>>> Posting number 22218, 
                                          dated 31 Aug 1997 04:06:43

Re: Vaccines and Autism: missing link
.....INTRODUCTORY POSTS.....
My readings have led to a possible connection, which I shall be presenting to the
autism list during the next day or several.

On Sun, 31 Aug 1997, Gregory... had written:
> it does seem that there is a susceptibility or a pre-existing immune
> dysfunction for the vaccine to have such an effect on the child.

Here is a not too technical summary. Consider the kids who plunged into autism
within days or weeks subsequent to a vaccination:
1.    The causal link between the vaccination and the onset of autism (in some
cases) may well have been the background presence of latent CNS-infection (ie,
already in place, dormant) by one of the herpes viruses, already in residence in
autism-related parts of the CNS when the vaccination occurred.
2.    My hunch is that, in these "few" kids, the damaging virus was probably HSV-1
or HSV-2 (in most cases), because they migrate toward temporal lobe and/or
orbitofrontal parts of the human brain.
3.    Neurons generally don't present a high number of MHC-I or MHC-II molecules,
which is part of the reason why HSV and other stealth-like viruses can hide in
neurons of the CNS. While the virus is dormant, the neuron does not die. With no
MHC-I or MHC-II presentation, the person's own immune system (eg, T cells and/or
microglia) will not act against those neurons.
4.    The vaccination (eg, MMR) will induce a high level of prolonged cytokines
release. Some of these cytokines (eg, interferon gamma) (IFN-g) can lead to MHC-I
expression in those neurons. Temporal lobe neurons that had already been latently
affected with HSV would then present small HSV-related proteins -- eg, in MHC-I
molecules now present on the neurons -- because the MHC-I expression was induced by
the IFN-g that had been induced by the vaccination.

    {This is about as non-technical as I can express these concepts.
    {I have citations to back up every step in the rationale.
    {I have not yet found an article presenting the entire rationale.

5.    The neurons likeliest to die would those that had already acquired a subacute,
non-viremic, latent infection with HSV-1 or HSV-2.
6.    Other deleterious processes can accompany vaccination -- eg, cerebral edema,
known preferentially to affect the temporal lobes and cerebellum (eg, cite 1; also
bax/bcl distributions). This kind of edema can occur even if HSV is not present.
7.    I'll bet most parents are skeptical about an HSV CNS connection in their own
child, but such a possibility can not be ruled out a priori, because the only
diagnostic steps that can verify or rule out "subacute, latent HSV in the CNS" (i)
are too invasive to have been used, and (ii) would have required a lab method still
not in widespread use (PCR).
8.    Recurrent otitis media (all those ear infections) are, in some kids, caused
by HSV, sometimes in conjunction with other bacteria and/or viruses and/or fungi
(eg, Candida).
9.    Nasal and gastrointestinal entry is also documented for HSV; again, when that
entry occurs, other critters are often present too.

Thus, I've come to believe that a small subgroup of autistics whose autism was
late-onset, in temporal association with vaccination, may have had a "subacute,
latent HSV CNS infection" as the causal link between the vaccination and the
occurrence of autism.
      Relatedly, the topic "common variable immune deficiency" (CVID) -- whether
genetic and/or infectious in origin --  will shed additional light upon yet another
subgroup of kids with autism, though a subgroup overlapping the vaccination/autism
kids. In other words, with citations presented in my CVID paper, some cases of CVID
are not "purely genetic" and are instead caused by one or another pathogen. 
      Thus, the immune deficiency mentioned by Gregory may, in some kids with
autism, have been the result of pathogens including HSV that had become latently
embedded in neurons of the temporal lobe -- just waiting for the fuse to be lit, the
vaccination's IFN-g release being the fuse; the embedded virus, a bomb about to
explode; onset of autism the result...
      Clearly, this model of causation does not account for most autisms but, as
justified by citations, may explain the sudden, post-vaccination onset of autistic
traits in a small subset if kids who had HSV already embedded (albeit subclinically
and thus unnoticed) in autism-related areas of the CNS. 


                                          >>> Posting number 37858, 
                                          dated 27 Feb 1998 20:26:39

.....MMR INCREASES INTESTINAL PERMEABILITY.....
Interferon gamma is the primary cytokine produced by children responding to a MMR
vaccination (1). Interferon gamma has long been known to increase intestinal
permeability and blood-brain permeability (eg, 6-8). We appear to be justified in
thinking that an MMR vaccination will augment tendencies towards increased
intestinal permeability and towards increased blood-brain barrier permeability. As
a result, various macromolecules will be able to cross these barriers in
extraordinary and not necessarily healthful ways.


                                          >>> Posting number 37859, 
                                          dated 27 Feb 1998 20:47:14
             Vaccinations: MMR, IFN-gamma, viral infections

.....MMR, INTERFERON-GAMMA, HSV.....
There is an additional ramification to the fact that interferon gamma is the primary
cytokine produced by children responding to a MMR vaccination (1). Consider a very
small subgroup of children (i) in whom herpes simplex or varicella had acquired
access into neurons of the CNS. The exterior surface of CNS neurons do not present
MHC-I molecules, a fact that various herpes-class viruses exploit as they live
within neurons. The non-expression of MHC-I molecules is one way that our nervous
system generally is protected against immune attack. However, interferon gamma is
one of the substances that tends to induce MHC-I expression. So, in my opinion, at
least some of the children who became autistic soon after a MMR vaccination may well
have had an extremely subclinical CNS infection by one of the neurotrophic
herpes-class viruses (eg, HSV1, HSV2, HHV3 or, somewhat differently, HHV6). The
intra-neuronal infection was latent and undiscovered by the child's immune cells
until (i) the MMR induced a sustained pulse of interferon gamma (1), (ii) the
latently infected neurons began presenting viral particles in the grasp of
IFNg-induced MHC-I molecules, and (iii) those neurons soon became targets for immune
activity and were killed or became apoptotic (and died).

Cites for many of these immune-related concepts have been presented several times
in prior posts a while or several ago. Fascinatingly, rapid loss of eye contact
subsequent to vaccination is one trait that could have been induced by the
vaccination-response mechanism outlined in prior paragraph, due to intraneuronal,
transynaptic migratory routes into the central amygdala (those cites too were
presented in the earlier posts).


REFERENCES

1. Pabst HF et al. Kinetics of immunologic responses after primary MMR vaccination. 
Vaccine.  15(1):10-4, 1997 Jan.
  To study the kinetics of humoral as well as cellular immunity to measles and to
test for associated immunosuppression 124 12 month old children were studied twice,
before routine MMR and either 14, 22, 30, or 38 days after vaccination. Plaque
reduction neutralization (PRN) titres were determined at these time points and
lymphocytes were evaluated to identify changes in proportions of phenotype, their
capacity to generate cytokines and to respond to blast transformation (BT) to
measles hemagglutinin (HA), tetanus toxoid and Candida antigen. The PRN titre and
BT to HA plateaued at 30 days and CD8+ and NK cells increased after immunization.
Interleukin 2, 4, and 10 showed no significant changes. There was mild suppression
of BT at 14 and 22 days post-immunization. Interferon-gamma was the principal
cytokine produced after primary measles immunization, suggesting primary measles
immunization induces predominantly a TH1 type response.

2. Madara JL.  Stafford J. Interferon-gamma directly affects barrier function of
cultured intestinal epithelial monolayers.
          Journal of Clinical Investigation.  83(2):724-7, 1989 Feb.
  Although epithelia, which often are in intimate contact with lymphoid cells, may
bear receptors for various cytokines, it is unclear whether cytokines directly
effect epithelial function. We examine the effects of the cytokine interferon (IFN)
on barrier function of cultured monolayers of the T84 human intestinal epithelial
cell line. Gamma IFN, in concentrations and exposures required to show its other
biological effects, directly affects such monolayers. Monolayer resistance is
substantially diminished by gamma IFN. Such effects were not due to cytotoxicity as
judged morphologically and by LDH assays. Solute fluxes and dual Na+-mannitol flux
analysis indicate that the resistance decrease is due to an effect of gamma IFN on
tight junction permeability. The effects of gamma IFN on monolayer barrier function
were not duplicated by the cytokines interleukin 1, interleukin 2, or tumor necrosis
factor. We speculate that such products of activation of lymphoid cells might
influence barrier function of intestinal, and perhaps other epithelia in disease
states.

3)  Huynh HK.  Dorovini-Zis K. Effects of interferon-gamma on primary
cultures of human brain microvessel endothelial cells.
          American Journal of Pathology.  142(4):1265-78, 1993 Apr.
  Primary cultures of human brain microvessel endothelial cells were used to study
the effects of human recombinant interferon-gamma (IFN-gamma) on cerebral
endothelium in vitro. Incubation of monolayers with various concentrations of
IFN-gamma (10 to 200 U/ml) for 12 to 96 hours induced surface expression of class
II major histocompatibility complex (Ia) antigen in a time- and
concentration-dependent manner. In immunogold-stained cultures, labeling was
observed as early as 12 hours, was maximal after 48 hours, and persisted at plateau
levels in the continuous presence of the cytokine. Expression was blocked by
coincubation with anti-IFN-gamma antibody and was reversed 4 days following removal
of IFN-gamma from the culture media. Endothelial cells treated with IFN-gamma for
3 to 4 days became spindle-shaped, extensively overlapped, and frequently formed
cellular whorls. These changes did not occur in the presence of anti-IFN-gamma
antibody and reversed upon removal of IFN-gamma from the media. The morphological
alterations were associated with increased permeability of confluent monolayers to
macromolecules as compared with untreated cultures. The results of these studies
indicate that human brain microvessel endothelial cells respond to in vitro cytokine
stimulation by undergoing profound morphological, functional, and permeability
changes. We conclude that cerebral endothelium may play an important role in the
initiation and regulation of lymphocyte traffic across the blood-brain barrier in
inflammatory disorders of the human central nervous system.

4. Planchon SM et al. Regulation of intestinal epithelial barrier function by
TGF-beta 1. Evidence for its role in abrogating the effect of a T cell cytokine.  
Journal of Immunology.  153(12):5730-9, 1994 Dec 15.
     Maintenance of the integrity of the single-cell-thick intestinal epithelium as
an in vivo barrier between environmental Ags and mucosal immunocytes is pivotal for
health. The T cell cytokine IFN-gamma consistently disrupts this epithelial barrier
in vitro...

5. McRoberts JA.  Riley NE. Modulation of growth factor and cytokine-induced
increases in T84 cell monolayer permeability by media components.      Am J of
Physiology.  267(2 Pt 1):C537-43, 1994 Aug.
  Previous studies have shown that insulin, insulin-like growth factors, and
interferon-gamma cause an increase the paracellular permeability across T84 human
colonic epithelial cell monolayers... Together, these results strongly suggest that
insulin, insulin-like growth factors, and interferon-gamma increase the permeability
across T84 cell monolayers through a common mechanism that is modulated by
glucose-derived metabolites and oxidative metabolism.

6. Adams RB et al. IFN-gamma modulation of epithelial barrier function.
Time course, reversibility, and site of cytokine binding.
Journal of Immunology.  150(6):2356-63, 1993 Mar 15.
     The single cell-thick intestinal epithelium forms a crucial barrier between the
host and environment, and is modeled in vitro by a monolayer of polarized, highly
differentiated T84 epithelial cells impermeable to most macromolecules because of
functional intercellular tight junctions.       [Intestinal CMV is another way to
increase permeability.] ...our data demonstrate 1) only the monolayer's basolateral
surface is IFN-gamma responsive, whereas the apical (microvillous) surface is no;
2) the alteration in electrical resistance of epithelium is prolonged (5 days), even
after a single (24 h) exposure to IFN-gamma, but nevertheless is reversible; 3) the
effect is likely receptor-ligand mediated, because it can be partially blocked by
IFN-gamma receptor-specific monoclonal Ig; 4) an alteration in tight junction
function (a paracellular pathway) rather than cell necrosis or a transcellular
pathway is responsible for IFN-gamma-induced monolayer dysfunction because
permeability to a 44,000-Da macromolecule (horseradish peroxidase) did not increase,
and intracytoplasmic T84 cell enzymes were not released into the media; and 5) the
biologic phenomenon could not be induced by a species (alpha) of class I IFN, making
IFN-gamma reasonably unique in this regard. Given the proximity; activation status,
and capacity of T lymphocytes for cytokine production in mucosa, we suggest that
IFN-gamma-induced changes in epithelial permeability may be a major cause of altered
intestinal barrier function in vivo.

7. Madara JL.  Stafford J. Interferon-gamma directly affects barrier function of
cultured intestinal epithelial monolayers.  Journal of Clinical Investigation. 
83(2):724-7, 1989 Feb.
8. Huynh HK.  Dorovini-Zis K. Effects of interferon-gamma on primary cultures of
human brain microvessel endothelial cells.  American Journal of Pathology. 
142(4):1265-78, 1993 Apr.


                                         >>> Posting number 22244, 
                                          dated 31 Aug 1997 10:20:11
Re: Vaccines and Autism: missing link, herpes?


.....CONVERSATION WITH A PARENT.....
On Sun, 31 Aug 1997, Linda... wrote:
> ...Thank you for posting this, I had almost ruled out HSV-I and HSV-II.
> I was under the false impression that ELISA was a confirming evaluation > of
titres. I would also be interested if these children could have come > in contact
with this virus at delivery and/or by c-section. Having a 
> completely normal pregnancy and aquiring leg weakness that lasted for
> years after the surgery has always made me curious...


Tc: Acquisition of HSV is known to occur during the parturition, during the neonatal
period, and even later. If a neonate shows signs of raging HSV viremia, everyone
will notice and treatment will ensue. I am more interested in cases wherein the
neonatal and/or infant's HSV, if at all, will be far less severe, thus will not
receive treatment, and may (with regard to the periphery -- skin, blood, mouth, etc)
be suppressed by an otherwise healthy immune system. In such cases, the virus' entry
into the peripheral and/or central nervous systems may occur gradually, may not be
noticed, may require additional factors (eg, prolonged diarrhe or HSV otitis), and
may become quite focal within the CNS, with gradual migration into one or another
focal locales within the temporal lobes.
      Importantly, no one knows the extent to which this has occurred in kids with
autism -- if at all (and as anecdotal responses to acyclovir suggest); the
occurrence would be only in a subgroup, eg, 1%, 5%, 15%, 30% etc, and no one knows
the size of this subgroup. But, in appropriate kids, when CNS HSV is identified
early and acyclovir is started promptly, neurological sequelae are far less drastic.

      Thus, I wonder how many cases within the autistic-spectrum may be the result
of unperceived, undiagnosed, untreated HSV that, while minimally or seldom apparent
peripherally, nonetheless progressed gradually and quite focally into autism-,
aphasia, and/or epilepsy-related areas of the CNS?

Regarding sources of HSV: it is so prevalent, so all around, and one article now
somewhere in the piles mention it could come from anyone who had contact with the
neonate/infant. Dad, nurses, siblings, and many etc.
      Your leg symptom may or may not be linked. My conversational hunch is that a
possible (and certainly not proven link) might occur because HSV can enter neurons
of the peripheral nervous system and therein also be quite focal. But your phrasing
suggests that the leg weakness finally went away, so the leg weakness link is
another of autism's tantalizing mysteries.

Thank you for sharing!


.....POSTING HISTORY.....

>>> Posting number 22218, dated 31 Aug 1997 04:06:43
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock 
Subject:      Re: Vaccines and Autism: missing link

>>> Posting number 22244, dated 31 Aug 1997 10:20:11
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      Re: Vaccines and Autism: missing link, herpes?

>>> Posting number 37858, dated 27 Feb 1998 20:26:39
Date:         Fri, 27 Feb 1998 20:26:39 -0700
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      Vaccinations: MMR, intestinal permeability, interferon gamma

>>> Posting number 22273, dated 31 Aug 1997 17:28:29
Date:         Sun, 31 Aug 1997 17:28:29 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      Re: MMR Vaccines and Autism & herpes as missing link?