The danger of "Danger"

Kenneth Frauwirth kfrauwir at
Fri Jun 4 00:57:41 EST 1999

In article <7j6t5n$r7e$1 at>,  <cunlij at> wrote:
>“Almost”, you will probably have noted. And, I contest, that applies to
>Donald’s view of intracellular self/non-self discrimination. I
>wholeheartedly agree that the process begins intracellularly.
>Similarly, I agree that its roots are in dealing with internal
>(intracellular) disorder. But, self/non-self discrimination? No, I
>don’t accept that one.

I'll admit that I am one of those immunologists without the tools (or
probably the inclination) currently to grasp entropy arguments regarding
intracellular self/non-self discrimination.  However, having some
experience with the antigen processing field, my take on things is that 
the biochemical evidence strongly suggests that non-self peptides are
*not* preferentially displayed.  Peptides can be extracted from cells and
analyzed, either by mass spec/sequencing or by T cell recognition, and
these methods indicate that virally expressed antigens are not presented
in especially high copy number on MHC Class I; the same antigens are
presented with similar efficiency in stably transfected cells (making them
effectively "self").  Likewise, the rejection of MHC-mismatched tissue
grafts represents a very potent immune response, despite the fact that
the allo-antigens being recognized are "self" for the tissue being

I'll admit that I'm far from convinced by the "Danger" model - recent data
from the Matzinger lab (seen on a poster at a Keystone meeting in March)
indicates that even a fully healed allo-skin graft can be rejected,
leaving one to question what is providing a "danger" signal.  However, it
is also clear that something beyond simple infusion/expression of an
antigen *is* necessary, and it is reasonable to posit that systems able to
recognize the hallmarks of infectious agents (non-mammalian cell
components in bacteria and fungi, dsRNA from viruses, etc) have been
selected during evolution.  These cannot explain the ability of the immune
system to reject foreign (but not self) mammalian tissue grafts, but
neither can models of cell-intrinsic self/non-self discrimination, it
seems to me.

Ken Frauwirth
Ken Frauwirth (MiSTie #33025)  kfrauwir at
Gwen Knapp Center for Lupus and Immunology Research
University of Chicago

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