"Danger" or "Alarm"?

John H. johnhkm at netsprintXXXX.net.au
Thu Feb 24 21:55:29 EST 2000


Over the past few months I've been attempting to understand neuro-immune
interactions and noting this thread it seemed to me that that the idea of
the immune system being simply about good guys and bad guys is a hopelessly
constrained view of the immune system.

I've been ploughing through the reading at a fair rate but my understanding
lags behind the plethora of data. The immune-cns interactions clearly
indicate that the immune system plays an important regulatory role, even in
non-pathological states, in general homeostasis. il1 levels vary through
light periods and so help to regulate sleep and appetite, as does tnfa, and
both of these act independently. Rich fatty diets ("cafetaria diet") will
after 4 days substantially raise il1 in the gut, leading to vagus nerve
activation of cytokine stimulation and release in the CNS (hypothalamus I
believe), thus increasing sleepiness and loss of energy in high fat diets;
probably because il1 has also been shown to inhibit glutamate (primary
excitatory neurostransmitter). I'm wondering if this explains some of the
effects of minimal caloric intake diets.

There is also a series of confusing interactions between the glucocorticoids
and some cytokines, leading to further of as yet poorly understood
downstream effects (eg, crh release - mast cell degranulation, tnfa,
histamines, serotonin release, too much stress and hippocampal cells go a
dying via apoptosis). The CNS generally seems to exist in a rather uneasy
relationship with the immune system (hence the blood brain barrier, many
neuropathologies appear to be partly immune response "driven") and at
present I am led to believe that the immune system is not some "fully
integrated defence system" so much as a series of strategies culled over
time to address whatever contingencies may arise. (Although the degree of
evolutionary preservation of apoptotic pathways is quite remarkable!)

The self - non self may be a good start but it is only that and ultimately
misleading. Cells can undergo apoptosis through a variety of mechanisms and
my guess here is a sort of probability function, generally the immune system
gets it right but even in all of us it is making mistakes. A full
understanding of the immune system will not be possible unless the model
includes the functions of the immune system in relation to various other
biological systems(CNS, HPA axis, cell differentiation and morphology). You
need more than molecules to understand complex systems. Perhaps James Clerk
Maxwell, that old wily physicist, can help, "The laws of probability is the
true logic of nature."

Another confusing issue I am confronted with is the fact that tnf belongs to
the cytokine superfamily incorporating ngf, nerve growth factor, and has
some affinity for trka and p75ntr, neurotrophin receptors (this being one
possible pathological immune process). I find it paradoxical that such a
primary immune cytokine should share such similiarity with the primary nerve
growth factor ngf and over expression of tnf can significantly and dose
dependently alter ngf levels in varying levels throughout the cns (some
areas up, others down) and of course lack of trophic factors leads to ... so
perhaps tnf a can cause "auto apoptosis" in some cns regions. Vaguely, I
remember reading that the immune and nervous systems have similiar embryonic
origins, and given that these two biological systems are the most powerful
mnemonic systems in nature may be that should not be surprising(memory is
the bedrock of intelligence). Nor such intricate interactions between the
two for that matter.

Maybe the general perception is that immunology is about good guys and bad
guys but clearly the immunologists I've been reading don't think about it in
those terms. I can't even see the functionality of the axiom. In point of
fact I cannot recall one instance where this metaphor was used. Well, except
here.

Good luck to you immunologists 'cause you're gonna need it,
(v. interesting though)


John H.
Remove 4x


Mike Clark <mrc7 at cam.ac.uk> wrote in message
news:ant221927354Pk=+ at mrc7acorn1.path.cam.ac.uk...
> In article <38AC84C2.C0BFCAC8 at home.com>, D Forsdyke
> <URL:mailto:forsdyke1 at home.com> wrote:
> [snip]
> >
> >      Thus, "self" is the ULTIMATE FRAME OF REFERENCE in a
> > biological system. Self is that which is encoded in your
> > genes at the time of your first appearance on this planet.
> > Genes which change during your life (so that different gene
> > products are synthesized) may either be considered as still
> > "self" (e.g. antibody variable region genes), or be considered
> > as transformed to "not-self" (e.g. a potential oncogene, ...
> > which you hope the immune system will attend to).
> >
> Hi Donald,
>
> I've been away at conference so I'm picking up this thread on my return.
>
> Do you really think in this context antibody V-genes are always seen as
> self? I've made several anti-idiotypic antibodies in the past and the
> easiest way to ensure the anti-idiotype is to immunise the same strain of
> animal from which you got the original idiotype. This avoids the plethora
> of anti-Fc and anti-allotype antibodies that you get when immunising other
> strains or even species.
>
> I strongly suspect that we are not tolerant of all of our self
> immunoglobulin idiotypes but we are on the whole naturally 'ignorant' of
> some, 'tolerant' of some and make 'anti-idiotypes' to the rest!
>
> Take a look at
>
> http://www.biospace.com/articles/020700.cfm
>
> This is a good example I think of where ignorance of immunology is
manifest
> in the biotech industry. The idea in the article is that because
transgenic
> mice with human V-genes make human like antibodies they will be
> 'non-immunogenic' in patients. The 'false' marketing  assumption made
about
> these mice is that immunogenicity is only a function of sequence.
Hopefully
> no serious immunologist would these days adhere to this concept?
>
> >     I have an uncomfortable feeling that I have not thought this matter
> > through as thoroughly as I should have done. Advice/input/ opinion would
> > be welcome. For more, see the URL below.
> >
> > Donald Forsdyke. Discussion Leader. Bionet.immunology
> > http://post.queensu.ca/~forsdyke/prions.htm
> >
>
>
> Mike Clark,                        <URL:http://www.path.cam.ac.uk/~mrc7/>
> --
>  o/ \\    //            ||  ,_ o   M.R. Clark, PhD. Division of Immunology
> <\__,\\  //   __o       || /  /\,  Cambridge University, Dept. Pathology
>  ">    ||   _`\<,_    //  \\ \> |  Tennis Court Rd., Cambridge CB2 1QP
>   `    ||  (_)/ (_)  //    \\ \_   Tel.+44 1223 333705  Fax.+44 1223
333875
>






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