"new" immune theory..

Derya Unutmaz unutmaz at IRIS02.BIOCINE.IT
Thu Apr 13 02:55:56 EST 1995

In article <ralph.1148086064A at>,
Ralph M Bernstein <ralph at ccit.arizona.edu> wrote:
>    having an idea for a new theory is fine, but it seems to all be a part
>of the immune response-this may be a part of the way the immune system
>works, not _the_ way the immune system works.  after reading alot of the
>postings out there, alot of people have come up with exceptions to this new
>idea that i didnt think of, and i bet that there are alot more out there. 
>so maybe this is just an additional way to look at _some_ types of
>immunological interaction? 

Ken Frauwirth (MiSTie #33025) replied:

>I think that this points out one of the major problems with specialization in
>to me to be rather reasonable that *both* types of recognition (self vs.
>nonself and "danger" vs. "non-danger") are working, although at different 
>levels.  While a "danger" signal may be necessary (or at least very helpful)
>in kicking off an immune response, it is clearly not enough.  There is
>definitely a selection against auto-responses.  The requirement for a "danger"
>signal is typified by the need for adjuvant during immunizations.  In fact, 
>this probably evolved to prevent us from reacting with every innocuous foreign
>substance that we contact (esp. food).  However, the H-Y graft rejection
>illustrates that a danger signal is not sufficient.  Female mice reject skin
>grafts from syngeneic male mice (one could argue that tissue damage from the
>graft is the "danger" signal), but not from syngeneic females.  Thus, there is
>clearly a need for foreign antigen as well.

	I fully agree with Ken that " ..*both* types of recognition (self vs.
nonself and "danger" vs. "non-danger") are working..". I also think that, although 
"danger" paradigm is very helpful, this may not necessarily be in the form of 
"tissue damage". Ian A. York (york at mbcrr.dfci.harvard.edu) gave a very good 
example as DNA vaccination, (although you may argue that even this may be inducing 
a minimal damage when you inject the DNA!). Another example could be oral 
immunization. For example, Cholera toxin b subunit or non-toxic mutants of heat-
labile toxin of E. Coli can be very effective oral adjuvants in inducing response 
to many antigens. I think what Polly Matzinger implies by "danger" is some 
triggering signal to cells which are responsible for processing and presenting the 
antigen (mainly dendritic cells for primary responses, but also macrophages, B 
cells). This triggering signal could be either in the form of "tissue damage" 
which would cause a minor inflammation thus indirectly activate the APC (antigen 
presenting cells), or as molecules directly capable of signalling APC  eg. 
bacterial products (LPS), or antigens that are specifically targeted and easily 
uptaken by APC. These signals would in turn induce differentiation of APC and 
migration to lymph nodes to search for the right T cells for presentation. This 
sensing mechanism, also involving other cell types like NK cells (Mike Clark, 
mrc7 at cam.ac.uk) would make sure that it's worth responding to this "foreign" 
intruder. Of course, there are also other limitations, which decides 
immunogenicity of an antigen, at the level of processing and presentaion.
	Nevertheless, when the immune system decides to respond, it still responds 
to foreign antigens! So self- non-self discrimination is there, but this is also 
quite felxible, since not all the self reactive T cells are deleted in the thymus. 
Mainly those which bind antigen+MHC with high affiny (or avidity) are negatively 
selected. In fact the same antigen can both positively or negatively select T 
cells, depending on its concentration (check out two papers published in Cell, at 
the beginning of last year, by Tonegawa and Bevan groups). So, the immune system 
also decides whether a self antigen is worth responding in the form of deleting 
part of the valuable immune repertoire.



Derya Unutmaz, M.D.
Immunobiology Research Institute
Via Fiorentina 1,
53100, Siena, Italy
E-mail: Unutmaz at iris02.biocine.it
Tel: +39-577-24 34 41
Fax: +39-577-24 35 64

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