In article <87n2eq$mse$1 at news4.isdnet.net>,
"Pierre" <sonigo at cochin.inserm.fr> wrote:
>> I understood that the self/nonself discrimination is a widely debated
view,
> because of some difficulties (schematically, amongst many) :
> 1) It is difficult to imagine theoretically an accurate mechanism for
such
> discrimination, given the diversity of self and non self.
> 2) It is shown experimentally that the discrimination does not hold
> (autoimmunity, tolerance, etc.)
>> I do not understand how the replacement of "self/non-self" by
> "mess/non-mess" solves the two points above, except by making the
> theoretical fundations of immunology more messy ;)
>> 1) How cells can recognize (are instructed to recognize) mess from
non mess
> ?
> 2) Mess/non mess can explain everything because mess is even more
difficult
> to define than self. So we can say anything to fit the theory : ie
> autoantigens are self but messy, weak antigens are non self but non
messy,
> etc.
>> What do you think ?
> Pierre
Pierre
It seems to me that you may have fallen straight into the trap of
traditional thinking. You are talking about non-self and messy
ANTIGENS. Antigens are not classified as self, non-self, messy or tidy.
Phagocytes have, from the very beginning of metazoan evolution been
adept at finding and tidying up tissue (cellular) mess. An infarction,
an area of crushed cells, spilt cells for a variety of reasons. What is
more the tissue mess can be divided into "messy mess" where cells spill
their cytoplasms and "tidy mess" where apoptotic cells are quietly
removed without any great inflammation. Indeed, so silent and efficient
is this process that it is only in the last few years that we have
become aware of the staggering volume of cells that are silently
removed by adjacent cells and phagocytes - without significant
inflammation. An analogy is like knowing what is garbage and tidying it
up in strong plastic bags ready for disposal when the garbage cart
comes along. "Messy mess" is like throwing it about with gay abandon
and without any intention to try and package it ready for disposal. The
colony considers this situation a serious threat. Seeing inside-out
membranes, spilled Il-1 (not pro-inflammatory when confined inside
apoptosing cells/bodies), seeing intracellular structures such as
mitochondia in the extracellular tissues - these are all pro-
inflammatory. Antigens presented dominantly in this sort of milieu will
provoke a strongly aggressive anamnestic immune response. It is only
the paucity of precursor T-cells specific for self antigens that
dampens aggression to self (because widespread apoptosis tends to mop
them up into "tolerance"; by elimination or by a positive suppression
of inflammation - probably just the former).
So on your two points
1) Phagocytes have been recognising and clearing away tissue mess from
time immemorial. This is their raison d'etre.
2) Mess is easy to define - not only that but we already know a lot of
the features that characterise it (above). Polly Matzinger has proposed
that the innate recognition of various bacterial features may, indeed,
be the recognition of intracellular mitochondria - obligate
intracellular organisms of bacterial origin. Everything can be looked
at from another perspective.
Jamie
--
Waterside Health Centre, SO45 5WX, UK
Home pages
http://www.ndirect.co.uk/~greenprac/jamie/jamie%20main.htm
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