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

Pierre sonigo at cochin.inserm.fr
Mon Feb 7 13:21:15 EST 2000


----- Original Message -----
From: "Jamie Cunliffe" <cunlij at my-deja.com>
Newsgroups: bionet.immunology
Sent: Saturday, February 05, 2000 11:13 PM
Subject: Re: The immune system is dead! Long live the immune system!


> In article <389C4454.851B9936 at home.com>,
>   D Forsdyke <forsdyke1 at home.com> wrote:
>
> >   Try this. Disorder is when something "not-self" happens. "Not-self"
> > may be a foreign bug, or "self" that has gone sour so that it is now
> the
> > same as "not-self". Are we just using different words to describe the
> > same thing? Ultimately, we have to get down to the chemistry so that
> we
> > can understand why "disorder" and "not-self" can be equated.
>
> New perspectives are usually about describing the same facts in
> different words. What you are saying here seems to me to be pretty much
> the same as the concept of (whole cell)-healthy-self and (whole cell)-
> other-than healthy-self.  And, yes, ultimately, we might be able to get
> to describe what is happening at a quantal level, let alone a chemical
> level; but until that is possible a more analogous model is helpful.
>
> You have (earlier) implied a need for internal cell surveillance - a
> process whereby individual zygote-derived-cells monitor their own
> internal health. Now, David Lo's group have come up with some objective
> facts that support this contention strongly (Immunological Reviews 169
> p225, 1999, Integrating innate and adaptive immunity in the whole
> animal).
>
> What I believe we must do is to escape from this old idea that antigens
> are divided into self and non-self (the foeatal/neonatal imprinitng of
> self ) and that there is a horror autotoxicus to self antigens. Far
> from avoiding attack on self antigens the system is as happy to use
> self antigens as it is to use foreign antigens when they are presented
> in a stressed/messy presentation (disordered presentation). It is only
> the fact that the lymphocyte pool has been greatly depleted of self-
> reacting lymphocytes simply because of the mass apoptosis (controlled
> shutdown) that goes on constantly in the body. The vast mass of self
> cells that become disordered sense the crisis internally and do the
> decent thing by apoptosing. I repeat below a paragraph from my web
> pages.
>
> The whole process works through differential rates of cell death.
> Irremediably dysfunctional cells are expected to do the decent thing
> and die early by trashing their cytoplasms. In the process, they
> sanitise their contents. The fact that infection is a frequent cause of
> intracellular dysfunction is of no interest to the system. Cells don't
> think 'I am - or you are - infected'. They realise 'I am - or you are -
> irrecoverably sick'. The corollary is that there is a differential
> nurturing of healthy-self-cells that are in junctional communication
> with their neighbours. The adaptive 'immune system' simply remembers
> some caricature of those cells (or their debris) that failed to do the
> decent thing last time and it then watches out for similarly
> caricatured cells (and their debris) the next time round.
>
> The real problem is the old, simplistic way of assuming that the system
> categorises antigens into self and non-self. This is, I contend, plain
> wrong and wildly misleading. An organism that doesn't cause stress or
> make a mess (create disorder) doesn't provoke any aggressive responses
> to its antigens.
>
> I am content that this presents a fundamentally different perspective
> from seeing the system as a "bug hunting system".  We need to
> vigorously exorcise this idea that the system is looking for bugs. OK,
> it latches onto the most unusual antigens associated with the mess left
> by PATHOGENS (which, by definition make a mess); this is not in
> dispute. This leads to the illusion that the system is a discriminator
> of self from non-self. I contend that it is not!
>
> Jamie

I understood that the self/nonself discrimination is a widely debated view,
because of some difficulties (schematically, amongst many) :
1) It is difficult to imagine theoretically an accurate mechanism for such
discrimination, given the diversity of self and non self.
2) It is shown experimentally that the discrimination does not hold
(autoimmunity, tolerance, etc.)

I do not understand how the replacement of "self/non-self" by
"mess/non-mess" solves the two points above, except by making the
theoretical fundations of immunology more messy ;)

1) How cells can recognize (are instructed to recognize) mess from non mess
?
2) Mess/non mess can explain everything because mess is even more difficult
to define than self.  So we can say anything to fit the theory : ie
autoantigens are self but messy, weak antigens are non self but non messy,
etc.

What do you think ?
Pierre







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