The immune system is dead! Long live the immune system!

Pierre sonigo at cochin.inserm.fr
Fri Feb 4 15:17:00 EST 2000


"Jamie Cunliffe" <cunlij at my-deja.com> wrote news:
87ccbf$ihv$1 at nnrp1.deja.com...
<snip>
> Let me first sum up the current perspective and then the challenging
> perspective.  The conventional view is as follows:
>
> "Hey guys (immune cells that is) the bugs are out there, let's go get
> and kill 'em. While we're about it we'll remember what they look like
> so that we can kill 'em quicker next time."
>
> The challenging view is:
>
> "Oops. Something's making a (tissue) mess. Better go tidy up the mess.
> While we're about it we'll remember the most unusual characteristics
> (antigenic signatures) of this mess so that we can be alerted quicker
> and be more aggressive next time a similar mess turns up."
>
> The article that brings all this to a head is the "From terra firma ..
> etc" article which is detailed at my web site
> (http://www.ndirect.co.uk/~greenprac/jamie/jamie%20main.htm) as are a
> series of other articles and comments that put meat on this challenging
> perspective. To loosen the old view's grip you will have to be prepared
> to sever your belief that the reigning "immune system" takes any
> POSITIVE interest in bugs other than a few (evolutionarily primitive)
> amoebocyte decisions about what is likely to be food ( - PAMPs and all
> that stuff).
>
<snip>
>
> Jamie

You might be interested in the following :

Clonal selection : cell competition for food

What kind of advantages could be obtained by selfish cells (as opposed to
the complete multicellular organism) during the immune response ? It was
proposed in the early ages of immunology, by Elie Metchnikoff or Paul
Ehrlich, that immune functions derive from nutritive functions. Since then,
multiple interactions between immunity and metabolism were studied, but
their mechanisms remain elusive (see ref. 9 for examples and discussion).
Such a difficulty might come from modern biology tending to classify the
molecular world between two entities: one set of molecules is seen as
involved in ubiquitous metabolic and house-keeping activities (for instance,
metabolic substrates and enzymes driving metabolic chains); the other
functionally distinct set would comprise those molecules involved in the
regulation of specific cellular functions (transcriptions factors, kinases,
antigens and signaling molecules, .). In contrast, in a Darwinian model of
embryonic development, such a distinction is absent. Cell differentiation is
not instructed by regulatory molecular signals. It is directly driven by
metabolism, providing the selective constraints stabilizing random
variations of cell phenotypes (10,11).


Is metabolic selection at the cell level able to provide a coherent
interpretation of immune cell differentiation and function ? The simplest
solution is that selection by signal would be replaced by selection by
resources. Such resources would be of a metabolic nature, as present in the
antigen. In the following story, let's examine the effects of this
translation : lymphocytes are depicted as diverse animals in a natural
reserve, and antigens as diverse food. The story illustrates that clonal
selection, leading to proliferation of the most efficient antigen-binding
cells, might be interpreted as a competition between specialized predators
for access to alimentary resources.


Mr Antigensignalling : The zoo director wants our research group to
determine exactly which food is the best for each animal in the reserve. As
food capture is a complex recognition and signaling system, we should take
one individual of each animal species in the reserve for complete molecular
dissection. Using detailed description of teeth, especially within frozen
aliment-teeth complexes*, digestion mechanisms, 3D structural models and
molecular design, we will surely determine how each specific food acts on
the reproduction of each specific animal.


Mr Antigenfood : That is a great idea. It will convince the zoo director to
buy a new powerful computer. So we can play the last flight simulator.


Mr Antigensignalling : Are you crazy ? We have a huge repertoire of billions
of rapidly reproducing and evolving animals in the reserve. With such a
diversity, we will have huge calculation needs to reconstitute every
molecular details.


Mr Antigenfood : Don't worry, Sig. The experiment is already ongoing without
the computer. First, I have asked to reduce the overall feeding in the
reserve. Then, every week, we provide only one kind of food. The animals
will compete for the food. At the end of the week, we just count the
animals. The animals who have the best capture and digestion efficacy for
the food will be for sure the most activated and reproductive in the
reserve. The less efficient animals have no access to the food. They just
sleep and are not able to reproduce.


Mr Antigensignal : Good idea ! And to make the animal reproduction and
activity more detectable, why don't we use food adjuvants ? Let's attach the
food to a big energetic molecule. **


* refer to crystals of antigen-antibody complexes.


** Immune response is more efficient when the antigen is associated to a
molecule called adjuvant. In an extreme situation, small molecules (haptens)
are not able to induce an immune response if they are not coupled to a large
protein (carrier) (see ref. 12 for a review). As the hapten is able to
interact specifically with the specialized antigen receptor, it remains at
present unclear within the signal-triggering representation why it is not
able to cause cell proliferation and activation when alone. This might be
more easily understood if lymphocyte proliferation does not require a
signal, but a metabolic advantage provided by the antigen as a nutritive
resource. The carrier molecule might thus constitute a metabolic resource
absent from the hapten.


Full text available at :
http://www.heraclitean.com/hbg/essays/immunometab_sonigo/

Pierre






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