Evolution of the immune system

L.A. Moran lamoran at gpu.utcs.utoronto.ca
Fri Dec 4 15:18:54 EST 1992

Don Forsdyke asks,

     "But Larry, is it not true that certain evolutionary developments
      virtually arrest certain species in a frozen state so that other 
      avenues of evolution are closed off for them. Once the giraffe 
      had decided to go the route of elongating its neck it rapidly 
      reached perfection regarding its particular ecological nitch. 
      Necks evolved long before the giraffe, but if one wanted to study 
      the properties of necks, the giraffe, rather than Homo sapiens 
      would seem an ideal example."

I'm not sure that I understand Don's point here. Every single extant species
is the product of many years of evolution and they all have specialized
characters of one sort or another. While it's true that not all avenues
are equally accessible (we are unlikely to sprout wings, for example), I don't
think that it is helpful to think of any species as being in a "frozen state".
Don, did you mean this as an argument in favour of "living fossils"?

By the way, if one wanted to study necks in general then giraffes would be
the worst organism to choose since it has a such a specialized structure.
It would be better to concentrate on organisms that had more common looking

I mentioned that 'phage and viruses have sophisticated defense mechanisms
that were probably not evolutionarily related to those of mammals. This
prompted the following from Don Forsdyke:

     "I presume here you are talking about interactions of viruses with
      their hosts. These are largely intracellular (e.g. the evolution of
      restriction enzymes by bacteria and anti-restriction enzymes by 
      phage). Now, are you saying that the immune systems of mammals do 
      not have an intracellular component? What is all this business about
      intracellular processing of protein antigens and peptide presentation 
      in association with MHC class I? Can we learn anything from the great 
      facility of bacteria to form inclusion bodies of expressed FOREIGN 
      proteins? I think you go too far in saying it is "unlikely" that this 
      is evolutionarily unrelated to mammalian intracellular immune 

Actually I was thinking about tail fiber genes and the fact that they have
a constant region and a variable region that is involved in interactions
with the bacterial receptor. Some 'phage have a number of variable regions
that can be attached to the constant region by recombination. This gives
rise to different tail fibers that alter host range specificity. The genes
for bacterial receptors also show considerable variation in different strains;
this is presumably a result of selection for 'phage resistance. Restriction
and modification are other examples of bacterial defense mechanisms.

I stand by my statement that these mechanisms are not evolutionarily related
to those of the mammalian immune system. This does not mean that the 
bacteriologists can't profit from the knowledge gained through immunology
and vice versa. Different organisms may use similar strategies and mechanisms
that are not necessarily related by evolution. Comparative studies are very
profitable because they broaden one's horizons and stimulate thinking in
new directions. We lose this advantage if we try to interpret everything in
terms of its relevance to mammalian immunology or if we believe that the
mammalian systems are the most "advanced" and everything else is primitive.

Finally, Don closes with;

     "Well, Larry, what about the heat-shock proteins. Highly conserved 
      and guess where some of them map on mammalian chromosomes...the 
      MHC complex!"

The HSP70 genes are found in all living organisms. In eukaryotes there are
several different HSP70 genes that form a gene family. The most important
are hsc70, which produces an abundant cytoplasmic product found at all times
in all cells, and BiP, which is also expressed in all cells and localized
to the endoplasmic reticulum. In addition there are genes for mitochondrial
and chloroplast versions of HSP70's (mBiP and cBiP in my terminology) and
some genes that are developmentally regulated. Most eukaryotes also have
a few genes that are strictly inducible by stress, they are assumed to be
involved in the repair of damage caused by stresses such as high temperature.

These genes are the most highly conserved genes known in all of biology and
this reflects their fundamental importance as chaperones that catalyze the
folding of proteins and their assembly into macromolecular structures. It
is not surprising that MHC class I and class II molecules might use chaperones
such as hsc70 and BiP since evolution of this system in vertebrates is a
relatively recent event while the functions of the chaperones have been
honed over millions of years. (Other chaperones are also important.)

The genes found in the MHC locus of mammals are the inducible genes that have
nothing to do with the immune system as far as we know. There are dozens of
genes in this region that do not play a role in antigen presentation. The
important genes are hsc70 and BiP and they map elsewhere.

Speculations in the literature that there is an evolutionary relationship
between HSP70 genes and class I genes are not supportd by the data on 
alignments - there is no such relationship. Attempts to force a class I
structure on the C-terminus of HSP70's by making predictions of secondary
structure are also without value. I don't know where class I and class II
molecules came from but they certainly didn't evolve from an HSP70 gene.

Don, I realize that I may be overreacting to your comment. Can you explain
why you think that it is significant that some of the stress inducible
members of the HSP70 family map to the class III region along with many
other genes that are not functionally related to histocompatibility?

Laurence A. Moran (Larry)

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