Something unknowable in immunology? Simple logic?

Dina Fonseca dfonseca at mail.sas.upenn.edu
Sat Jan 22 17:21:04 EST 1994

In article <p_travers-190194124802 at macmhc.cryst.bbk.ac.uk> p_travers at icrf.icnet.uk (Paul J Travers) writes:
>	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)

To me, this begs the crucial question:
Are there true peripheral antigens?
I mean by this, are there proteins expressed and presented in the periphery,
to which tolerance must be established by peripheral mechanisms? For which
failure of tolerance induction would lead to autoimmunity?
Surely such self proteins must exist? 
How could tolerance to such proteins possibly be established?

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