Further notes about the morphostasis concept - split files

(61) Comments posted on Polly Matzinger's researchgate project

[16th January 2017]

Polly, I have been tempted to put in my twopenn'orth (two penny worth) as these issues you raise have kept me entertained for many years. The trigger for this interest was dealing with a patient with Behçet's syndrome and neurological complications back in 1976. For many, the continuing perception of the immune system is that

• it functions as a ‘bug' hunting, chasing and killing system.
• this is dominated by and commanded by the adaptive immune system.
• though the immune system involves itself in other activities, these are merely spin offs from this primary rôle.

I believe that this is woefully wrong. I have various guesses about what our immune (tissue homeostatic / morphostatic / integrity) system is doing. These include:

• It is a resource and debris management system that is able to clear away dysfunctional self (zygote derived) cells (and their debris) and set in motion the restitution and reconstruction of damaged tissues.
• As such, its primary driver is inflammation and its executors, a variety of innate immune cells that are dominated by phagocytes. Inflammatory cells invades tissues, destroy damaged elements and then help to reconstruct cellular architecture (hence morphostasis).
• The adaptive immune system acts as inflammation's memory. Our "immune system" is thus an inflammo-centric NOT a lympho-centric system.
• This probably does not go deep enough as many other innate immune mechanisms are also deployed. These include prostaglandin perturbations, RNA activity, ubiquitins, proteosomes, autophagy, apoptosis, complement, defensins, NK-cells, ILCs and more. These are anciently acquired mechanisms and they are probably all still retained and rolled out in ontogeny in the same sequence in which they evolved. Adaptive B-cells and lymphocytes arrived late and only in the vertebrates.
• T-lymphocytes DO NOT target or kill micro-organisms. They "recognise" chopped up peptide debris presented in a groove in a Class I or II Mhc molecule. As such, lymphocytes only "recognise" the cell surface location of processed (thus already chopped up) proteins. The effector arm of all adaptive immune responses relies on the focalisation, acceleration and exaggeration of innate immune mechanisms. Apoptosis is one (Class I Mhc presentation) and inflammation another (Class II Mhc presentation). Neither lymphocytes nor antibodies "kill". They simply enhance innate attention once activated (encouraging apoptosis is an innate mechanism).
• The old perception that antigens (epitopes) are categorised into self or non-self is better looked at in a completely different way. The things that are "recognised" are peptides tucked into Mhc grooves. Peptides from dismantled self proteins are very commonly (massively) encountered following apoptosis. They are also encountered in the foetal thymus, where there is massive lymphocyte apoptosis. Most precursor T-cell receptors fail to get the "kiss-of-life" from a self Mhc molecule and probably die by neglect through apoptosis. This should lead to an "amplified" self tolerance of peptides processed after ingestion of these dying lymphocytes. When similar peptides are re-encountered in an inflamed tissue environment they can enhance focal tolerance.
• My perception is that all debris (self and non-self derived) is processed and presented in Mhc grooves. Self peptides are copiously encountered following controlled cell shutdown (apoptosis for instance) and will polarise their matching and so far uncommitted T-cells into suppression. The remaining uncommitted T-cells have not yet encountered their matching peptides and these represent unusual peptides that may be encountered for the first time during a damaging infection. The damage will favour a pro-inflammatory or pro-apoptotic (and thus aggressive) commitment.
• The old assumption was that self reactive lymphocytes need to be eliminated in utero (foetal elimination for vertebarates without a uterus) rather than being committed to suppression. This was an inevitable consequence of interpreting experimental observations in the light of bug/non-bug, self/non-self theories of immune activation. There really should be no reason to doubt that tolerance to self antigens comes about because they are usually met following controlled, non-inflammatory shutdown of apoptosiing self cells. Central and periphereral tolerance are, by this view, probably a similar process. Observations made in the light of this possibility are already looking very promising.
• Now, the debris mopping process suggests an origin for B-cells. They act as fastidious phagocytes, only ingesting debris that their Ig-receptors interact with. I guess that they started out, in evolution, as the "eaters" of targeted cell debris, and had a liking for specific Ig superfamily ligands; I suspect that these were used in the developmental resorption of redundant tissue cells. These would have given rise to the V region genes. So B-cells probably started out as fussy APCs that sought out debris sporting specific ligands. In this respect, they need T-cell help to stimulate the "factory" production of all serum immunoglobulins excepting IgM.
• Should the concept of an inflammo-centric immune system prove correct, then this suggests an origin for class control. The initiating inflammatory cells (various phagocytes lineages) tailor their innate response to the offending pathogenic stimulus. Then they instruct the various involved lymphocyte to ramp up and exaggerate a similar sort of inflammation when the previously categorised peptide debris reappears in Mhc grooves. (As you say, the instructions originate from within the affected tissues.)
• All disease is auto-rejective (auto-immune if you like) to some measure. And adaptive lymphocytes can target self tissues. That's the way of clearing the debris of dysfunctional (mostly) self cells – and the nutritional resource that this represents. This debris has similarities to the anciently established dietary predilection of free living amoebocytes; this includes biomaterial, bacteria, viruses and essential chemicals and elements. If "you" don't eat the resources and dispose of it "yourself", then "someone else" will and they might then win the proliferation/population struggle.
• In the absence of some defining strange peptide debris (strange equals rarely or not seen before) there will be no "foreign" antigen to latch onto to focalise and exaggerate an aggressive innate immune environment. If the mess keeps coming (cells are "dying badly" as you say – I've called it an uncontrolled or catastrophic demise) then, eventually, newly emergent marrow T-cell precursors will probably be found ready to be committed to aggression towards self derived peptides. This is probably what is happening in adjuvant induced auto-rejective disease (auto-immunity if you like).
• The micro-organisms that escape early elimination – and thus persist to do damage – have probably evolved (often within the span of a human's lifetime) to have a peptide debris that is closer to the identity of self cell peptide debris. Now we are probably talking about an escape from natural killer lymphocyte identity checks. Much evidence now indicates that the aggressive activation of NK-cells stimulates down-stream adaptive T-cell responses.

Is any of this helpful in moving the concept along?

Reference:- Matzinger P. "Project: autiimmunity: are we asking the right question?"