Further notes about the morphostasis concept – split files

(32) Conception blinkers

The bug hunting, chasing and killing – war like – metaphor arms us with a set of blinkers that makes it almost impossible to escape this perspective and perceive anything else. Here is a very recent commentary on innate immunity.

"Innate immunity is activated by the recognition of a set of molecules that are found only on invading substances rather than on cells of the body. Any sign of things such as bacterial lipopolysaccharide, double–stranded RNA and bacterial flagellin will trigger an inflammatory response."

Well, no: this is not right. We already know that these TLR stimulants, associated with friendly gut bacteria, lead to tolerance. Otherwise we would destroy our intestines. Yes: (in my opinion) they do lead on to the activation of an adaptive immune response but the decision to provoke an aggressive or a tolerant response still depends upon an association with, or absence of, priming damage. In fact, lymphocytes are charged to reproduce the priming inflammatory (or non–inflammatory) milieu that was originally encountered in association with these TLR triggers. The commentary goes on:

"White blood cells, called dendritic cells, will engulf pieces of the invading organism and ferry them to the adaptive immune system command centres in the lymph nodes. It is here that the body plans the most successful and impressive attack on pathogens; producing tailor–made molecules to hunt down and destroy the attacker."

Well, no, again, in my opinion. They engulf all debris they encounter and it is particularly attracted to ingest debris that triggers TLRs. Indeed, the debris is a metabolic resource (including bacteria that are an anciently recognised food source for amoebocytes). For Tc and Th immune responses to occur, this debris is chopped up into peptide chunks by the antigen presenting cell's protein degradation system. Dendritic cells present representative peptides of this debris to the adaptive immune system so that an appropriate tolerant (inflammation suppressing) or aggressive (inflammation amplifying) immune response will be activated and reproduced on reencountering this debris – when in its original stimulating form (that is, peptide displayed as an Mhc/peptide membrane "flag"; this may equate to a recognition of diverse allo–Mhc ligands). It is, of course, correct that the subsequent immune activation can favour the ultimate destruction of pathogenic (damage causing) organisms. But, it is only ramping up an inflammatory clearance when it recognises this memorised debris. This is debris that was, in a prior encounter, presented on self cells by self–Mhc/peptide molecules, because it was previously associated with damage (Th recognition) OR, because it is encouraging self–cells into apoptosis if similarly tagged self–cells have previously died in an uncontrolled fashion (Tc recognition). Tc and Th cells do not recognise (pathogenic) organisms. The apparent attack on micro–organisms is a "sideways" strategy; it occurs because peptide debris, representative of the pathogenic stimulus (that may well include micro–organism debris), is either presented in an inflammatory milieu, that provokes an aggressive inflammatory response, or it encourages self–cells that display appropriate Mhc/peptide "flags" to commit suicide. Any microbe "killing" is a bystander effect of the adaptive immune system's acceleration of inflammation (an innate immune response); or it is effected by the apoptosis (and internal sanitisation) of infected self–cells (apoptotic cells are "silently" cleared by innate immune mechanisms).

Think about it !! Examine – every time it is paraded – the use of the term pathogen as a synonym for a pathogen micro–organism. Does this interpretation effectively put perceptual blinkers around the minds of the writers?

Immunological Reviews has just published an edition concerned with immunological tolerance. In its introductory paper it states, "The adaptive immune system endows vertebrates with the ability to identify and target pathogens for elimination during primary infections and to form memory cells that provide accelerated responses and/or protection upon subsequent encounters with that pathogen." Well let's rephrase that: "During primary infections, the innate immune system endows vertebrates with an ability to process the debris generated in the wake of infection by the respective pathogenic organisms. The adaptive immune system can then be triggered to encourage an accelerated inflammatory response (that enhances protection) upon any subsequent encounter with debris characteristically generated by that pathogenic organism." This is particularly true of cytotoxic and helper T–cells that recognise Mhc/debris combinations and these must be encountered in the same form to be able to trigger subsequent recognition (ie, processed debris – short peptides cradled in Mhc grooves). It is not the native pathogenic organisms that is recognised and attacked.

Antibodies are different. However, we can view B–cells as "targeting phagocytes". B–cells only ingest debris that displays, somewhere on its structure, an epitope that is "grasped" by the B–cell's immunoglobulin cell surface receptor that is then gathered in for ingestion; this debris is then processed by a B–cell into representative peptides that are then presented as Mhc/peptide membrane "flags" that can be "recognised by T–helper cells (a process similar to dendritic cell presentation). These T–helpers thatn enable the clonal proliferation of respective B–cells and then their clonal expansion into plasma cell "antibody factories". Now, on fresh encounters of the same B–cell Mhc/peptide (processed) peptide debris, respective B–cells can be clonally expanded, very rapidly. This requires the same conditional presentation in the Mhc molecule's peptide groove and then recognition by the previously primed T helper cells. Effectively, the B–cell – by enabling the release of freely circulating antibodies – is endowing all the innate immune system with an ability to capitalise upon this same specialised way of recognising specific, targeted debris. Antibodies simply amplify the ingestion and subsequent peptide–fragment–presentation of the antibody–tagged debris.

In Janeway's Immunobiology (8th Edition) there is a header that reads "Pathogens can damage tissues .... ". Whoops. This should read "Pathogens damage tissues .... ". Even if it were written as "Pathogenic organisms" the same would apply. We should be referring to the damaging property when we call an organism a pathogen.