Don,
Boy, thatÕs a deep one. I wonder if one of the reasons for the
(relatively) low traffic in this group is that it is often difficult to
give off-the-cuff answers to the questions being asked, and by the time one
has gone away to think about it, the momentum has been lost. But let me
give my £0.013p (ca 2¢) worth.
The issue raised by Coutinho revolves around the notion that lymphocytes
are tolerised (deleted?) by antigens they encounter while immature. The
argument then runs that if most lymphocytes are produced at a time when the
body is already exposed to foreign antigen then these antigens will also
tolerise immature lymphocytes. In fact, one can extend this notion to
include the induction of anergy in mature lymphocytes by antigens
encountered in the absence of costimulatory signals and suggest that common
foreign antigens will continually be presented and continuously anergise
potentially responsive lymphocytes.
First, letÕs leave aside the caveat that for T cells, any antigen
encountered after puberty will meet predominantly mature T cells and will
not generate the first of these mechanisms, since we have to be able to
account for responses in juveniles with active thymi. I can think of a
number of factors that would account for the fact that (Ž pur si muove) we
can discriminate self from nonself, or at least from potentially pathogenic
nonself. Whether they constitute the Òother levels of organisation in the
immune systemÓ to which Coutinho refers, I leave to others more
philosophically inclined.
I suggest that part of the answer lies in the dosage of antigen seen by
the immune system. The odd bacterium that manages to penetrate the body
and gets knocked off by non-adaptive mechanisms (alternative complement
pathway, phagocytes, acute phase proteins) may not provide a sufficient
antigen dose either to stimulate or to eliminate potentially reactive
cells; the system remains ignorant of the antigen. In that state,
potentially reactive cells continue to be produced and await a sufficient
antigenic stimulus.
Part of the answer undoubtedly lies in the mechanics of infection (this
probably is a higher level of organisation of the immune system). When an
organism establishes an infection, it usually does so in a tissue, rather
than directly into the bloodstream. Antigens in tissues are drained in
lymphatic fluid to peripheral lymphoid organs where they encounter naive,
mature T cells, and in general do not get carried to the thymus to delete
immature T cells or to the bone marrow to delete immature B cells.
Thirdly, pathogens are often capable of non-specific stimulation of the
immune system; macrophages, B cells and probably T cells have receptors for
bacterial cell wall components (LPS, mannans) that are able to activate the
cell, and in the case of B cells and macrophages can induce costimulator
expression; these cells will now activate rather than anergise.
Gamma/delta T cells and NK cells may play a similar role in responding to
viral infections (there is a report of a patient with an NK cell defect
with acute sensitivity to viral infection), in the case of NK cells most
probably through the production of interferon. I could go on at length but
the short answer is that the immune system may be able to recognise
pathogens as nonself because they tell it they are.
Finally, it may be important for the immune system not to respond to a
large number of innocuous environmental antigens, pollens, food antigens,
commensal (nonpathogenic) bacteria in the gut and it is here that the
question of tolerance by non-self antigens may be most important. Of
course, this gets us back to the discussion of mucosal tolerance and the
other current thread .....
All correspondence happily entered into ..
Paul
--
Paul J Travers phone : +44-(0)71-631-6262 (office)
ICRF Structural Biology Unit " " " 6268 (lab)
Birkbeck College fax : +44-(0)71-436-8918
Malet Street
London WC1E 7HX email : p_travers at icrf.icnet.uk
England or : paul at histo.cryst.bbk.ac.uk
