The immune system is dead! Long live the immune system!

Jamie Cunliffe cunlij at
Thu Feb 10 08:45:00 EST 2000

In article <38A20F8F.1837C940 at>,
  D Forsdyke <forsdyke1 at> wrote:
> Hello,
>         BEFORE we all go rushing to the literature, why not do
> a bit of thinking? What is "danger"? It is a word applied when
> one has a certain sort of information about something. For example,
> as you approach a sunny beach you might be confronted with a sign
> saying "DANGER. LAND-MINES". In order to write that sign, someone
> had to discern that among the objects on the beach there were some
> compatible with humans (sand, pebbles, weed), and some incompatible
> ("land-mines").
>     Thus, first there was a binary discrimination event. The
> decision to use the "D-word" either followed or did not follow
> this event. In biological systems, a convenient nomenclature
> for this binary decision-making process is that it involves
> discrimination between "self" and "not-self".
>      The ability to carry out this discrimination is SO important
> that it is likely to have arisen among the very first living forms
> (unicellular). The mechanisms which evolved there may then have been
> modified and adapted when multicellular organisms arose.
>      That's enough for a start. NOW let's go and read the literature!
> For a start we could do worse than visit the web-site below.

I agree that the "danger" perception would be all well and good for an
educated human adult with a great deal of experience. Now, here, I
reckon, is one of the real dangers of anthropomorphising (see JRicks
reply 2/04/00 in earlier thread). Can you image an amoebocyte or
phagocyte rolling up, with towel and sunglasses on a beach and
thinking "what's dangerous, safe, self or non-self?". It is all very
well extrapolating back, having seen a sophisticated, highly
evolved "immune system" at work and thinking that it is categorising
things into self/non-self, danger/non-danger or what you like. But, I
suggest, the primitive amoebocyte must use a much simpler strategy -
and all subsequent embroidery is built around these simpler approaches.
Undoubtedly, a sophisticated system of cells in mammals (etc) ends up
looking as though it is discriminating self from non-self.  But it is
unlikely that this strategy of remembering everything that is likely to
be or has been a threat in the past can be catalogued in some sort of
internal amoebocyte library.

Now turn the perception on its head and think what it is that a
primitive metazoan needs to preserve. It is colony form and function.
How are you going to achieve that (without lymphocytes! - they are a
long way down the evolutionary wish list). First you want to develop
some way of marking healthy-self-intact-cell-membranes. You need an
internal surveillance mechanism to check all is well within the cell.
You need a system that, under stress, will create a generally
inhospitable environment to any interlopers BUT, that implies, you use
substances that are relatively innocuous to healthy self cells (as an
example - restriction endonucleases). You need a redundant system that
will allow irreversibly sick cells to be tidily wasted and replaced
without significant damage to tissue structures. Now if this looks like
a bug hunting system, it is not. It is intended to produce a
differentially uncomfortable environment for other-than-healthy-self
cells and an environment that healthy-self cells are differentially
likely to survive.

Complement is probably the most ancient set of "discomfort" molecules.
Outside-out membranes are deliberately seeded with embedded proteins
that avert the cascade from making them a sweet dish for phagocytes and
riddling them with large leaky holes. Phagocytes secrete all but a tiny
fraction of the relevant complement related proteins - thus,
primitively, they are not reliant on the humoralisation of the
complement components - this is a specialisation that follows the
emergence of vascular systems. But inside-out membranes won't be
protected, nor inside-inside membranes (organelle membranes). So, in
this respect, complement is following - very much - the mess/non-mess
or order/disorder discrimination.

I guess the ultimate "decision" is very simple. All cytoplasm has to
remain membrane packaged, and preferably communicating, for it to be
tolerated in the zygote derived colony. The only "needs" now are for
the primitive phagocytes to work out what typifies stressed or spilt
cells. They may retain a primitive and limited catalogue of
determinants typical of bacteria (for food recognition or because it
has learnt that they always tend to provoke a tissue mess - I suspect
the former).

The categorisation of antigens into "to be tolerated" or "to be
attacked" is a late acquisition of immune (morphostatic) systems. It
simply helps to separate the activation from the effector roles of
phagocytes. Antigens may today be classed as "to be tolerated" and next
month "to be attacked" reverting the following month to "to be
tolerated". This is particularly true of antigens that are a normal
constituent of healthy-self-intact-membranes and particularly true of
cell mediated immune responses.

And, yes, of course - the differential aggregation of previously
separated embryo cells uses cell adhesion molecules that are still
intimately involved in immune cell interactions and the development of
the Mhc and antigens. Sponge cells sport the same abilities. So they
are at the base of cell-cell docking and the primordial origin of the
immune (morphostatic) system.

PS, I note that I am still too heretic/wrong to be included among
your "Theoretical immunology" sites.

Waterside Health Centre, SO45 5WX, UK
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