"The danger theory: 21 years later."
In September 2012, Thomas Pradeu and Edwin Cooper published an article, The danger theory: 20 years later", in Frontiers in Immunology. On re–reading this, this year, I was prompted to put my ideas forward but they are not acceptable for the journal and the criticisms may well be fully justified. However, having worked on it, it is a pity that the ideas are not available to those who might find them interesting. So here is the response I prepared. There are some final alterations that I would have asked to have to have included and this is the version presented here. However, to make it plain what was rejected, I have outlined the changes at the end of this PDF article.
It was deliberately written as a 2000 word "essay" and it was always intended to provoke interest in a non–standard outlook on immunology. Should this be what the community currently believes, then someone should write an article that puts the point of view clearly and succinctly. (It is now obvious that there is a rapidly evolving and changing perspective towards this view.) Because the conclusions are arguably "tautologous" (things that become obvious in retrospect – stating them is stating the obvious), I did not include arguments for and against. These arguments are left to readers and researchers to explore. I warn them, in the beginning, not to assume anything I have written is right. It is up to them to decide if this perspective is valuable or dung heap trash. With 2000 words I have to cut to the core.
This is entirely about extra–cellular morphostasis. It says nothing of intracellular morphostasis (including eicosanoids, RNAi, intracellular debris management, intracellular protein management, autophagy and apoptosis). These intracellular morphostatic mechanisms are another part of the "story". This current "story" is all about moulding "danger" into a wider perspective.
"We shall not cease from exploration, and the end of all our exploring will be to arrive where we started and know the place for the first time." T. S. Elliot.
The "danger" metaphor
I don't think the metaphor of "danger" is appropriate. This page is a convenient place to discuss this. From my spell as an industrial physician (contracted to BP for a while) I was exposed to chemical plant safety procedures. One of the most important strategies is that it is important to proactively anticipate hazards (dangers). "Danger" is very much an intellectual, anticipatory concept. Experience tells us that rip currents are dangerous, pools of water on supermarket floors are dangerous, walking under ladders and scaffolding without head protection is dangerous. These are all learnt from bitter experiences followed by the proactive application of some intelligent anticipation. A good principle for hazard identification is to report and analyse every uncontrolled, adverse event – however minor. This is the uncontrolled event "iceberg". If we only look at the bit "above water" (the bad accidents) we ignore "an iceberg base" of useful information. Trivial events flag up the potential for much greater damage. Danger assessment is anticipatory – what we call proactive rather than reactive. However, at base, danger assessment is ultimately rooted in a reactive system. Damage has been done; if we ignore it, it will happen again and perhaps far more seriously next time. In the body, damage leads to an inflammatory response. If adaptive immunity remembers the signature of all damaging events (provocation of inflammation) and ramps up the response to a similar incident on a re–encounter (anamestic/adaptive immune amplification and acceleration) we end up with what is akin to an anticipatory "danger" response. The critical thing to realise is that, only once it has been triggered, does adaptive immunity become an anticipatory system to alert the body to a potential "danger". Danger "classification" is the consequence – not the precipitant – of adaptive immunity. Damage is the precipitant – however trivial that initiating event may be. In this way, the vertebrate lineage has anticipated modern industrial safety practice by many hundreds of millions of years. So, the metaphor for priming adaptive immunity should not be "danger"; it should be "damage" (and this includes uncontrolled self cell death). Once primed, adaptive immunity is transformed into what is – effectively – a "danger" or "hazard" alerting system; now it has become an "intelligent", anticipatory and proactive system.
Polly Matzinger's "danger theory" is, almost universally, described as a "danger induced activation of adaptive immune cell aggression". However, most – including Polly – interpret it as a "damage" precipitated aggressive–immune–cell–activation theory. I think that this would be better described as a "debris classification theory of adaptive immune cell recruitment and activation". This encompasses both tolerant and aggressive outcomes. Cells from the phagocyte lineage are heavily involved in debris management. They, therfore, both command the initiation of the adaptive immune cell response and act as the effectors of the "memorised and amplified" tolerance or attack.
It is expedient to say a few words about this. There is a continuing conviction that Th and Tc immune responses are targeted at "pathogens" (this term is generally seen as a synonym for "pathogenic organisms"). However, if we regard the debris clearance as simply the processing of debris associated with tissue disruption (micro–organisms being part of this debris) what the antigen presenting cell does is to process this debris then chop it up into short segments (peptides) that then fit within the MHC groove. These combined molecules are then "recognised" rather like allo-MHC molecules (the altered self bit). When the appropriate epitopes are re-encountered they must have already been processed into the same form (Mhc+peptide). The activation of Tc and Th cells depends upon finding similar peptide/MHC ligands on the membranes of self cells – either tissue cells (in association with MHC Class I molecules – to encourage the apoptosis of self cells carrying these ligands), or phagocytic cells (in association with MHC Class II molecules – that trigger a greatly enhanced inflammatory response in the immediate vicinity). In neither case can it be logically stated that it is the micro-organism that is targeted; however, it does result in them having a hard time of it in consequence of a proximal recruitment and "angry" activation of phagocytes. Once T helper cells prime B–cells, then this dependency on an association with a self MHC molecules is sidestepped and there can be a more specific attack on epitopes other than MHC/peptide combinations.
This analogy make make things clearer. Say we sifted through everyones trash and then broke it down into short component parts. We could then note whenever that trash appeared in a controlled and non disruptive way. Conversely, we may find that certain trash turns up around disruptive and damaging events. Thus, we could use trash associations to classify the previous context in which the trash was generated. So, we could rapidly deploy strong arm agents to the area and make them prone to aggressive actions. Or, conversely, we could recruit sparse tolerance agents to the area to ensure that an invasion by aggressive "police agents" is dampened down. The latter would otherwise interfere with normal functions.
Rejection notes: The final editorial comments were these:
"It cannot be accepted for publication because:
- The quality of the manuscript is substandard and below the generally accepted standards of the community.
- The paper has been reviewed by three reviewers.
- All of them conclude on the confused presentation, not in line with common practice.
- In addition this opinion paper does not appear to include recent understanding."
I think that this rejection could be justified for a variety of reasons but not with the excuse that, "it is plain wrong". I have not come across a synopsis that succinctly states these principles. If this is what the community currently believes, then someone should present these points clearly, succinctly and with all the necessary "padding" to render it politically correct. A detailed analysis and presentation would give room for crediting all who have contributed relevant ideas and research. A 2000 word précis does not allow this – and I have no funding to cover publication charges.
A valid critique is that it has already entered the "Anyway, it is not new" stage
The penultimate paragraph could be improved slightly by adding the phrase in bold italics:-
"In conclusion, it is now clear that:
- complement plays a constructive role in both development and regeneration;
- inflammation and, in consequence, both innate and adaptive immunity are critical participants in the response to virtually all pathology (including obesity, psychiatric illnesses, dementia); "virtually" is probably redundant;
- gut microbes are actively tolerated – even farmed;
- in the CNS, debris clearance is the task of the immune system;
- cancer is disturbed tissue homeostasis; it emerges during periods of prolonged inflammation."