>>> Posting number 22316, 
                                          dated 1 Sep 1997 11:08:27

.....INTRODUCTION.....
Readings in medical journals and sharings on the autism lists reinforce my
wondering, How many cases of autism are caused by subclinical viral-presence in the
CNS? PCR-based studies have shown that certain viruses can invade migrate into small
areas of the CNS, can do so without generating an obvious encephalitis, and in
various neuroanatomical locations can remain dormant for long periods of time. 
      One such virus is Herpes Simplex (HSV), which is strongly linked to
epilepsies, language loss, and limbic effects and may play a causal role in a
subgroup of kids with autism or Landau-Kleffner syndrome. However, HSV is
ubiquitous; many people, even children have anti-HSV antibodies, thus an important
issue is why would HSV be able to enter the CNS of a very few children while
allowing most to confine the virus in tissues outside the CNS? 
      One answer may be found amidst special circumstances such as prolonged
diarrhea, which would enable the virus to enter tissues of the gastrointestinal
tract, from which it is capable of migrating into the CNS. 
      Another answer may be found amidst Impaired Immunity, which can arise from
various causes, eg, genetic and/or infectious. For example, the findings of Reed
Warren and colleagues have established among autistic children a statstical link
between null (ie, non-functional) alleles of the complement-C4b gene, whose protein-
product has an important immunological function. In contrast, some immune-system
alterations are known to arise as an effect of various infectious agents -- eg,
viruses, bacteria, or fungi. In fact, these various infectious agents can, in some
individuals, induce an immune impairment justifying diagnosis as CVID, and in such
cases glutathione deficiencies are common.

.....CVID.....
From person to person, CVID has a wide range of clinical presentations. Many
"subtle" but very significant genetic-errors of T-cell function have been linked to
CVID. However, in some individuals, CVID may be induced by viral pathogens (eg,
3,5), often with a gastrointestinal link (eg, 1).
      In my herpes readings, I came across a study that mentioned a number of traits
(actually, signs and symptoms presented at a medical facility) that strongly echoed
many anecdotes shared by autism parents. Before presenting tidbits from Conley et
al (1), certain guidelines are helpful: 
      (i) CVID has a wide range of traits, symptoms, diseases and has much
      inter-individual variation, and 
      (ii) many medical articles about a disease or syndrome tend to focus
      upon severe cases, because they illustrate "ultimate" ramifications and
      classical forms. As a result, descriptions of individuals with less
      severe but nonetheless real manifestations do not always find their way
      into medical literature. 

Here are some apparent parallels between CVID and certain traits mentioned by many
parents who have participated on the autism-list:  Neonate/Infant period: "Six of
the eight patients had initial signs of the disease [CVID], persistent secretory
diarrhea, recurrent upper respiratory tract infections, or both, in the first year
of life." (1) And, in keeping with the "squeeky-hinge gets the grease, worst cases
get the attention" principle: "Autoimmune manifestations included idiopathic
throbocytopenia (4/8), hemolytic anemia (3/8), parotitis (2/8), and Guillain-Barre
syndrome (2/8)." (1)
      Now lets consider some symptoms occasionally mentioned by autism parents and
mentioned by Conley et al: "In addition to the expected sinusitis, otitis, and
pneumonia caused by encapsulated bacteria, these patients also had severe infections
with viruses of the herpes group." (1)
      And some additional findings: "Infections typical of hypogammaglobulinemia,
particularly otitis media and sinusitis, were seen in all patients...." Other
findings included, tho' not in every patient, Haemophilus influenzae, Camplyobacter
jejuni (& diarrhea), E. coli overgrowth (with diarrhea). (1)

The parallels continue: "Several of the patients had severe infections with viruses
of the herpes group... These infections usually occurred when the patients were not
being given gammaglobulin or immunosuppressive agents... several of the patients
were noted to have exacerbations of their autoimmune disorders in association with
upper respiratory tract or gastrointestinal infections, clinically attributed to
viruses... Infections that are associated with immunosuppressive therapy were also
seen, including pneumocystis pneemonia and mucositis caused by Candida albicans."
(1)      [remember, severe-cases in this article]
      In 4 patients, "Persistent, foul, watery diarrhea with steathorrhea" was seen.
"Additional gastrointestinal manifestations...[included] acholrhydria with severe
hemorrhagic gastritis, and chonic active hepatitis."(1) 
      "Specific antibodies directed against exogenous antigens such as ABO(H) blood
group substances, tetanus toxoid, rubella, and Epstein-Barr virus were usually
absent. This was true even before the onset of hypogammaglobulinemia in patient 4."
(1)
      "Patients 6 and 8 were born after prolonged...[parental]... infertility, and
patient 8 received an exchange transfusion in the newborn period for
hyperbilirubinemia." (1)

Tc:  In recent years, additional articles have described aspects of CVID. Many of
these articles explore genetic errors that affect "minor" aspects of T-cell
function. However, some authors published in respected journals appear to have found
a CVID-subgroup wherein certain infections may be the primary cause of the child's
having T-cell, B-cell, and antibodies patterns like those in the more traditional
(ie, genetic) CVID, as well as having illnesses associated with CVID (eg, 2-5).
     As we shall see, a crucial factor in infection-induced CVID may be *glutathione
deficiency* -- which can inhibit T-cell induction of B-cell activity. Furthermore,
several autism-parents have described their child's elevated levels of tumor
necrosis factor alpha, and we see that elevated TNFa is also a player in CVID
processes (eg, 2-6).
     Not only is glutathione an important intracellular antioxidant, but a
non-depleted amount of glutathione is needed for proper immune function; and amidst
these biochemical pathway, we find the word "sulfur" again and again -- as parent-
researchers Vicki, Minc, Susan et al have been saying -- see also cites 7-8, as well
as 2-6).
      Reference 9 describe cytomegalovirus in a gastrointestinal setting, a "worst
case, squeeky-hinge" case, in an adult, but nonetheless instructive regarding the
relationship between gi-tract viruses and some of the symptoms attendant therewith.

Teresa

<1>  Conley ME.  Park CL.  Douglas SD.
Childhood common variable immunodeficiency with autoimmune disease.
     Journal of Pediatrics.  108(6):915-22, 1986 Jun.
  Clinical and laboratory findings in eight patients with childhood common variable
immunodeficiency and autoimmune disease are described. Six of the eight patients had
initial signs of the disease, persistent secretory diarrhea, recurrent upper
respiratory tract infections, or both, in the first year of life. Autoimmune
manifestations included idiopathic thrombocytopenia (4/8), hemolytic anemia (3/8),
secretory diarrhea (4/8), arthritis (2/8), chronic active hepatitis (2/8), parotitis
(2/8), and Guillain-Barre syndrome (2/8). In addition to the expected sinusitis,
otitis, and pneumonia caused by encapsulated bacteria, these patients also had
severe infections with viruses of the herpes group... Additional findings included
fluctuating levels of serum immunoglobulins and markedly diminished in vitro
antibody production by B cells. The clinical course was relapsing and remitting, and
dominated by the autoimmune manifestations of the disease...

<2> Aukrust P et al. Decreased levels of total and reduced glutathione in CD4+
lymphocytes in common variable immunodeficiency are associated with activation of
the tumor necrosis factor system: possible immunopathogenic role of oxidative
stress. Blood 86.4.1383-91 1995.
<3> Aukrust P et al. Persistent activation of the tumor necrosis factor system in
a subgroup of patients with common variable immunodeficiency -- possible
immunological and clinical consequences. Blood 87.2.674-81 1996.
<4> Jaffe JS et al. Functional abnormalities of CD8+ t cells define a unique subset
of patients with common variable immunodeficiency. Blood 82.1.192-2001 1993.
<5> Suthanthiran M et al. Glutathione regulates activation-dependent DNA synthesis
in highly purified normal human T lymphocytes stimulated via the CD2 and CD3
antigens. Proc Natl Acad Sci USA 87.3343-7 1990.
<6> Robinson MK et al. Glutathione depletion in rats impairs T-cell and macrophage
immune function. Archives of Surgery 128.29-35 1993.
<7> Staal FJ et al. Glutathione deficiency and human immunodeficiency virus
infection. Lancet 339.909-12 1992.
        [Tc: although a focus is HIV, the article is an excellent
         review of glutathione pathways, including acetylcysteine,
         GSH-S-transferases, etc.]
<8> Staal FJ et al. Redox regulation of signal transduction: tyrosine
phosphorylation and calcium influx. Proc Natl Acad Sci USA 91.3619-22 1994. [much
on TNF-alpha herein too].

<9>    Freeman HJ.  Shnitka TK.  Piercey JR.  Weinstein WM. Cytomegalovirus
infection of the gastrointestinal tract in a patient with late onset
immunodeficiency syndrome.
       Gastroenterology.  73(6):1397-403, 1977 Dec.
  An adult with the late onset immunodeficiency syndrome developed intractable
diarrhea. Widespread cytomegalovirus (CMV) infection of the gastrointestinal tract
was detected antemortem with detailed morphological studies and viral culture. The
CMV-type cells were especially numerous in his severely ulcerated colon. Electron
microscopy of infected cells in rectal biopsy material revealed the characteristic
features of CMV infection. It is likely that the CMV infection contributed to the
symptom complex and the mucosal injury. Unusual opportunistic infections as a cause
of diarrhea should be considered in patients with late onset immunodefociency,
especially if Giardiasis is ruled out.

 
            >>> Posting number 22537, dated 4 Sep 1997 05:54:41
            CVID 2: glutathione & autism & herpes CMV EBV etc TNF-alpha


......Introduction: CVID, not necessarily genetic in origin......
The preceeding post called attention to similarities between a number of anecdotes
from autism parents and traits associated with CVID, as described in an article
about 8 very severe cases of CVID (1).
      An important issue is whether or not CVID is "only genetic" in origin OR
whether some cases of CVID might be acquired and thus accurately described as "not
genetic" in origin. This issue is imporant to autism because various immune
atypicalities are, in various subgroups, associated with autism (eg, altered ratios
of T-cell subsets, lower IgA, complement 4b characteristics, etc). Furthermore,
altered immune function is present with various pathogenic processes associated with
autism. Thus, whether a child's or parent's CVID is "only genetic" and/or is "not
genetic" is worth understanding as best we can, circa 1997.

......NEJM article......
A person wanting to research CVID would probably encounter a 1995 review published
in the New England Journal of Medicine (2), "The Primary Immunodeficiencies". In
that review, Rosen et al summarize recent developments regarding 6 "primary
immunodeficiencies", including CVID.
     I find the article to be somewhat misleading regarding CVID because neither the
introduction nor the CVID-specific section mentions the possibility that some cases
of CVID are non-genetic in origin, induced by infection and/or (quite relatedly)
glutathione deficiency. In a reviews presented by respected journals, a reader ought
be able to expect thoroughness. (Oh well...)
     This is not to say that "focusing upon genetic aspects" is not an important
topic, but the authors present rhetoric conveying an underlying presumption that
CVID is genetic, and that's that. Instead, in one short sentence the authors could
have mentioned the other category of causation, and provided at least one cite.

......CVID caused by infection........{some technicals follow}......
Consider some rhetoric an an article by Jaffe et al (3):  "The finding that CD8+ T
cells with a distinct phenotype and function occur in a subgroup of CVI patients
bears on the pathogenesis of CVI in yet another way. It has been observed that CD8+
T cells with a surface phenotype similar to that of these CVI... patients [a certain
subgroup] are found transiently in patients with acute viral infections and
chronically in patients with persistent viral infection... The possibility must
therefore be considered that the CD8+ T cells in CVI [same subgroup] are
'footprints' of a chronic viral infection that is the basic cause of the [CVID]
disease."
      Clearly, the Jaffe et al quote is a bit soft, in suggesting the possibility
that viral infections ought be considered as possible causes of CVID in some
individuals. Thus, let us look further.
    An important clue can be found in Suthanthiran et al, who describe glutathione
as a primary participant in T-cell proliferation (4). Additional participants
include alpha-glutamylcysteine-synthetase, N-acetylcysteine, and cysteine (4), as
well as glutathione disulphide, etc (5). Another used rats to more fully explore
mechanisms by which "glutathione depletion... impairs T-cell and macrophage immune
function" (6), and the authors conclude with a discussion of the clinical relevance
to humans, ie, that glutathione deficiency (whether from malnourishment or from
other causes such as infection) can induce an ongoing immuno- deficiency that
creates increased risk for acquiring additional infections and/or for retaining
infections already present (6).
      More recent articles (with informative introductions and discussions) include
two by Pal Aukrust and colleagues, who write:  "Adequate concentrations of
glutathione are required for a variety of immune functions, including lymphocyte
activation..., natural killer activation..., and lymphocyte-mediated
cytotoxicity..."
     Aukrust et al are well aware that many cases of CVID are derived from various
and minor genetic immune-system glitches, but these researchers also focus upon the
CVID subgroup in whom the infection-worsening immunodeficieny is of viral origin,
via a glutathione pathway:
    "The reason for decreased levels of glutathione in CD4+ lymphocytes among CVI
[ie, CVID] patients is unknown. However, the association between glutathione
deficiency and persistent immune activation,... suggests that glutathione depletion
in CD4+ lymphocytes may be cause by inflammatory stress leading to... [excessive]...
consumption of glutathione..."
    "Several immune functions such as cytotoxic T-cell activation..., maintainance
of normal numbers of circulating CD4+ lymphocytes..., and of particular interest,
generation of Ig secreting cells... seem to be partly dependent on adequate
glutathione levels... the present study shows for the first time glutathione
abnormalities both in plasma and in CD4+ lymphocytes and monocytes, but not in B
lymphocytes, among CVI patients. Our findings may suggest increased oxidative stress
in CD4+ lymphocytes among CVI patients. [Thus] The results support the notion that
T-cell and monocyte abnormalities, particularly abnormalities in CD4+ lymphocytes,
may be of importance in the immunopathogenesis of CVI."
     "Furthermore, chronic immune activation and particularly activation of the TNF
system seems to be important in the development of the... glutathione
abnormalities." (7)
     In a more recent article (8), Aukrust et al look further at TNF-alpha and write
in their conclusion: "These phenomena may [in some cases] reflect a fundamental
immunologic dysfunction in CVI, but they may also be secondary to chronic
infections... [and] chronic viral infection has been suggested... in the
pathogenesis of CVI [citing 9,10].

......Discussion & speculation...... 
With regard to autism, there is a large subgroup wherein gastrointestinal problems
were or are present. Occasionally, viruses have been identified, oftentimes, not.
Some viruses appear to be able to remain quite localized, and some can migrate from
the gi-tract to the CNS, and latent CNS-infections via HSV are likely to be
unperceived thus undiagnosed.
     Consider specific cases of autism wherein the child had an extended period
during  which his or her symptoms were akin to those seen in CVID (see post
beginning CVID 1 for traits & cites). Were the various infection-related traits due
to an acquired-CVID induced by a virus, possibly embedded in the gi-tract? Possibly,
in a few such kids, HSV was the virus? And, if so, did the HSV migrate towards the
brain, into the temporal lobes? While staying within neurons and not inducing
viremic encephalopathy? Waiting until a systemic immunosuppression or flood of
cytokines led neuronal death via viral re-activation and/or increase neuronal MHC-I
presentation of virus-derived epitopes? Don't know. Can't say, but the paragraph's
sequence of events parallels various studies already in the med literature (11).  
                  --- Teresa

<1>  Conley ME.  Park CL.  Douglas SD. Childhood common variable immunodeficiency
with autoimmune disease. J Ped 108.915-22 1986.
<2> Rosen FS et al. The primary immunodeficiencies. NEJM 333.7.431-40 1995.
<3> Jaffe JS et al. Functional abnormalities of CD8+ T cells define a unique subset
of patients with common variable immunodeficiency. Blood 82.1.192-201 1993.
<4> Suthanthiran M et al. Glutathione regulates activation-dependent DNA synthesis
in highly purified normal human T lymphocytes stimulated via the CD2 and CD3
antigens. Proc Natl Acad Sci USA 87.3343-7 1990.
<5> Staal FJ et al. Glutathione deficiency and human immunodeficiency virus
infection. Lancet 339.909-12 1992.
  [Tc: although a focus is HIV, the article is an excellent review of
   glutathione pathways, incl acetylcysteine, GSH-S-transferases, etc.]
<6> Robinson MK et al. Glutathione depletion in rats impairs T-cell and macrophage
immune function. Archives of Surgery 128.29-35 1993.
<7> Aukrust P et al. Decreased levels of total and reduced glutathione in CD4+
lymphocytes in common variable immunodeficiency are associated with activation of
the tumor necrosis factor system: possible immunopathogenic role of oxidative
stress. Blood 86.4.1383-91 1995.
<8> Aukrust P et al. Persistent activation of the tumor necrosis factor system in
a subgroup of patients with common variable immunodeficiency -- possible
immunological and clinical consequences. Blood 87.2.674-81 1996.
<9> Jaffe JS et al. Functional abnormalities of CD8+ t cells define a unique subset
of patients with common variable immunodeficiency. Blood 82.1.192-2001 1993.
<10> Spickett GA et al. Role of retrovirus in acquired hypogammaglobulinemia. Clin
Exp Immunol 74.177- 1988.
<11> Cites within series of posts (by me), bit.listserv.autism, August , early Sept
1997, search string = "autism & herpes" (sans the " " marks)  Staal FJ et al.
Redox regulation of signal transduction: tyrosine phosphorylation and calcium
influx. Proc Natl Acad Sci USA 91.3619-22 1994.           [much on TNF-alpha herein
too].
                         ^^^ ^^^^^
   Gastroenterology.  73(6):1397-403, 1977 Dec.
...It is likely that the CMV infection contributed to the symptom complex and the
[intestinal] mucosal injury. Unusual opportunistic infections as a cause of diarrhea
should be considered in patients with late onset immunodeficiency, especially if
Giardiasis is ruled out...


            >>> Posting number 33299, dated 7 Jan 1998 02:32:58
            Acquired deficiency of interleukin-2

Here are a citation and abstract from a study documenting that IL-2 deficiency can
be acquired, even by monozygotic twins whose twin-sibling does not have the IL-2
deficiency (1). Since the Kaye et al study was published (1986), studies
increasingly have shown that some cases of diabetes have infectious pathogens as
etiologic factors, which may be related to the monozygotic twins' discordance for
diabetes and for IL-2 deficiency.

Kaye WA et al.
  Acquired defect in interleukin-2 production in patients with type I diabetes
mellitus.
          New England Journal of Medicine.  315(15):920-4, 1986 Oct 9.
  Deficient production of interleukin-2 has been reported in Type I diabetes, but
its cause has not been elucidated. We therefore measured interleukin-2 production
in 27 patients with Type I diabetes, 20 patients with Type II diabetes (6 requiring
insulin), 5 monozygotic twin pairs discordant for Type I diabetes, and 10
nondiabetic persons with islet-cell antibodies. Interleukin-2 production was
decreased in patients with Type I diabetes as compared with controls (35.8 +/- 2.5
vs. 61.6 +/- 4.6 percent, P less than 0.001). Interleukin-2 production did not
differ between patients with Type II diabetes and controls, regardless of whether
the patients used insulin. Twins with Type I diabetes had decreased interleukin-2
production as compared with normal controls (33.2 +/- 5.4 vs. 61.6 +/- 4.6 percent,
P less than 0.001) and with their nondiabetic twins (33.2 +/- 5.4 vs. 54.5 +/- 3.4
percent, P less than 0.005). Interleukin-2 production in nondiabetic twins and in
nondiabetic persons with islet-cell antibodies was normal. There was no correlation
between glycosylated hemoglobin levels and interleukin-2 production in any diabetic
group. We conclude that patients with Type I diabetes have an acquired defect in
interleukin-2 production, whereas patients with Type II diabetes do not, and that
this defect is not correlated with an ongoing autoimmune process, with
hyperglycemia, or with insulin administration or oral hypoglycemic therapy. Thus,
the defect appears to be related to marked beta-cell destruction, although not to
the metabolic consequences thereof or the responsible autoimmune process.


            >>> Posting number 23598, dated 18 Sep 1997 08:32:30
            CVID 3 THI: transient hypogammaglobulinemia of infancy

......defining THI......
"Physiologic hypogammaglobulinemia occurs between 4 and 6 months of age when
maternal IgG has decreased and the infant's own active production is not yet fully
developed. On occasion, immunoglobulin production remains below that of age-related
controls but spontaneously attains normal levels at a later time. This is referred
to as transient hypogammaglob- ulinemia of infancy (THI), an entity of unknown
incidence or cause. THI may be associated with recurrent infections in some infants
but may remain without symptoms in others." (1)

Tc: Note that "physiologic hypogamm..." and what Dressler et al call "THI" are both
temporally limited, ie, both categories are transient, so already the medical
literature has provided linguistic pitfalls. The time of "physiologic hypogamm...",
as Dressler et al explain the term, looks like a time of enhanced risk. Now, let's
link THI with some traits often described on the autism list:
      "Of 247 patients referred to the Pediatric Immunology Clinic... for recurrent
infections, 13 patients were found to have an abnormal delay in the onset of IgG
synthesis and prolongation of the physiologic hypogamma- globulinemia of infancy."
(2)
      "Clinically, these patients were first observed with recurrent otitis media,
respiratory infections, bronchitis and/or asthma, and formula intolerance."  (2)

Tc: Now, let's consider some parallels in a different study:
      "Examination of 136 children who were referred to the Pediatric
Gastroenterology Clinic... for chronic or severe diarrhea... revealed that 31
patients (22.8%) had serum immunologlobulin levels below the 5th percentile for
age." (3)
      "Comparison of our patients with hypogammaglobulinemia and those with chronic
diarrhea but normal immunoglobulins revealed that the former group are younger at
presentation (mean, 8.2 months) and at the onset of their diarrhea (3.1 months): the
figures for patients without hypogamma- globulinemia were 18.2 and 8.2 months,
respectively." (3)
      And, citing Gryboski and Kocoskis 1980, Glassman et al write: "The association
between chronic diarrhea and transient hypogammablobulinemia of infancy was first
reported in a study which noted that 40% of infants with gastrointestinal allergy
had a transient immunoglobulin disorder..." (3).
      Also, "IgA deficiency was present in all but two of our patients with
hypogammaglobulinemia of infancy. Isolated IgA deficiency has frequently been
associated with gastrointestinal disturbances, including diarrhea." (3).

Tc: A possible link to altered intestinal permeability, the development of food
hypersensitivies, and the possibility of viral causation (in some kids) is suggested
by the Gryboski and Kocoshis article, whose abstract is remarkably clear:

Immunoglobulin deficiency in gastrointestinal allergies.
      Gryboski JD.  Kocoshis S.
            Journal of Clinical Gastroenterology.  2(1):71-6, 1980 Mar.
  Multiple gastrointestinal allergies were studied in 98 infants and children.
Combined sensitivities were milk and soy in 61, soy and gluten in 34, and milk and
gluten in three. Two clinical groups became apparent: those infants with early
diarrhea (1-6 months of age) with strong family history of atopy or food allergies
and without prior intestinal infection; and those children up to age 3 years who
developed chronic diarrhea and gastrointestinal sensitization after an acute viral
or bacterial gastroenteritis. Transient or "late turn-on" immunoglobulin disorders
were present in nearly half of the milk-allergy infants studied, and in nearly a
third of the entire group. Such a high incidence of immunoglobulin abnormalities has
not been previously reported in children with allergic gastroenteritis.

Tc: Statistically, most kids who have pTHI probably do not become autistic, even
though the gastrointestinal symptoms and food hypersensitivies are so similar to
many autism-parent anecdotes. Thus, an important question is, what might be
different in the kids who have these pTHI symptoms and then proceed to be diagnosed
as autistic?

.....HSV AUTISMS? LINKED TO CVID & pTHI?.....
My additional readings in herpes-virus literature appear to have strengthened the
likelihood that oral/gastrointestinal HSV is a causal factor in some cases of
autism, particularly in kids whose medical history is akin to the pTHI traits, the
rationale is as follows:
        Orally ingested HSV, whether from one's own mild ulcerations and/or from
sources outside the person, can venture into the gi-tract (3b). If that gi-tract has
had the flora removed (eg, by diarrhea, by antibiotics, etc), then the HSV is
likelier to take root in the intestinal wall. From there the virus can enter the
enteric nervous system and proceed to the vagus, which is bi-directionally
interconnected with certain subregions of the amygdala (4). Luckily, HSV has been
used to trace neuroanatomy in dozens of studies. Several such articles describe that
HSV within parts of the gi-tract actually migrate not only to the vagus but also
into the central nucleus of the amygdala (5).
        That region of the amygdala is very involved with emotional regulation,
food-intake responsiveness, responses to sensory modalities, responses to faces, and
(via interconnections with nearby amygdala subregions) with responses specific for
eye-contact with other individuals.
        Thus, in a child who, during prolonged THI not only had the THI-typical
gastrointestinal symptoms but who also (during that episode) acquired a bit of HSV
within the gi-tract, then over a period of weeks or months, that gi-tract HSV could
migrate not only into the vagus but also into the central amygdala.
        In such a child, the resulting traits would appear as atypical emotional
responses, sensory hypersensitivies, eye-contact avoidance, along with the
THI-typical phenomenon of food hypersensitivies and benefits from gf/cf diets.
        Given that HSV can remain within neural circuits and not become sytemic HSV
viremia, such a child might (aside from the gastrointestinal problems) finally grow
to being very healthy, once he or she had outgrown the pTHI that had created or
contributed to the conditions in which a bit of HSV could become attached to the
wall of the intestines.

Conclusion: The traits and relationships sketched hereinabove (i) are extremely
similar to traits reported by many autism-parents; (ii) are based upon citations
documenting the ability of HSV to migrate (especially during a period of pTHI) from
the wounded gi-tract into a portion of the brain (central amygdala) that is so
central to many dysregulations seen in autism. Are some, or perhaps even many, cases
of autism the result of HSV that entered the CNS via the gastrointestinal, enteric
nervous system, vagus to amygdala route?

Teresa

ps: Furthermore: the prolonged THI seen in some kids may be the result of
virus-induced intracellular glutathione deficiency (as sketched and cited in CVID
1 and CVID 2, as recently posted).

1) Dressler F et al. Transient hypogammaglobulinemia of infancy. Acta Paediatrical
Scandinavia 78.767-74 1989.

2) Cano F et al. Absent specific viral antibodies in patients with transient
hypogammaglobulinemia of infancy. Journal of Allergy & Clinical Immunology 85.510-3
1990.

3) Glassman M et al. High incidence of hypogammaglobulinemia in infants with
diarrhea. Journal of Pediatric Gastroenterology and Nutrition 2.465-71 1983.

(3b) Karvonen AL, Lehtola J.  Gastric mucosal erosions; a clinical history and
findings and the possible role of herpes simplex infection in aetiology.  Ann Clin
Res 1983 Aug;15(4):137-41.
   To reveal the aetiology and pathogenesis of chronic gastric erosions, selected
clinical and laboratory variables in 117 patients with different types of gastric
mucosal erosion as a predominant finding at elective gastroscopy were studied and
the results compared with age- and sex-matched controls. Recurrent symptoms were the
only characteristics in the symptomatology of the erosion patients compared with the
controls (p less than 0.001). Recent ingestion of analgesics was associated with
incomplete (type IIa) erosions (p less than 0.001) and was common especially among
female patients. Irregular working hours were also reported by patients with this
type of erosion (p less than 0.025). Smoking was more common among erosion patients
than controls (p less than 0.05). Herpes labialis lesions (cold sores, fever
blisters) occurred in 10 of the erosion patients, but in only one of the
corresponding controls (p less than 0.01). Herpes simplex/virus antibody titres of
1:32 or more were associated with the erosions (p less than 0.05), particularly the
complete (type I) ones (p less than 0.01). Thus, the various factors probably of
importance in the aetiology and pathogenesis of gastric mucosal erosions are the
same as those discussed in peptic ulcer disease, which points to a common aetiology
and pathogenesis. The possibility of herpes simplex/virus aetiology in some, perhaps
complete type, erosions is suggested.
      [Thnx to Linda Carlton for finding this citation.]

4) Gesser RM.  Valyi-Nagy T.  Fraser NW.  Altschuler SM. Oral inoculation of SCID
mice with an attenuated herpes simplex virus-1 strain causes persistent enteric
nervous system infection and gastric ulcers without direct mucosal infection.    
Laboratory Investigation.  73(6):880-9, 1995 Dec.
<5>  Rinaman L.  Card JP.  Enquist LW. Spatiotemporal responses of astrocytes,
ramified microglia, and brain macrophages to central neuronal infection with
pseudorabies virus.
     Journal of Neuroscience.  13(2):685-702, 1993 Feb.             eof


            >>> Posting number 23617, dated 18 Sep 1997 15:02:56
            CVID 3 THI: transient hypogammaglobulinemia of infancy

Susan,

This topic excites me. I sense that we are looking at one of the causal pathways in
autism. Too much is fitting together for this to be mere coincidence, and these
notions have numerous citations to back them up!
Some comments interspersed:

On Thu, 18 Sep 1997, Walter & Susan Owens wrote:
> Great post, Teresa! Several questions.  Has anyone made a point to graph the Ig
recovery of those with THI to see how soon they overcome their
hypogammaglobulinemia?

Tc: THI is a vague category, with much inter-individual variation. In many ways the
findings in THI remind me of the diverse findings in CVID and in acquired-CVID.
Also, there is much interindividual variation with regard to when a child with pTHI
regaings a normal-esque immune profile.
      Note that most THI studies were done in the years prior to PCR, in the years
prior to molecular awareness of acquired-CVID and its infection and glutathione
connections.

>I would be curious as to whether the graph would have the same shape as
a normal Ig acquisition curve, but only moved farther down the axis, or
whether it shows a slower or more rapid increase.

Tc: If we look at individual cases, then each child's section of increased
intestinal permeability might differ from person to person. That kind of difference
would affect T-cell and even immunoglobulin reactivities of the kind seen as
hypersensitivity to milk or to other foods.

> I'd also be interested if the low figure on wheat intolerance might be
merely a consequence of the age of the children they were observing. Can you tell
from what you read?

Tc: I'll have to read that article enroute to, at, or after the conference. I spent
the afternoon getting some additional articles, including some re: HHV-6. Remind me
of the question after the conference. I do have the article.

> Have you ever heard of a study that compares Ig levels of those breastfed vs.
formula babies?  Certainly someone has done that!  I do think it could be possible
that the Ig's in breastmilk may stay mainly in the gastrointestinal tract and not
migrate in great quantity to peripheral
blood.  Ever read anything that addressed that?

Tc: Excellent questions, easily evaded by someone who must tear herself away from
the med libraries today, so as to pack...

> Has anyone measured other factors of the immune system of those with THI
besides the Igs?  Perhaps the body concentrates on developing innate
immunity before it becomes competent in acquired immunity, and perhaps
demands put upon innate immunity may exhaust factors that would work  towards
maturing acquired immunity.  I'd love to see a book that addressed this issue.

Tc: One great clue: there is a study that identifies anti-HSV T cells of the
gamma-delta lineage, many of which are in the gi-tract and participate in the common
mucosal immune system. This has many significances, including (but, must wait... see
my CD5+ paper for some neat clues...)...

                           [from a prior post by TCB]
>>>  That region of the amygdala is very involved with emotional regulation,
food-intake responsiveness, responses to sensory modalities,
responses to faces, and (via interconnections with nearby amygdala
subregions) with responses specific for eye-contact with other individuals.

> placques and tangles.  They know sulfation and inflammation are relevant,
though...It may be that some of the effects of viruses travelling into brain regions
relate to an exhaustion of local sulfate chemistry involved in immune activation.

Watch all the glutathione/sulphur "stuff" in an article coming your way.

Teresa

whose intensely hyper-focused library perseveration...
      ^^^^^^^^^ ^^^^^ ^^^^^^^         ^^^^^^^^^^^^^
must stop go pack...
>>> Posting number 22316, dated 1 Sep 1997 11:08:27
Date:         Mon, 1 Sep 1997 11:08:27 -0700
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      CVID 1: glutathione & autism & herpes CMV EBV etc TNF-alpha

>>> Posting number 22537, dated 4 Sep 1997 05:54:41
Date:         Thu, 4 Sep 1997 05:54:41 -0600
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      CVID 2: glutathione & autism & herpes CMV EBV etc TNF-alpha

>>> Posting number 33299, dated 7 Jan 1998 02:32:58
Date:         Wed, 7 Jan 1998 02:32:58 -0700
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      Acquired deficiency of interleukin-2

>>> Posting number 23598, dated 18 Sep 1997 08:32:30
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      CVID 3 THI: transient hypogammaglobulinemia of infancy

>>> Posting number 23617, dated 18 Sep 1997 15:02:56
Sender:       SJU Autism and Developmental Disablities List
              
From:         Teresa Binstock
Subject:      Re: CVID 3 THI: transient hypogammaglobulinemia of infancy