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
>immunology?
>
nifty.
regards, ralph m. bernstein
520 626 6061/ 2091
