Self/nonself discrimination

[FORSDYKE at QUCDN.QueensU.CA]

In article <32m3kjINNso8 at early-bird.think.com>, york at mbcrr.dfci.harvard.edu (Ian
A. York) says:
>In article <94226.084939FORSDYKE at QUCDN.QueensU.CA> <FORSDYKE at QUCDN.QueensU.CA>
>writes:
>> . . . there is the
>>possibility that, over evolutionary time, each gene fine-tunes its protein
>>concentration to the other proteins with which it has been travelling through
>>time.
>
>But.     (1) If that were the case, surely the evolutionary pressure on
>intracellular parasites would ensure that they too would produce their
>proteins below the aggregation threshold, thus preventing antigen
>presentation altogether.
>
             Yes, I quite agree. In the papers I elaborate on this and
             provide a rationale for the evolution of the heat-shock response
             which plays a critical role in ic s/ns discrimination. On the
             other hand, at some stage during the life-time of its host a
             pathogen may want to leave the host cell (e.g. virus). Thus it
             may be forced to exceed the concentration limit regarding its
             own proteins.

>        (2)  This discussion is based on the premise that normal
>intracellular proteins are not presented and therefore an explanation
>is needed as to why they aren't.  .  As I pointed out this is not
>correct; normal proteins are presented, the process of thymic education
>ensures that T cells do not respond to them.

         No, it is not based on that premise. One can postulate a threshold
         MHC occupancy rate below which no T cell stimulation would occur.
         The following quotation from the J.Biol.Systems paper may help:
         "Evidence bearing on the existence and effectiveness of an intracell-
          ular s/ns discrimination system might be obtained by comparing the
          ratios of peptides derived from self and from not-self proteins which
          could be recovered from the purified MHC molecules of cells infected
          with viruses (Rammensee et al, 1993). It would be predicted that
          virus-derived peptides would be selectively presented. Since s/ns
          discrimination would occur at the intracellular (ic) level, negative
          selection at the thymus level would be less important. Thus, there
          should be many peripheral T cells specific for MHC complexes with
          peptides derived from intracellular self proteins, as noted by Schild
          and coworkers (1990)."
                                 Sincerely, Don Forsdyke
                                 Discussion Leader. Bionet.immunology