The following seven items were posted to the autism-list on April 2, 1999.
The subject heading of each original posts contained the words "intestinal
permeability" so that the topics would be easily findable in the archives 
of St. Johns University.

1. intestinal permeability, food allergy, autism
2. intestinal permeability, food allergies, sucrose test
3. intestinal permeability, eczema, food allergy, asthma, TNFa
4. intestinal permeability, asthma, Candida albicans
5. intestinal permeability, interferon gamma, MMR vaccination
6. intestinal permeability, familial, infectious, environmental
7. intestinal permeability, blood brain barrier, MMR vaccination

The posts follow in order:


Post #1: intestinal permeability, food allergy, autism

The following citations are well known to many autism-list participants but
may be useful to others and will serve as background for several subsequent
posts, each with slightly different subject headings and topics.

1. D'Eufemia P et al. Abnormal intestinal permeability in children with
autism. Acta Paediatrica.  85(9):1076-9, 1996 Sep.
  We determined the occurrence of gut mucosal damage using the intestinal
permeability test in 21 autistic children who had no clinical and laboratory
findings consistent with known intestinal disorders. An altered intestinal
permeability was found in 9 of the 21 (43%) autistic patients, but in none of
the 40 controls... We speculate that an altered intestinal permeability could
represent a possible mechanism for the increased passage through the gut
mucosa of peptides derived from foods with subsequent behavioural
abnormalities.

2. Lucarelli S et al. Food allergy and infantile autism. Panminerva
Medica.  37(3):137-41, 1995 Sep.
  The etiopathogenesis of infantile autism is still unknown. Recently some
authors have suggested that food peptides might be able to determine toxic
effects at the level of the central nervous system by interacting with
neurotransmitters. In fact a worsening of neurological symptoms has been
reported in autistic patients after the consumption of milk and wheat. The aim
of the present study has been to verify the efficacy of a cow's milk free diet
(or other foods which gave a positive result after a skin test) in 36 autistic
patients. We also looked for immunological signs of food allergy in autistic
patients on a free choice diet. We noticed a marked improvement in the
behavioural symptoms of patients after a period of 8 weeks on an elimination
diet and we found high levels of IgA antigen specific antibodies for casein,
lactalbumin and beta-lactoglobulin and IgG and IgM for casein. The levels of
these antibodies were significantly higher than those of a control group which
consisted of 20 healthy children. Our results lead us to hypothesise a
relationship between food allergy and infantile autism...  [a relationship not
in all autism-spectrum children but in a subgroup].



Post #2: intestinal permeability, food allergies, sucrose test

Infections are linked to intestinal alterations, for instance, Vera et al
examined intestinal damage in regard to H. pylori, using a sucrose-excretion
test. Several quotes from their article:
     "...increased sucrose excretion is not a marker of H. pylori
colonization but rather of the presence of [intestinal] mucosal lesions."
     "The results of this study emphasize that the gastric mucosa may be
a portal of entry for macromolecules from the diet or from microorganisms,
as shown in experimental models... At the intestinal level, this may be
relevant for the establishment of tolerance or for the appearance of food
allergies in predisposed individuals..."
     "To our knowledge...the first study using the sucrose permeability
test in children; it shows that this technique is easy to apply,
inexpensive, and reliable. Furthermore, it is accepted by them without
difficulty and may constitute a valuable screening procedure for children
at risk of gastric damage."
Tc: The article was supported by an editorial cited below (Meddings J).

1. Vera JF et al. Sucrose permeability in children with gastric damage and
helicobacter pylori infection.  Journal of Pediatric Gastroenterology &
Nutrition  24(5):506-511 1997.
Ab:
Background: Increased permeability to sucrose has been recently shown to
be a good marker of gastric mucosal damage in adults.
Methods: This test was evaluated in 40 children consulting for recurrent
abdominal pain and the results were correlated with endoscopic and
histologic findings and with the presence of H. pylori.
Results: The gastric mucosa was considered endoscopically normal in 31
children; 3 had duodenitis, and 6 had mild gastritis. Abnormal endoscopic
findings were associated with increased urinary sucrose excretion (MANOVA
F = 7.30; p = 0.002). In the 6 children with mild gastritis, mean sucrose
excretion was twice that of controls (0.060 +/- 0.024 vs. 0.029 +/- 0.018,
respectively; p = 0.019) and significantly higher than the group with
duodenitis (0.037 +/- 0.013;p = 0.038). The specificity and sensitivity of
sucrose permeability test for detection of gastric damage were 90.3% and
83.3%, respectively. N. pylori was detected in 62.5% of children including
all patients with mild gastritis, in 2 out of 3 with duodenitis and 17 out
of 31 endoscopically normal controls. No differences in sucrose excretion
were observed in relation with the presence of II. pylori or histological
findings in the control group.
Conclusions: Urinary sucrose excretion is a good marker of mucosal gastric
damage in children and may be used as a screening test in large groups of
populations.

2. Meddings J. Sucrose -- How sweet it is. J Ped Gast Nutr24.621-2 1997.
3. Philpott DJ et al. Enterohemorrhagic escherichia coli o157-h7 infection
and colitis in children. J Pediatric Gastroenterology & Nutrition.
24(5):623-625 1997.
          [There are several kinds of E. coli and different
          effects per strain are known.]
From the article:
-- "Enterohemorrhagic Escherichia coli (EHEC) is... an important agent of
both acute non-bloody diarrhea and hemorrhagic colitis...
-- "Life-threatening systemic complications can also result from infection
including the hemolytic uremic syndrome (HUS) and thrombotic
thrombocytopenic purpura (TTP...).
-- "Both children and the elderly have an increased incidence of
symptomatic EHEC infection and are at greater risk for the development of
HUS and TTP as complications following infection..."
-- "Many physicians fail to consider an infectious origin of these
symptoms [including non-bloody diarrhea and abdominal pain] due to the
lack of fever and negative routine stool culture results. In addition, the
ability to recover this pathogen decreases with time from the onset of
diarrhea... Misdiagnoses have occasionally led to invasive diagnostic and
therpeutic procedures or the inappropriate use of antibiotics..."
-- Article also contains a description of how "EHEC adheres to, but does
not invade, [GI-tract] epithelial cells in vivo and vitro...", thus EHEC
is less likely to be found in stool samples, thereby providing a basis for
missed diagnoses.
-- "These... changes could lead to changes in epithelial permeability and
ion secretion in infected [intestinal] epithelial cells."



Post #3: intestinal permeability, eczema, food allergy, asthma, TNFa

These citations speak for themselves; some are quite technical.

1. Majamaa H.  Isolauri E. Evaluation of the gut mucosal barrier:
evidence for increased antigen transfer in children with atopic eczema.
Journal of Allergy & Clinical Immunology.  97(4):985-90, 1996.
Ab:
BACKGROUND: Intestinal antigen handling determines subsequent immune response
to the antigen. Antigens are absorbed across epithelium along two functional
pathways. The main pathway is degradative, which reduces the immunogenicity of
the antigen. A minor pathway allows the transport of intact proteins, which is
crucial for antigen-specific immune responses. ...
CONCLUSIONS: Our results may reflect a primarily altered [intestinal] antigen
transfer in patients who have atopic eczema, which may initiate and perpetuate
prompt immune responses to common environmental antigens, including foods.

2. Businco L et al. Food allergy and asthma. Pediatric Pulmonology -
Supplement.  11:59-60, 1995.
Ab:
Food allergy (FA) is one of the causes of atopic dermatitis (AD), of acute
urticaria, of reactions of the gastrointestinal tract, and of acute systemic
anaphylaxis, but its role in asthma appears to be less clear. The prevalence
and incidence of subjects with food-induced wheezing have not been well
studied. In addition, the number of subjects with proven food-induced wheezing
by double-blind, placebo-controlled oral food challenge (DBPCOFC) has been
small. At the moment wheezing is considered unusual in food-hypersensitive
subjects, and wheezing as the unique symptom of FA is rare. Furthermore, most
cases of food-induced asthma have been observed in children. Food allergy may
trigger allergic respiratory symptoms through two main routes: ingestion or
inhalation. Children with asthma, who are allergic to foods, present some
particular features such as AD and a related significantly elevated total
serum IgE level. Alternatively, FA may occur in patients who are "high IgE
responder" and more prone to become sensitive to many allergens, including
foods. Therefore, children with asthma and a history of AD and/or elevated
total serum IgE level should be carefully assessed for FA. We have shown that
a significant proportion of children with IgE-mediated cow's milk allergy
experienced asthma following DBPCOFC with cow's milk.

3. Reekers R et al. The role of circulating food antigen-specific lymphocytes
in food allergic children with atopic dermatitis. British Journal of
Dermatology.  135(6):935-41, 1996 Dec.
Ab:
In this study we evaluated antigen-specific in vitro responses of peripheral
blood lymphocytes to lipopolysaccharide (LPS)-depleted food allergens in
children who reacted to food challenge (cow's milk or hen's egg) with a
deterioration of their atopic dermatitis (AD). Some of the children showed
immediate symptoms (urticaria, bronchial asthma or gastrointestinal symptoms)
as well. The proliferation of casein-stimulated lymphocytes from children
reacting to cow's milk (age 0.7-5.9 years) was significantly higher (P < 0.01)
than the proliferation of lymphocytes from 15 children with AD without milk
allergy (age: 2.1-9.1 years). Twenty-eight T-cell clones (TCC) were
established from the blood of three children sensitized to cow's milk and
hen's egg who reacted to double-blind, placebo-controlled oral food challenge
both with a deterioration of AD and with immediate symptoms. Surprisingly, 16
of 28 casein- or ovalbumin-specific TCC were CD8+. All TCC produced high
amounts of IFN-gamma upon stimulation with concanavalin A. In addition, 75% of
the CD4+ TCC and 44% of the CD8+ TCC secreted IL-4. Our results indicate that:
(i) food-specific proliferation of blood lymphocytes can be detected in
patients with clinically relevant food allergy with LPS-depleted allergens in
vitro and (ii) circulating food-specific lymphocytes are CD4+ and CD8+ T cells
with the capacity of producing both type 1 and type 2 cytokines.

4. Majamaa H et al. Intestinal inflammation in children with atopic eczema:
faecal eosinophil cationic protein and tumour necrosis factor-alpha as
non-invasive indicators of food allergy. Clinical & Experimental Allergy
26(2):181-7 1996.
Ab:
BACKGROUND: Food allergy is contemplated in atopic eczema. Early recognition
of food allergies is difficult and the diagnosis is often missed because of
the non-specificity of symptoms. New non-invasive tests are clearly needed...
CONCLUSION: We conclude that in children with atopic eczema food allergy is
associated with intestinal inflammation indicating that more general
immunologic disturbances than previously thought take place in these patients.
We further suggest that faecal eosinophil cationic protein, tumour necrosis
factor-alpha and alpha-1 antitrypsin distinctly indicate various reaction
types of food allergy. Parallel testing with eosinophil cationic protein and
tumour necrosis factor-alpha may significantly enhance the accuracy in
diagnosis of food allergy in patients with atopic eczema.

5. Marini A et al. Effects of a dietary and environmental prevention
programme on the incidence of allergic symptoms in high atopic risk
infants: three years' follow-up.    Acta Paed Suppl 414.1-21 1996.
Ab:
A prospective case-control study is presented to assess an allergy prevention
programme in children up to 36 months of age. Infants born at three maternity
hospitals were followed from birth: 279 infants with high atopic risk
(intervention group) were compared with 80 infants with similar atopic risk
but no intervention (non-intervention group). The intervention programme
included dietary measures (exclusive and prolonged milk feeding diet followed
by a hypoantigenic weaning diet) and environmental measures (avoidance of
parental smoking in the presence of the babies, day care > 2 years of life)...
Atopic dermatitis and recurrent wheezing were found in both the intervention
group and the non-intervention group from birth up to the second year of life,
while urticaria and gastrointestinal disorders were only present in the
non-intervention group in the first year of life. Conjunctivitis and rhinitis
were present after the second year in both the intervention group and the
non-intervention group. Relapse of the same allergic symptom was less in the
intervention group (13.0%) than in the non-intervention group (36.9%). In
comparison to the non-intervention group, there were fewer intervention group
cases with two or more different allergic symptoms (8.7 versus 32.6%), and
they were more likely to avoid steroid treatment (0 versus 10.8%) and hospital
admission (0 versus 6.5%). Babies in the non-intervention group fed with
adapted formula were more likely to develop allergies than breastfed babies in
the same group. In the intervention group the breastfed infants had the lowest
incidence of allergic symptoms, followed by the infants fed the hydrolysed
formula (ns). Infants in the intervention group fed the adapted formula had
significantly more allergies than the breastfed and hydrolysed milk fed
infants, although less than their counterparts in the non-intervention group.
Of the affected subjects in the intervention group, 80.4% were RAST and/or
Prick positive to food or inhalant allergens. Total serum IgE values detected
at birth in the intervention group were not predictive, but at 1 and 2 years
of age, IgE values more than 2 SD above the mean in asymptomatic babies were
found to predictive for later allergy. In breastfed babies the total IgE level
at 1 and 2 years of age was lower than in the other two feeding groups. Of the
various factors tested in the non-intervention group, the following were the
most important in the pathogenesis of allergic symptoms: (i) formula
implementation begun in the first week of life; (ii) early weaning (< 4
months); (iii) feeding beef (< 6 months); (iv) early introduction of cow's
milk (< 6 months); and (v) parental smoking in the presence of the babies and
early day care admission (< 2 years of life). All the preventive measures used
in this study (exclusive breastfeeding and/or hydrolysed milk feeding, delayed
and selective introduction of solid foods, and environmental advice) were
effective at the third year of follow-up, greatly reducing allergic
manifestations in high atopic risk babies in comparison with those not
receiving these interventions



Post #4 intestinal permeability, asthma, Candida albicans

Prior citations in this series linked increased intestinal permeability with
(i) a large autism-subgroup, (ii) various intestinal pathogens, (iii) and
asthma and food allergies. The abstracts herein do not specifically mention
intestinal permeability but do link asthma and Candida albicans within the
gastrointestinal tract, a phenomenon well known among many parents of autism-
spectrum kids.

1. Tanizaki Y et al. An increased level of specific IgG4 antibodies against
Candida albicans in patients with bronchial asthma. Journal of Asthma
29(5):343-8, 1992.
  Specific IgG4 antibodies against Candida albicans in sera were measured in
  76 asthmatics. The increased level of specific IgG4 was found in cases
  10-40 years old sensitive to house dust mite and/or Candida albicans, in
  cases with steroid-dependent intractable asthma (SDIA) and in elderly
  cases. The frequency of SDIA was the highest in cases 41 to 60 years old
  with higher frequency of increased IgG4 antibodies. The results show that
  specific IgG4 increases in relation to IgE-mediated immune response,
  long-term steroid therapy, and aging. All of these conditions may induce
  depressed cell-mediated immunity.

2. Miura K et al. Reaction of mononuclear cells from patients with bronchial
asthma to Candida albicans. Tohoku Journal of Experimental Medicine
164(1):1-12, 1991 May.
  This study was undertaken to investigate cytokine production of
  mononuclear cells (MNCs) from patients with bronchial asthma stimulated by
  antigens of Candida albicans in vitro... These results suggest that
  Candida albicans can contribute to the augmentation of cytokine
  production in bronchial asthma, especially in some of atopic type.

<3>  Koivikko A et al.  Relationship of immediate and delayed hypersensitivity
to nasopharyngeal and intestinal growth of Candida albicans in allergic
subjects. Allergy 43(3):201-5, 1988 Apr.
  ...These findings are in agreement with the concept that impaired
  cell-mediated immunity to C. albicans may lead to increased IgE
  response...

Tc: The development of a young infant's gastrointestinal immunity was reviewed
in a monograph currently available at:
                 http://www.jorsm.com/~binstock/cd5-iga.htm

4. Ito K et al. Immunologic analysis of steroid-dependent asthma. Annals of
Allergy 62(1):15-20 1989.
  In order to analyze steroid-dependent asthma immunologically, IgE
  antibodies to mite (Dermatophagoides farinae), Candida albicans, and
  Aspergillus fumigatus were measured in 112 asthmatic patients. IgG and IgG
  subclass antibodies to mite were also measured. The rate of patients who
  were positive to candida IgE RAST was higher in atopic steroid-dependent
  patients than in atopic steroid-independent patients (P less than
  .01)...

5. Savolainen J et al. IgE, IgA and IgG antibodies and delayed skin response
towards Candida albicans antigens in atopics with and without saprophytic
growth. Clinical & Experimental Allergy 20(5):549-54 1990.
  Immunoblotting and RAST were used to analyse IgE, IgA and IgG responses to
  antigens of Candida albicans. These were compared with the delayed skin
  response and C. albicans carriage in 40 atopic subjects. The majority of
  the atopic patients showed a strong IgG and IgA antibody response towards
  mannan, a carbohydrate, but only occasionally to proteins. Altogether 22
  of the 40 patients showed specific IgE towards C. albicans by
  immunoblotting. The IgE response was mainly towards proteins, particularly
  to ones with molecular weights of 29 kD and 46 kD, and only in eight out
  of 22 IgE-positive subjects towards mannan. The IgG and IgA responses to
  mannan and the total IgE response towards C. albicans assessed by RAST
  showed an association with C. albicans carriage, whereas the delayed skin
  response showed an inverse relationship. The immunological parameters
  characteristic of C. albicans carriage were found to be C.
  albicans-specific depressed delayed skin response and elevated IgE, IgA
  and IgG responses. This situation in the atopics presenting such
  parameters may favour simultaneous sensitization and exposure by
  colonization. The degree of sensitization may be sufficiently high to
  produce symptomatic allergy, such as asthma, in some individuals during
  occasional overgrowth of C. albicans, e.g. due to antibiotic therapy.

6. Savolainen J et al. Candida albicans and atopic dermatitis. Clinical and
Experimental Allergy.  23(4):332-9, 1993.
  The role of sensitization and exposure to Candida albicans in atopic
  dermatitis (AD) was studied with skin-prick tests, yeast cultures and
  immunoblotting in 156 young adults with AD attending the Department of
  Dermatology, University of Turku, during 1983-89. Eighteen patients with
  allergic rhinitis without eczema and 39 non-atopics were included as
  controls. Parameters associated with severe AD were simultaneous anti-C.
  albicans IgE and saprophytic C. albicans growth. A statistically
  significant correlation between C. albicans sensitization (specific IgE
  antibodies) and AD symptoms was observed only in patients with saprophytic
  C. albicans exposure. No correlation between C. albicans-specific IgE and
  AD severity was shown in patients without gastrointestinal growth.
  Furthermore, severe eczema was seldom seen in patients without saprophytic
  C. albicans growth. The most important IgE-binding components of C.
  albicans in immunoblotting were 27 and 46 kD proteins and mannan, a
  polysaccharide. IgG and IgA antibodies to C. albicans, mainly towards C.
  albicans mannan, were found in practically all 70 sera studied. These
  results suggest a continuous exposure and induction of IgE antibodies by
  C. albicans in AD patients. Severe phases of AD in colonized patients are
  associated with IgE synthesis against C. albicans. These findings suggest
  a role for C. albicans in the exacerbations of AD but the clarification of
  this subject needs double-blind placebo-controlled treatment trials.
                                                                       eof


Post #5: intestinal permeability, interferon gamma, MMR vaccination

Interferon gamma is known to alter intestinal cells in ways consistent with an
increasing of intestinal permeability (1-2,5-8). In twelve-month-old infants,
a primary effect of the MMR vaccination is the production of interferon gamma
(3). Together, these several citations suggest that, for some children,
sequelae to the MMR would include increased intestinal permeability and
ramifications therefrom -- eg, enhancement of a tendency towards food
hypersentitivity (4).

Teresa

1. Madara JL.  Stafford J. Interferon-gamma directly affects barrier function
of cultured intestinal epithelial monolayers. Journal of Clinical
Investigation  83(2):724-7 1989.
  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... 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.

2. Unno N et al. Nitric oxide mediates interferon-gamma-induced
hyperpermeability in cultured human intestinal epithelial monolayers.
Critical Care Medicine.  23(7):1170-6, 1995 Jul.
  OBJECTIVE: Incubation with interferon-gamma has been shown to increase the
permeability of cultured monolayers of intestinal epithelial cells.
interferon-gamma (250 to 1000 U/mL). The effect of interferon-gamma on
permeability was dependent on both the concentration of the cytokine and the
duration of exposure to it...
  CONCLUSIONS: These results suggest that upregulation of nitric oxide
biosynthesis plays a pivotal role in the increase in permeability of
intestinal epithelial (Caco-2BBe) monolayers induced by interferon-gamma.
Increased production of nitric oxide induced by proinflammatory cytokines,
such as interferon-gamma, may be an important factor contributing to gut
mucosal hyperpermeability in sepsis.

3. Pabst HF et al. Kinetics of immunologic responses after primary MMR
vaccination. Vaccine 15(1):10-4, 1997.
  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... Interferon-gamma was the principal cytokine produced after
primary measles immunization, suggesting primary measles immunization induces
predominantly a TH1 type response.

4. Heyman M et al. Mononuclear cells from infants allergic to cow's milk
secrete tumor necrosis factor alpha, altering intestinal function.
       Gastroenterology.  106(6):1514-23, 1994 Jun.
  BACKGROUND/AIMS: Intestinal dysfunction observed during cow's milk allergy
(CMA) is incompletely understood, and neither the effector cells nor the
mediators responsible have been clearly identified. This study was undertaken
to better characterize the implication of mononuclear cells in food allergy...
  CONCLUSIONS: These results indicate that during CMA, the high level of
TNF-alpha released by mononuclear cells after milk protein challenge acts
synergistically with IFN-gamma to increase the intestinal permeability.

5. Sanders SE et al. Assessment of inflammatory events in epithelial
permeability: a rapid screening method using fluorescein dextrans. Epithelial
Cell Biology 4(1):25-34 1995.
  Cultured intestinal epithelial monolayers serve as models for mechanistic
studies of intestinal inflammation. One crucial aspect of epithelial function
modulated by inflammation is permeability. Indices of permeability typically
obtained are transepithelial resistance or more formalized assays using Ussing
chambers modified for cultured monolayers. ....Exposure of intestinal
epithelia to mucosal-derived lymphocytes or to soluble lymphocyte products
(interferon-gamma, interleukin-4 or interleukin-13) increased FD flux [a
measure of permeability] in a dose-dependent fashion...

6. 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...

7. 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.

8. 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.
     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.
...our data demonstrate 1) only the monolayer's basolateral surface is
IFN-gamma responsive, whereas the apical (microvillous) surface is not; 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.



Post #6: intestinal permeability, familial, infectious, environmental

A recent study used measures of intestinal permeability in relatives and
spouses of patients with Crohn's disease. The familiality of Crohn's has long
been interpreted as necessarily genetic in origin. However, the finding of a
highly increased rate of intestinal permeability in the the Crohn's patients'
spouses led the authors to conclude that non-genetic factors ought be
considered.

1. Peeters M et al. Clustering of increased small intestinal permeability
in families with Crohn's disease.  Gastroenterology.  113(3):802-7, 1997.
  BACKGROUND & AIMS: Small intestinal permeability is increased in a
  proportion of patients with Crohn's disease (CD) and a subset of their
  healthy relatives. A primary permeability defect was postulated in the
  pathogenesis of the disease. The aim of this study was to identify a
  possible genetic pattern in the distribution of CD and/or abnormal
  permeability. METHODS: Differential urinary excretion of lactulose and
  mannitol (L/ M) in complete CD families was determined. Controls included
  healthy families and families with ulcerative colitis. Pedigrees were used
  to compare the distribution of CD and/or increased permeability. RESULTS:
  The L/M was significantly increased in patients with CD. Seventeen of 67
  first-degree relatives (25%) had a ratio greater than the upper limit (P95
  = 0.0170). Permeability results of CD families showed a highly significant
  familial aggregation. The lack of a genetic pattern in relation with CD
  and occurrence of disturbed permeability especially within generation,
  points toward a shared environmental factor. Five of 14 healthy spouses
  (36%) of patients with CD had also an increased permeability, and
  prevalence of increased permeability was not higher in families with known
  familial occurrence (P = 0.85). CONCLUSIONS: This large family study
  confirms an increased permeability in a subset of healthy relatives of
  patients with CD. However, the absence of a typical family pattern and the
  high prevalence in spouses is in favor of a common nongenetic factor or a
  subclinical disease manifestation.


Post #7: intestinal permeability, blood brain barrier, MMR vaccination

Prior posts in this series offered citations establishing that interferon
gamma increases intestinal permeability, and that MMR sequalae include a large
release of interferon gamma among infants aged 12 months (2). Another effect
of interferon gamma is that it also increases permeability of the blood-brain
barrier and, for instance, thereby allows more infiltration of the brain by
otherwise peripheral lymphocytes (1).

Importantly, since most children who receive the MMR do not appear to have
experienced major neurologic damage, other factors -- ie, factors in addition
to the MMR's production of interferon gamma -- must be present, whether they
be genetic and/or infectious.
     Nonetheless, since many parents associate vaccinations with their child's
plunge into autism-spectrum traits, the search for possible mechanisms is
important and could lead to improved pre-vaccination screening criteria
whereby children at-risk for adverse sequelae from vaccinations could receive
waivers.

1. 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.

2. Binstock, Teresa. Series of posts to bit.listserv.autism, April 2, 1999,
with the phrase "intestinal permeability" in each post, without the quote
marks. (These posts are presented in their entirety on this webpage.)