentially towards the infected cells. Since there will be only a few precursor Tc cells available that are specific to the local tissue (previously mostly mopped up by apoptosis) and they are, anyway, young and resistant to recruitment into aggression, the differential clonal expansion of aggressive Tc cells strongly favours the strange over self antigen.
- Cells that die suddenly in trauma (eg, 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 traumatically killed cells don't spill much Il–1 whereas infected cells do. Spilt Il–1 is a strong contender to be one of the danger signals (eicosanoids – membrane purturbations – are another). Nevertheless, Dressler's syndrome is the occasional severe autoimmune sequel to a massive heart attack – so trauma does increase the risk of auto–immunity. Similarly, in burns and major trauma, auto–immune activity is easy to demonstrate – indeed, it is the probable cause 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 piecemeal self destruction (4).
- 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 representative peptides presented on the APC's surface. On any future encounter of a similarly caricatured APC (NOT of the pathogen nor of its native antigen), the inflammatory response can be ramped up quickly – bringing in copious aggressive phagocytes and Tnk cells. This is designed to give inflammation a memory. The phagocytes still have to sort healthy self cells from the rest but they are now souped up to carry out this job in a big way.
- Since extensive tissue destruction is undesirable, phagocytes need to be inhibited when the Th1 cell amplification process gets too intense. Phagocyte activity is consequently inhibited (as, eg, in a boil) and this increases the amount of debris that is left to be cleaned up; the IgM free antibody system arose to act as a debris mop. Macrophage derived cells (B–cells) sporting an immunoglulin receptor internalise targeted debris then, when their peptide+Mhc epitope meets a suitable Th2 T–cell receptor, they are triggered to produce a sea of free IgM that tags this 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 self–tissue destruction. But this inhibits the clean disposal of mess and IgM release is an attempt to compensate for this. All the other immunoglobulins have evolved as shells that envelope IgM (eg, IgG, IgA, IgE).
- Thymic tolerance is probably targeted primarily at enhancing tolerance to lymphocytes (perhaps macrophages and epithelial cells too) to pre–emptively inhibit their auto–rejection. These cells are frequently exposed to mess making agents (lymphocytes 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 sea water (with many mess making constituents) is passed across the large convoluted surface of the gills.
So, in synopsis, 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 cytoplasm. In the process, they sanitize 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.
Finally, some thoughts on how the morphostatic response progresses from the innermost shell and progressively employs each successive shell 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 (eg, the dumping of representative peptides on the cell surface in association with Mhc molecules). Phagocytes then try to remove cells or organisms that start making a mess – and they are mostly successful. But this can fail. Then, the identity system that they use has probably been overcome by the agent that precipitated the crisis. So, Tnk cells are brought into play. These are more specific about self identity (and are dominantly directed at disconnected cells). Even so, some mess makers still lead to cytoplasmic rupture. Now the Tc cell system is brought into play to focus (remembered) attention on suitably caricatured cells. The Tc cell killing 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 it having been previously encountered in an inflammatory environment. 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 averted by macrophage anergy – and this represents a failure of Th1 clearance. This anergy leads to lots 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'm going to stop here. I have omitted complement here for brevity – that is covered in the other articles (1,2).
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 immune (morphostatic) system. Remember, also, 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 agents, the move to the outer shells is early and for others it is late. Could this, with the extra superimposition of gradual genetic divergence of the zygote derived colony, be the source of the immune changes found as an animal ages?
Finally, note the following points. An established paradigm can accumulate a huge surfeit of apparent anomalies and yet still survive as the valid framework for the 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.
- Cunliffe J. Morphostasis and Immunity. Med Hypotheses 1995; 44: 89–96 & Errata 44:428
- Cunliffe J. Morphostasis: an evolving perspective. Med Hypotheses – in press.
- Cunliffe J. From terra firma to terra plana – danger is shaking the foundations. Med Hypotheses – in press.
- Regan MC, Barbul A. ; Faist E, Ninnemann J, Green D, editors. Immune consequences of trauma, shock and sepsis: mechanisms and therapeutic approaches. Springer–Verlag, 1989; The role of the wound in posttraumatic immune dysfunction. 1043–1049