Self/nonself discrimination

FORSDYKE at QUCDN.QueensU.CA FORSDYKE at QUCDN.QueensU.CA
Thu Aug 11 07:27:35 EST 1994


In article <32aup7$o8v at lyra.csx.cam.ac.uk>, mrc7 at cus.cam.ac.uk (Dr M.R. Clark)
says:
>
>In article <94222.092643FORSDYKE at QUCDN.QueensU.CA>,
> <FORSDYKE at QUCDN.QueensU.CA> wrote:
>>
>>In article <325mua$1me at lyra.csx.cam.ac.uk>, mrc7 at cus.cam.ac.uk (Dr M.R.
>Clark)
>>says:
>>>In article <94211.144113FORSDYKE at QUCDN.QueensU.CA>,
>>> <FORSDYKE at QUCDN.QueensU.CA> wrote:
>>>>In article <31bhe8$3f1 at agate.berkeley.edu>, frauwirt at mendel.Berkeley.EDU   n
>>>>Frauwirth (BioKen)) says:
>>>>
>>>>>How could a cell recognize a "non-self" antigen (e.g. viral protein) that
>>>>>was synthesized by its own ribosomes?
>>>>
>>>>     It is proposed that over evolutionary time cells have fine-tuned self
>>>>protein concentrations to the concentrations of the other self proteins
>>>>with which they are moving through time. The cytosol is so crowded that
>>>
>>>I cannot accept this argument about concentration because it assumes that
>>>there
>>>is no genetically or enviromentally determined differences between diverse
>>>individuals which can still lead to tolerance.
>>>Any reasonable hypothesis for tolerance must allow the system to operate
>>>without
>>>prior knowledge of what self is genetically! Most of us are after all       !
>outbred
>>
>>   Yes, we are outbred, but we only breed within (and thus define) our own
>>species. We are not threatened intracellularly by other members of our own
>>species. Within the species framework, cytosolic proteins fluctuate in
>>concentrations within limits determined by evolutionary selection. A mutant
>>which exceeded those limits would mark itself as 'foreign' and self-destruct
>>during embryogenesis. A foreign species (virus) which attempted to acquire an
>>intracellular foothold would have to avoid exceeding the concentration limit
>>on the proteins it encodes. Above this limit self-aggregation would occur and
>>the intracellular s/ns discrimination system would be triggered. This would
>>destroy both the virus and its host cell. For more see J.Th.Biol 167,7-12;
>>J. Biol.Sys 2, in press.
>
>Sorry again, but I still disagree.
>Iit is possible to make transgenics expressing novel proteins
>such as ovalbumen. These can be expressed at various concentrations driven
>by different promotors active in different tissues. There rarely seems to be
>any problem in the animal achieving either a state of tolerance or ignorance
>of the protein.
>Tolerance mechanisms seem to be highly adaptable to the genetic and phonotypic
>make up of the animal.

   Some of the strongest evidence supporting the aggregation theory comes from
attempts to express foreign genes in cultured cells. Aggregation is the rule
rather than the exception. (e.g. Nguyen et al. 1989. J.Biol.Chem.264,10492).
There are no  programmed T cells in the cultures to destroy peptide-presenting
cells.A transgeneic simple multicellular organism,  without cell-mediated
immunity, would autodestruct cells containing the overexpressed protein. In
transgenics with cell-mediated immunity, there would be a possibility that the
expressed protein would educate the T cells during foetal development, so that
there would be no specifically programmed T cells capable of reacting against
cells inwhich aggregation of the hyperexpressed protein had occurred. This
education could also affect nascent B cells. As a result the transgenics would
be viable (as are "transgenics" infected with some viruses, which die
eventually because of the effects of the virus; e.g. leukaemia).

>The other side of the argument is that the concentration of peptide needed
>to bind to MHC is dependent upon the polymorphism of the MHC so as the
>affinity varies it would be necessary to adapt the concentration of
>self peptide.

     Actually, the  theory proposes that it is the concentration of the
cytosolic protein which is critical. If the concentration threshold is exceeded
then aggregation occurs.  This then triggers processing and peptide association
with MHC protein. If the MHC happens not to have sufficient avidity then there
would be no peptide presentation, but the linkage with the MHC protein is held
to be a local phenomenon and not necessarily diffusion-limited.

                             Sincerely,  Don Forsdyke
                             Discussion Leader. Bionet.immunology



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