Danger vs. self/non-self model

Ian A. York iayork at panix.com
Fri Jul 4 09:51:43 EST 1997

In article <5pbq32$n8k at agate.berkeley.edu>,
Ken Frauwirth (BioKen) <frauwirt at bacillus.Berkeley.EDU> wrote:
>room for significant overlap between them - they need not be mutually 
>exclusive.  Central tolerance seems to work on a self/non-self basis, while 

Absolutely.  Even peripherally, it seems likely that in many cases neither
"non-self", nor "danger", alone is sufficient to inevitably trigger a

>quickly, perhaps because you have not read Matzinger's and Fuch's presentation
>of it.  The basis is that one can *not* easily generate an antibody or T cell

I read the Ann Rev Immunol version of it in 1994, but haven't re-read it
for over a year, so I'm relying on my memory (like relying on a parachute
paccked by a chimpanzee on Prozac).  I should also state my bias--I work
on antigen processing and CTL, and I suspect that there may be slightly
different checks and balances in the antibody system. 

That being said, there are quite a few examples of antigens not associated
with dramatic "danger" signals which can lead to an immune response.  Last
time bionet.immunology had this discussion, I pointed at DNA vaccines,
which often can induce both humoral and cellular responses.  In many cases
you might argue that this is due to the inflammatory response to the
muscle damage of the injection; but there are also examples where the
local inflammation is minimal.  For example, delivery by the "gene gun" 
probably doesn't cause a lot more trauma than the slings and arrows of
daily life; there has been some success with mucosal delivery of the DNA;
and (I seem to recall, but can't find the paper) there has been some
success with intravenous injection of DNA vaccines coupled to promoters
specific for distal tissues, implying that the response was induced at a
site well away from the site of the injection trauma.

Where it's been looked at, responses have been fairly significantly
enhanced by delivering cytokines along with it, so certainly the "danger"
signal is an important part of the response.  I'm not yet convinced that
it is a sine qua non.  

I also have an unsupported feeling that the level of chronic low-grade
danger signals may be underestimated.  If you give a rat warfarin, the rat
will exsanguniate in a couple of days, just due to ongoing wear and tear.
This suggests there must be a lot of ongoing repair that we are entirely
unaware of, even in our pampered selves (and our even more pampered lab
mice).  That ongoing repair must be associated with some inflammation, and
so there must be a low-level 'danger' signal all the time (just as, of
course, there is always a low level of non-self impinging on the system).  

>is likely to result in tolerance to that antigen.  Instead, coinjection of an 
>adjuvant is necessary, and that adjuvant serves as the "danger" signal and 
>induces an inflammatory response.  My main problem with Matzinger's "danger"

I don't really agree with the "adjuvant induces an inflammatory response" 
suggestion.  Although I haven't paid close attention to adjuvant theory
since 1990 or so (when I stopped working with vaccines) I think that for
many adjuvants--in particular, the widely-used alum--the adjuvant effect
is not due to inflammation but rather to the depot effect.  (Though
certainly many of the more potent adjuvants used in research, like
Freund's Complete, induce a fairly spectacular inflammatory response.) 
Admittedly the state of the art of adjuvant theory consists mostly of
received wisdom congealed into dogma (or did when I was paying close
attention to it, anyway), but I think it's overinterpreting the data to
say that the adjuvant effect is due inflammatory responses. 

>While a danger signal may be needed to initiate a response, it still only
>works for an antigen that has not already been determined to be "self" 
>during T cell development.

The only difference I have with you, I think, is that when I said this
aloud I'd put a little more stress on the word "may".  

      Ian York   (iayork at panix.com)  <http://www.panix.com/~iayork/>
      "-but as he was a York, I am rather inclined to suppose him a
       very respectable Man." -Jane Austen, The History of England

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