Formal Challenge

NMF nm_fournier at ns.sympatico.ca
Tue Feb 17 01:08:13 EST 2004


Dear John H.,

> If chronic immunosuppression in epilepsy is induced by glucocorticoids
> then shouldn't we see other signs of this than just immunosuppression?
> Eg. Impact on hippocampus, changes in amygdala activity? If the
> glucocorticoids are that consistently elevated continuously then we
> might expect higher degrees of working memory deficit, increses
> incidences of cancer among epileptics?

This is exactly what you see.  The only problem is that you cannot assert a
direct casual role for elevated circulating glucocorticoids and the
processes you have suggested.  The brains of epileptics is obviously
associated with a variety of histopathological (i.e. neuronal dropout and
gliosis) and structural changes (i.e. mossy fiber sprouting).  The effects
on learning could very well be a reflection of the pattern of brain damage
exhibited in the brains of epileptic patients.  Which would be affected both
by the initial seizure disorder and related histological consequences as
well as by the pharmacological treatment employed to regulate convulsion
activity.  (More below).

 > Interestingly, if you induce the seizures on the same day that you
inoculate
> > the animal a potent immunofacilitative (immunoactive) response occurs.
That
> > is the animals displays a worsening of clinical symptoms associated with
> > EAE.
>
> This may be related to what Spolsky calls the "permissive period" of
> the stress response. Initially there is a rapid rise in cytokines
> facilitating an immune response but it takes a few hours for the
> glucocorticoid feedback to begin suppression. Thus as some studies
> have indicated acute stress increases the immune reponse. Additionally
> stress will induce mast cell migration across the BBB and CRF induces
> mast cell degranulation. Histamine and serotonin must impact on BBB
> function. I don't like the phrase "Blood Brain Barrier", should be
> "Blood Brain Border".

Exactly.  I really believe that pretty much every physiological system
exhibit time-dependent biphasic responses as well as compensatory
over-shooting processes.  The best example are the autonomic nervous system
for compensatory overshooting responses.  Another good example is GABA which
exhibit profound biphasic (excitatory and inhibitory) electrical responses
on cells.  (More below)

 Another issue I'd like to mention here is one study I read which noted
> differential immune activation depending on which paw, the left or the
> right, was subject to turpentine challenge. The laterality question
> basically, it seems right cortical activation seems to raise the
> immune reponse more so than the left.

We have never observed a difference regarding whether or not you inject
Freund's adjuvant in the left or right paw.  However, I do believe (don't
quote me on it) that there may be laterality difference regarding mast cells
degranulate on the right side of the body vs. left side of the body.
(more below)

 > One other interesting correlate that has clinical relevance is that
frequent
> > observation that following mild closed head injuries an extremely high
> > correlation with latter demyelinating processes is found.
>
> It is very common in the literature and very intriguing, hence my
> suspicion that myelin and\or ogcs are susceptible to immunological
> attack. OGCs constitively express hsp 50 on the cell surface and hsp
> 60 is a potent activator of the innate immune response via its
> endocytosis through scavenger receptors, I believe microglia can
> endocytose hsp60. Sometimes head injury commences ongoing
> degeneration, studies by Heim & Sontag have demonstrated dopaminergic
> cell loss occurring years after injury, a slow progressive decline. I
> have also noted studies showing, one year post injury, sustained NFkb
> activity and hsp 32 post injury. Given the hsp 32- iron linkage, and
> that dopaminergic cells contain high iron levels, and that iron
> facilitates reactive oxygen species generation, and the controversy re
> hsp 32 being sometimes protective and otherwise not, the latter
> through its ability to generate free Fe2, I wonder if on occasion
> self-sustaining low grade inflammation scenario is created and only
> needs a wink and nudge to to allow an adaptive\humoral driven response
> as occurs in EAE. I've been thinking about this for some time so
> pleased to note a recent article claiming that autoimmunity is
> principally driven by an out of balance innate immune response.

That's intriguing.   I wonder if heat shock protein 32 exhibit similar types
of action during epileptic seizures.  Microinjection of ferric compounds
into epileptogenic zones causes the elicitation of epileptiform and seizure
activity.  I've always wondered why dopaminergic neurons exhibit such high
levels of iron?  I know there are intense concentrations in the basal
ganglia (globus pallidus, substantia nigra), red nucleus, dentate nucleus
and mammillary body... but I never understood why particular aggregation of
this inorganic compound occurs int hese specific areas.  It seems that any
region of the brain that either plays a role in dementia-related processes
or rigidity shows extensive concentrations of iron.    (more below)

> Mild head injuries are starting to receive the attention needed. For
> years clincians have reported that some Mild head injury patients have
> ongoing problems, seem to suffer more from central fatigue, emotional
> lability, and heightened stress response. The data doesn't adequately
> differentiate types of mild head injury, it seems though that the
> effect is generic irrespective of where the injury occurred. One angle
> I would like to explore here is the possibility of permanent changes
> being induced in the BBB. Another intriguing possibility to explore is
> the work of Fleishman et al on Dendritic cells which have been
> demonstrated to remain at a cerebral injury site long after injury and
> are key regulators of APC reponses. There are other studies showing
> DCs will migrate back from the brain to lymphatic sites and it would
> be very interesting to see if DCs are resident in the Choroid Plexus.
> For your purposes I think a close look at DCs may be worthwhile.
> Microglia can also ramify into a DC like state. There is very little
> work on DCs in the CNS, I have a few refs, can provide if you wish.
> I pushing the above line because in cases of mild head injury with no
> obvious morphological changes problems persist. Hence not a physical
> injury per se but a change in immunological status within a given
> region of the CNS.

I completely agree with you.  It interesting that a subpopulation of those
patients following mild closed head injury often develop symptoms that are
indicative of an epileptic spectrum disorder.   Patients often report mild
to moderate functional deficits following injuries.  Often imaging,
electroencephalographic, and neurological examinations will come back
negative and unfortunately "functional" labels reserved for psychological or
psychiatric settings are commonly employed.  As you said there can
definitely be a variety of pathological changes, including immunological
(which would explain the high concordance of myalgic encephalomyelitsis,
chronic fatigue disorder), that may not be discerned through conventional
methodologies.  Often the length of time between the initial injury and
subsequent onset of injury are to great to be discerned as being causal
related.  Once again the example that we have been talking about between MS
and head injuries is a prime one.  It can be many years between a head
injury and the latter development of MS, so great that the capacity to
discern temporal association can not be readily discerned.

In case you are wondering dendritic cells are found in the choroid plexus as
well as in the meningeal layers.  (more below)

>
> MRIs
>
> Know bugger all about them but noted one study which cited a number of
> refs indicating that MRI imaging is subject to a number of factors
> which can repaint the picture.
>
> Have noted studies that indicate mast cells can be sensitive to the
> types of fields emitted by mobile phones but that's a contentious area
> ... . Nonetheless I have no doubt that electromagnetic fields can have
> both profound and subtle effects. Now excuse me, I'll put on my
> Persinger helmet, turn on the magnet, and visit God ... .
>
> Thanks,

The debate is still out there for electromagnetic sensitivity and
deleterious sensitivity to the electromagnetic signals emitted by moblie
phones.

I have actually tried the "helmet" and been exposed to those fields numerous
times, each with extremely interesting results.

Sincerely,

NMF





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