In article <37593E22.339D at post.queensu.ca>,
forsdyke at post.queensu.ca wrote:
> Yes, it is easy to get hung-up on this point. Your logic is that, if
> there is intracellular S/NS discrimination (IC-[S/NS]-D)then there
> SHOULD be preferential display of NS with MHC. However, this does not
> follow. The initial IC-[S/NS]-D acts as an alarm (present even in
> unicellular organisms) with multiple secondary effects such as
> increasing MHC gene transcription and MHC protein expression (in
> multicellular organisms).
I’d like to re-emphasise some of the points raised and get my doubts
assuaged if that is possible..
For Donald, how do you respond to the point that extensive elimination
of self reactive lymphocytes occurs in the thymus. Now, many see this
is a deliberate attempt to lay down a template of all likely self
specificities. However, it could equally be regarded as the suppression
of a response to any epitope presented during the course of tidy,
successful cell shutdown (the extensive apoptosis that occurs within
the thymus).
The counter, that apoptosis can induce aggressive immunity, must
incorporate the following point. A healthy cell dying traumatically
should have progressed effectively nowhere along the path to apoptosis.
The intracellular concentration of Il-1 should be very low. So, even
when it spills its contents into the extracellular milieu it should not
evoke strongly aggressive T-cell activation. On the other hand a large
mass of apoptotic bodies are like a juggernaut full of activated time
bombs. All’s well so long as you get them into the dismantling bay in
time – but if you don’t then you’re in serious trouble (it looks like
this might be the process in lupus – where the sheer volume of
apoptotic debris exceeds the system’s ability to clear away the “time
bombs” with sufficient promptitude).
In this view, the peripheral induction of tolerance is seen as exactly
the same sort of process as thymic induction of tolerance – but it now
includes both epitopes were and were not present on apoptosing
lymphocytes (macrophages and thymic epithelial cells too in all
likelihood). Successful controlled shutdown is “ordered” and tidy.
Necrosis and overwhelming apoptosis is “disordered” and messy.
My argument with intracellular “self/non-self” discrimination is that
it is no easier with this view than it is with the conventional view to
see what makes a protein self vs non-self – particularly as there are
so many related proteins (histones, cytochromes etc etc). However, the
system is clearly (already) set up to sense “disordered” proteins and
there is an effective chaperone system (to repair them), a
ubiquitinising system (to escort terminally disordered proteins off the
premises) and a proteosome system (to chop them into “bite sized”
pieces). Furthermore, the HLA antigens are designed and have complex
mechanisms to be loaded up with this “bite sized” debris and then hung,
flag like, off the cell membrane.
So, why is cell mediate auto-aggression so common (eg, T-cell auto-
reactivity to myelin basic protein after brain trauma or strokes is one
example - even before we look to adjuvant arthritis and its clinical
counterparts). And why is T-cell tolerance so common to viral proteins
presented during quiet apoptosis? There’s no self/non-self
discrimination going on here – just order/disorder discrimination.
Similarly, cells linked up, supported within stable connective tissues,
linked up through junctions and electrically synchronised
are “ordered”. Pathogenic bacteria proteolysing there way through the
extracellular matrix and out of communication and electrical synchrony
with ordered cells are characterised by their “disorder”.
I re-emphasise, 10 to the power 13 cells in the human body (remember,
most cancers are monoclonal in origin) is a striking reminder
of “order” within the zygote derived colony. Even if we all developed
100 cancers in a lifetime it would point to uncontained disorder in
only 1 in 10 to the power 11 cells of the bdy. By any measure we use to
comprehend it, that is an unfathomably small proportion. So, if it
ain’t your immune (my morphostatic) system that is maintaining this
order – what is?
Don’t forget that order/disorder discrimination (if you will just think
long about this) is going to appear very much the same as self/non-self
discrimination. But it ain’t! And the reward for escaping from this old
perception is an explosion in understanding.
“The difficulty lies, not in the new ideas, but in escaping the old
ones, which ramify, for those brought up as most of us have been, into
every corner of our minds.” ( John Maynard Keynes).
Jamie
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