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Formal Challenge

John H. johnhas at tpg.com.au
Sun Feb 15 04:51:56 EST 2004

Thanks Neil,

Been away myself so haven't had time to look at this closely but a few

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?

> 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".

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.

> 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.

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.


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 ... .



"NMF" <nm_fournier at ns.sympatico.ca> wrote in message news:<hPGWb.12600$y07.493096 at news20.bellglobal.com>...
> Hello John H.,
> Sorry I did not respond earlier but I have been out of town. With respect to
> your question on epilepsy and immunosuppression the field undoubtedly
> complex, however, I will present to you that data that is most prudent to
> the connection between limbic (temporal lobe) epilepsy and the experimental
> allergic encephalomyelitis (EAE) model of multiple sclerosis.  (This email
> response was written directly to John H. with relation to the specific
> questions that he asked.  Thus this email is rather long, but please free to
> respond with your comments).
> Complications with the immune system are commonly reported in patients
> affected with temporal lobe or limbic epilepsy.  Often these patients report
> and are found to exhibit greater incidences of colds, flues, or some other
> related immunocompromised illness.  (Ader wrote a chapter on it in
> Psychoneuroimmunology. published in the early 1980's  by Academic Press (?),
> that can be referenced to show the immunal changes associated with epilepsy.
> Also Engel's work is prudent here and can be referenced).  Even direct
> hemodynamic measures will reveal that the immune system of epileptics is
> essentially compromised and shows the patterns of chronic immunosuppression.
> Considering the copious interconnection between the
> entorhinal-hippocampal-amygdalar complex with the hypothalamus (specifically
> in this case with the anterior hypothalamus), direct influence by these
> pathways upon humoral and cellular immunity is extremely likely.
> Considering that limbic epileptiform activity will propagate along related
> efferent trajectories, activation of the hypothalamic region by this
> epileptic activity will routinely elicit potent anterior hypothalamic
> effects (a parasympathetically driven immunosuppressive response) on the
> nervous system and body.
> The original work by my colleagues Falter, Persinger, Chretien (1992) showed
> that there is a suppression in the secondary humoral response
> (immunosuppression) following lithium-pilocarpine induced seizures.
> (Lithium-pilocarpine is a routine model for evoking limbic seizures in rats.
> This model can reliably evoke similar mosaics of neuronal damage and
> behavioral consequences that are commonly reported in human forms of
> temporal lobe epilepsy and hippocampal sclerosis.  Generally, pretreatment
> of lithium is 4 hrs. or twenty four hours before a single systemic injection
> of the muscarnic agonist, pilocarpine can evoke behavioral convulsions and
> electronencephalographic seizures).  In this experiment the animals were
> previously exposed to some antigen - in this case they used human serum
> albumin (dissolved in Freund's adjuvant") in order to elicit a primary
> humoral response.  Giving a second injection of human serum albumin at  some
> latter time point will be associated with a heightened immunofacilitative
> response (i.e. the secondary humoral response.  This type of immune response
> is that basis of the mast cell degranulation-induced anaphylatic shock,
> which is associated with the direct vasodilatory action of released
> histamine by mast cells on proximal blood vessels and the consequential
> accompaniment in blood pressure drop that could lead to affixation).  They
> found that if you elicited seizures immediately after injecting human serum
> albumin the animals would display a marked immunosuppressive effect five
> days later.  However, assessment of humoral and cellular immunity through
> antibody binding capacity assays, showed us that a compensatory
> immunofacilitative effect occurs approximately 10 days following seizure
> induction.  Although they did not explore it in this paper, the original
> immunosuppressive effect is ultimately tied to the elevated levels of
> glucocorticoids that accompany the seizure induction process.  The
> glucocorticoids, or corticotrophins, are potent immunosuppressors - but this
> effect is dissipated and accompanied by a rebound in T-cell productivity by
> 10 days after seizure induction.
> Now here is where the issue becomes extremely complex.  In the EAE model,
> the inoculation procedure that causes the subsequent central demyelination
> is caused from the subcutaneous injection of emulsified extracted spinal
> cord (in Freund's complete adjuvant) into the hind footpads into a Lewis
> rat.   At different time points after inoculation if you induce epilepsy
> (through lithium-pilocarpine) differential activation of the immune system
> will occur.  Subsequent studies have shown that if you induce limbic
> seizures seven days after inoculation, there is a potent immunosuppressive
> response.  The animals also display less severe clinical manifestations of
> EAE (this is assessed behaviorally on a 5 point scale). Moreover, these
> animals also do not show the eventual conspicuous break down of myelin.
> Because the elevation in corticotrophin levels is significantly high the
> subsequent suppression of activated T-cell lymphocytic response will occur.
> Hence, the demyelinative action that occurs as a response of the
> hyperresponse of the immune system (through activated T-lymphocytes) by the
> EAE inoculation procedure is consequentially suppressed by the accompanied
> immunosuppressive action of the seizures.
> 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.
> The bidirectional effect of immunal responses accompanying limbic seizures
> suggests that the temporal process are scalar (show only magnititude) by
> nature.  That is the seizures facilitate the size of the inflammatory
> (immunal) response with little or no direct effect on the development of the
> inflammatory response.  Moreover, the bidirectional response in immunity is
> most likely mediated through the action of circulating corticotrophins.
> Considering that Gallagher's work have shown us that the afterdischarge (AD)
> duration following limbic stimulation has bidirectional components: that is
> ADs that are greater than 10s are accompanied with an increase in
> corticotrophin levels (and subsequent immunosuppressive properties),
> whereas,  ADs that are less than 10 s are associated with decreases in
> corticotrophin, it is very likely that the timing of the limbic seizure in
> conjunction with the temporal interval associated with EAE inoculation
> alters the magnitude of immune response.  Also bidirectonal compensatory
> changes in immunal responses, that is oscillations between immunosuppressive
> and immunofacilitation, can be influenced by the time of day treatment and
> the original state of immunal response in the animal at the time of
> treatment are all well-established findings.  All of this is ultimately
> derived through changes in the autonomic nervous system.  This is why
> specific treatments for some cancers are more beneficial during the
> circadian dominance in parasympathetic activity (i.e. during nocturnal
> periods), where immunofacilitative processes are at their highest and
> immunosuppressive actions are at their lowest.
> 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.  The reason for
> why this occurrence occurs is not known, but the reference you provided by
> McNamara is extremely important for providing some of the theoretical
> framework for why this occurs.   A review of the clinical literature will
> (or at least should) show you that the lability in the temporal lobe (and
> mesial basal regions, i.e. limbic system) is often significantly increasing
> following closed head injuries.
> In the context of what was presented earlier, I will provide you with my own
> theoretical (potential) explanation for this occurrence.  Following an
> initial head injury, there may be an associated increase in the lability of
> limbic regions (within the entorhinal-hippocampal-amygdala circuits for
> evoking epileptiform activity (i.e. seizures)), or at least the
> predisposition for developing such liabilities.    A common methodological
> practice for assessment of expected head injury cases is the referral to
> have magnetic resonance imaging diagnosis.  From this there is a possibility
> of a complex interaction from many seemingly independent variables.  When
> one considers that major transient changes (lasting ~ 3h.) to the blood
> brain barrier permeability occurs following MR imaging (a well-established
> finding that has been consistently demonstrated using gadolinium leakage
> techniques) and that cholingeric compounds are routinely used for the
> treatment of patients with head injury, the accompanied change in
> permeability of the blood brain barrier is sufficient to induce slight
> microhemorrhaging within the brain that could induce a mild immunal
> activation.  Moreover, cholinergic compounds can significantly perturb
> already predisposed epileptic foci to discharge (i.e. produce seizures).
> Considering from the previous work presented by Falter and colleagues (1992)
> and Missaghi and colleagues (1992), the importance of the temporal proximity
> between limbic seizures and accompanied immunal response, the original
> permeability change in the blood brain barrier and consequential
> microhemorrhaging into the surrounding parenchyma is extremely likely to
> produce an over-facilitation of this originally mild immunal activation.
> The over-faciliation of this immune reaction can over time lead to the
> development of demyelinating conditions and related symptomotology.
> It should also be noted that the high intensity magnetic fields associated
> with MR are not the only manners whereby one could induce transient changes
> in blood brain permeability.  One common finding is that  ELF (extremely low
> frequency: approximately 1 Hz to 1 kHz range) pulsed electromagnetic fields
> can induce significant permeability changes in blood brain barrier (Persson
> et al., 1992).  The intensity of some these time-varying electromagnetic
> fields are comparable to the type of processes found within natural (i.e.
> during some sudden commencement geomagnetic storms) or within some
> artificial (i.e. home environment with complex electronic gadgetry)
> environments.  A variety of thereotical and experimental reasons have been
> given as to why time-varying  fields may possess such biorelevant actions
> (see Sandyk, 1999; Terao and Ugawa, 2002; Persinger et al., 1972), the exact
> mechanism(s) regading how these  fields can evoke changes in the blood-brain
> barrier is currently not know.  Taken together, the consideration that these
> commonly occurring environmental conditions can interact significantly with
> the processes presented above strongly argue that demyelinating conditions
> may be evoked from the complex interaction of a variety of seemingly
> separate (or isolated) variables.
> Neil

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