Self/nonself discrimination

Dr M.R. Clark mrc7 at cus.cam.ac.uk
Wed Aug 10 11:20:55 EST 1994


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 (Ken
>>>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 each
>>
>>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      t
>>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.
>                            Sincerely,  Don Forsdyke
>                                        Discussion Leader. Bionet.immunology
i
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.
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.
Mike Clark





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