(63) The bug hunting and killing delusion (again)

Let me make this clear from the start. I believe that there is a delusion that T-lymphocytes are used to specifically target and kill microbes. The ability to chase, kill and assimilate microbes is a primitive amoebocytic (feeding) function, retained and executed by phagocytes. To kill microbes, the best strategy is to recruit phagocytes. Antibodies can damage microbes (even kill them) but their recruitment depends on the priming of B-cells by T-cells. And, ultimately, the resulting debris needs phagocytes to remove it.

Note, however, that all somatic cells derive from the same lineage. All are probably capable of carrying out the ingestion and assimilation of food/debris. However, phagocytes have retained this as an exaggerated and professional role. They are "deliberately" specialised for this process. That probably means that they are closer in function and action to primitive amoebocytes than somatic – "building block" – cells (that have substantially forfeited this capacity).

I have just downloaded an article, An introduction to immunology and immunopathology . This is hot off the BMC Immunology press (2nd half 2018). I thought that the title was promising and that it might tie immunology into general pathology and away from the tsunami-perception of the "bug hunting and killing" perspectives. Well, not so. Reading this article, you might be forgiven for thinking that this still dominant view is unchallengeable.

So, what is potentially wrong with this perspective? Let me tabulate the challenge in a series of questions:

• Is inflammation primarily (the initiation phase) and secondarily (the effector phase) involved in all adaptive immune responses?
• Is inflammation phylogenetically older than adaptive immunity? Does this make it more likely that adaptive immunity arose to enhance the memory of previously encountered inflammatory responses to different stimuli?
• Is it possible (even probable) that the immune system (the co-ordinated system of which adaptive immunity is just one facet) is centred around phagocytes (vs lymphocytes) with the inflammatory response acting as the command hub of all consequent responses?
• Is the adaptive immune system initiated and effected by cells of the phagocyte lineage?
• What is the core function of inflammation?
• Does inflammation have any relationship to tissue homeostasis?
• Do phagocytes have any role in tissue homeostasis?
• Is inflammation involved in both the destructive and resolving phases of immune responses (and, if the second point is correct, of tissue homeostasis too)?
• Could tissue homeostasis be the ultimate goal of all co-ordinated immune responses?
• Do lymphocytes "remember" microbes?
• Or do they "remember" the internal debris (CD8 presentation) or extracellular debris (CD4 presentation) of damaged, dying and disrupted tissues/cells? (These are "contaminated" by microbe debris that can be simultaneously presented as Mhc/peptide ligands.)
• Does all such debris lead to an aggressive T-cell reponse?
• Does apoptotic debris (controlled cell shutdown) lead to aggressive or regulatory T-cell responses?
• Could debris classification into aggression or suppression (on re-encounter) be made on the basis of "uncontrolled (self-)cell shutdown" vs "controlled (self-)cell shutdown"? The "self" bit is most likely both redundant and too restrictive. However, it does emphasises the very high volume (a mass action influence) of the predominant debris.
• Could the overriding "purpose" of the co-ordinated immune system be a drive towards tissue homeostasis rather than a direct attack on microbes? Is the apparent "attack on microbes" an illusion that emerges out of a primary response to disrupted tissue homeostasis?
• Is inflammation involved in just about all pathological processes? It might be mild in some but is it absent in any?
• Is the immune system (with varying degrees of T-cell recruitment) involved in processes like fractures, lacerations, injuries of various sorts and all those conditions that you can peruse within pathology and histopathology textbooks? Are we being blinded to an obvious inference?
• Is adaptive immunity involved in tissue regeneration/resolution? (Watch out, particularly, for gamma/delta T-cells and also the role of complement and adaptive immunity in synapse pruning in the CNS.)
• So, is the immune system (whether it be low grade inflammation through to a potent adaptive-immune-accelerated-inflammation) involved in every pathological process?
• If you believe that this is not so, how can you justify this viewpoint?
• . . . . more to come?
• (I can't resist putting this one in.) Is the use of the term pathogen (as a synonym for an infecting micro-organism) obfuscating to the point of being blinding?

If you don't understand the last question, then look up differing definitions of pathogen across multiple dictionaries – particularly the oldest ones. Question whether microbes are an indispensible accompaniment to the definition of a "pathogen".

IN SUMMARY: The zygote derived colony is dynamic. "Worker cells" are generated from stem cells, whenever needed. These "worker cells" live then die; the dying cells generate cellular debris; this debris is a rich source of nutrient for both the zygote derived colony and many foreign (ie, not zygote derived) competetive cells and microbes. All such debris needs rapid and efficient (re-)assimilation. Miscreant zygote derived cells must also be identified, trashed and reassimilated. It is a continuing and differential process of – self implied – cell birth (from stem cells), cell death (from aging, disease, attack, mutation and etc), sick-cell housekeeping+clearance then cell regeneration (again from stem cells). This is frenetically active within what appears, to us, to be a stable individual that we recognise as a single animal. This stability is rather like a constant river eddy, or standing wave, through which is flowing a torrent of water (analogous to the flow of cells from birth to death to renewal).

AN AFTERTHOUGHT: if you still think the purpose of the immune system is to protect us from (predominantly) many micro-organisms and don't understand how this is hiding a deeper understanding, then think of this analogy. The purpose of gravity is so that the sun can pull on the earth and the earth on the moon (and vice versa, of course). Ok, the assumption of this perspective allows us to take some shortcut approximations in calculating orbits and trajectories (good enough for NASA). This bows to our immediate interpretation of what we think we see. However, as Einstein taught us, this is an illusion. There is no action at a distance. As we get closer to a very large mass, distance gets traded for time and the passage of time slows the closer we get to it. It is this "time well" that determines "satellite" orbits – not an instant force at a distance where there is no physical attachment.

In the same vein, the overriding purpose of the adaptive immune system is to manage degenerating biological material, most of which is from degenerating zygote derived cells (self-cells) and then to try and reconstitute the original form. The "bugs" that damage us are inevitably associated with this degenerating debris and that is why they tend to attract aggressive adaptive IS responses. We rely upon the ancient and innate ability of phagocytes to chase and "eat" micro-organisms during the final microbe kill. Adopting the "chase, fight and kill microbes" perspective closes our minds to a deeper understanding of extended processes – particularly the regenerative/restorative functions of the adaptive IS.