Polly Matzinger's theory

R M Bernstein ralph at ccit.arizona.edu
Thu Jun 13 02:43:18 EST 1996

To Dr. Fuchs,

dr fuchs wrote:
>I am truly honored to be cited as Polly's former mentor, but in fact it 
>was just the reverse.  I agree that Science went overboard and that in 
>fact the Science paper of March 22 has nothing to do with "danger" or 
>self/nonself discrimination. It was our earlier paper in Science 
>(November 13, 1992) that established there is no such thing as 
>self/nonself discrimination by the immune system, or at least virgin T 
>cells.  In that paper we showed that both resting and activated B cells 
>are toleragenic (?tolerogenic?) antigen presenting cells for naive CD8+ T 
>cells.  My conclusion, then and now, is that naive T cells cannot 
>discriminate self from nonself because they will be rendered tolerant of 
>any antigen, self or foreign, that is presented exclusively by B cells.  

this is a conclusion that is may indeed be valid.  although this is not a
subject discussed during the conversations about 6mos/ a year ago, it was
the danger danger signal.  and as to being polly matnzgr's mentor, i am
sorry that i errored so seriously, and regret my mistake.  this i what i was
told, and what i thought that you wrote in our exchanges. 

you wrote:

>Now, if there is anyone out there who can refute that reasoning, I would 
>be happy to accept the possibility that there may be self/nonself 
>discrimination by the immune system.  

the idea of self/non self has now evolved to the point where it must mean
different things.  in the thymus, where self/ non self is a not-so-clear 
concept, that may rely on antigens presented by certain types of APCs (ala
kappler etc) (cortical vs med, so positive selection =intermediate binding
to "non self", or antigens presented by certain APCs), but is more likely
antigens presented by APCs at a certain time wherein the young t cells are
exquisitely sensitive to the "nails in the coffin" idea-too much stimulation
thru the receptor (this is clearly seen in FTOC anti CD3 experiments).  so
in the thymus, where "all" "self" antigens are supposedly presented, the t
cell precursor first sees "self".

i think that you suggest that in the perihphery/ perihpheral circulation,
where naive cells are present, b cells presenting alone delete naive t
cells.  although the CW says that in the perihphery, t cells that are naive
are waiting in the draining lymph nodes "hopefully" encountering antigen as
presented by dendridic cells (danger?).  the percentage of b cells in the
circulation that _are presenting_ to naive t cells is probably fairly low. 
wouldn't it be a bad idea for naive t cells to be activated by b cells in
the perhiphery, as the presentation and 2ndary signal pathways are key to
the regulation of autoimmunity?  haven't we known for some time that
non-2ndary signaling (like cytokines, b7/ctla4/cd28, etc) leads to deletion
of the naive t cells?

>dr fuchs wrote
>Fortunately, I was able to convince 
>Polly of my reasoning, and the rest is history.  She felt is might be 
>important to tag this concept, and her "danger" idea to the paper on 
>neonatal tolerance, which simply shows that Burnet and Medawar were a 
>little bit off in their tolerance model.  

well, i am glad that you were able to convince her.  as i said 6 mos
ago/year ago, this danger concept seems unnecessary.  and this concept was
really hyped up: dr matzngr said or was quoted -in science- as saying
something along the lines of -the danger signal is an unknown signal, or its
a new type of signal, etc-  it is sometimes hard to glean the benifits from
an idea when it is so inundated w/ "hype".

in the perhiphery, self is peptide that was presented in the context of your
specific mhc, whether or not it is a peptide mimic that is  "fooling" the
shape reading tcr.  non self is peptide that does these same things, albeit
not so well.  maybe the "danger-danger" signal is peptide in the perhiphery
that does these same things way too well-killing the cells.  

>dr fuchs wrote:
>I regret that I have appeared to answer questions selectively.  I am not 
>hiding, I may be reached anytime at Johns Hopkins Oncology Center (410) 
>955-8143 or on my beeper (410) 283-0313. 

i am not that in to it.  we tried to do this as non-hostile questioning
scientists in the newgroup / forum 6 mos ago/ last year.   the questions i
thought were valid to the theory went unanswered/ ignored /whatever.   

>dr fuchs wrote:
> Now how's that for service in 


regards, ralph m. bernstein

520 626 6061/ 2091

More information about the Immuno mailing list

Send comments to us at biosci-help [At] net.bio.net