Further notes about the morphostasis concept – split files

(03) E–mail to someone, 3rd July 1997

This is opinion but, again, I will use an authoritative style for good flow!

S/NS discrimination is the same as it has always been since metazoans first evolved. It is based on cadherins, selectins and IgSF CAMs plus others. It is the process that leads to one cell docking with another. It varies according to necessity (see the points I made about sorting in embryos, sperm–egg interactions and the general principal of identity recognition). All the clues go to point out that cells in junctional communication can be ignored – they'll be OK – Klas Kärre's "don't call us if you see one of these variety". I don't know which version of "From terra firma to terra plana ... etc" I sent you but it is mentioned in the latest version.

You say something in paragraph 2 that makes me wonder if you have completely thrown off the yolk of a redundant perception – it was probably just a slip of the tongue. Doug Green kicked off Day1 of the "Models of Immunological Tolerance" debate by saying that "the immune system (non–existent for me) evolved to maximally damage parasites while minimally damaging us." Wrong, wrong, wrong if he is talking (as I'm sure he is) about adaptive immunity. Forget antibodies – their role comes late in evolution. The innner shells of the adaptive immune system are the NK (Tnk said but NK meant) like cells, Tc cells and Th1 cells – appearing in that order. Individual cells have to stand up for themselves – they are expected to keep themselves healthy and deal with their own interlopers. If they don't succeed in this they are then expected to do the decent thing (apoptosis) and mulch their dangerous contents in the process. If they fail in this, then they can't expect any mercy from the phagocytic system. Any cell exhuding cytoplasmic contents is in for the rapid chop. Now this is what the Tc cell system evolved to enhance. By remembering the strangest caricature of cells that made a mess last time, similarly caricatured cells can be encouraged into an early suicide on any future encounter. What follows is tidy, enhanced, early apoptosis followed by neighbour replication to fill the gap. And, apart from pathogens (or grafts for that matter) that sport alloantigens in their ruse for mimicry, the only cells attacked by the Tc system are self cells sporting self class I + nonapeptide (the addition of various nonapeptides probably makes many of the self–class–I–molecules+nonapeptides look like allo–class I antigens). So Tc cells are specifically interest in attacking suspect self–cells!! So where is horror autotoxicus? Again, it is there but it is nothing like the lymphocyte brigade's perception. It is the protection of healthy, self cells, in quiet communication with their neighbours. (This is where the cancer story becomes so strong). Various bits of evidence suggest that NK and Tc cells are selectively aggressive to cells that have detached themselves (worked out that they are sick). The aggressive Tc cell pays hardly any attention to foreign organisms per se. It simply looks for (self) cells sporting internally generated (nonapeptide) debris like the debris that the terminally sick cell (that primed the respective Tc cell) sported as it died catastrophically.

Th1 cells evolved as an extension of Tc cells to enhance and focus inflammation. They gave it a memory. But any induced response simply delivers lots of angry phagocytes that then search round for "other than healthy self" cells. The angrier the induced inflammatory response, the more difficult it is to masquerade as a healthy self cell. And the ultimate can happen (aggression to all local self cells however healthy) and that is why a focal cut off is so necessary.

The whole of the morphostasis hypothesis was built on the structure of recurrent aphthous ulceration, Behcet's syndrome, multiple sclerosis, adjuvant arthritis and their relationship to tuberculosis. Tuberculosis, in particular, shows how the bacterium deliberately flouts the system by getting the adaptive immune process to concentrate on class–I+self–nonapeptide rather than strange class–I+tubercular–nonapeptide. In so doing it creates its own field of macrophage paralysis and a caseous soup that acts as a culture medium. The adaptive immune system, far from observing a horror autotoxicus to self cells, is designed to turn on them when they make a mess. And if they present no clearly strange class–I–nonapeptide specifities then a combination typical of the stressed tissue cell will be chosen (eg, adjuvant arthritis).

In short, Tc cells are designed to attack suspect, detached self cells.

So, yes, I agree with what you said about about lymphocyte receptors provided you are pointing out that this is part of their docking mechanism that brings them into the "communicating fold". But you say that it makes it more likely to leave self alone while dealing with the pathogen. I say that, in morphostasis, aggression is focussed on the potentially sick cell (one like this died catastophically last time), not the pathogen that makes it sick. The closest it gets to that is recognising some of the debris that the (potentially) sick cell is hanging off its cell surface as an advertisement of what is going on inside. The prime purpose is to enhance the apoptotic intracellular destruction of potentially mess making pathogens – just like the hypersensitivity response in plants. But plants are (evolutionarily) stuck with rigid cell walls.

Was that close to what you think?