Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
June 07, 2009
Introduction: A recently
published study links intestinal inflammation to an increased tendency
for excessive excitation within the CNS (17). This very important study
is free online. Note that the cytokine Tumor Necrosis Factor alpha
(TNFa) is etiologically significant in this gut-brain connection and
that TNFa has been found to be atypical in many autistic children.
Additional relevance of the relationship between peripheral
inflammation and CNS excitability (17) derives from the facts (a) that
casein induces TNFa in children with hypersensitivity to milk, and (b)
the gluten-free and casein-free diets have been found to lower TNFa.
- - - -
A newly published study reports that a gluten free diet (GFd) alters
intestinal flora and cytokines profiles in healthy human adults.
Whereas a person's "gut bugs" are important, so to is having an
appropriate array of cytokines. In the GFd study, flora profiles were
altered and cytokine expression was changed. Indeed, "TNF-alpha,
interferon-gamma, IL-10 and IL-8 production by PBMC stimulated with
faecal samples was also reduced... after the [GF] diet." (1)
Relevance to autism derives from several considerations. For instance,
many parents of autistic children try a gluten-free (GF) and/or
casein-free (CF) diet, and results are generally positive. Among
>2500 parents who reported effects of GF and/or CF diet, 3% noticed
negative effects, 31% noticed no change, and 66% reported improvements.
Importantly, the ratio of improved to got-worse ratio was 19 to 1 (2).
Thus, the new findings about gluten-free diets in health adults prompts
a question. Why might a GF-free diet help some and perhaps many
autistic children? Let's keep in mind the fact that GFd reduced
TNFa.
At least 14 studies describe atypical TNFa in autistic subjects (eg 3),
most of whom aren't healthy adult humans (1).
Studies of TNFa in autism:
Brain (3)
CSF (4, 6)
Periphery (7,8,12)
Gastrointestinal (5,9)
Gastrointestinal & food responses (7-9,11)
LPS challenge (8,13)
Negative findings, periphery w/o LPS-challenge (10,16)
Viral mouse model (14)
Skewed immunity to PBDE, BDE-47 (15)
Given these TNFa findings in autism, the finding that a gluten-free
diet can lower TNFa has relevance enhanced by an important new study,
which is free online. Riazi et al reported that "Microglial activation
and TNFalpha production mediate altered CNS excitability following
peripheral inflammation." (17) In other words, intestinal inflammation
contributed to the induction of microglial activation and to increases
in CNS excitability. Furthermore, increased levels of TNFa in the brain
were etiologically significant to excitability. The findings by Riazi
and colleagues suggest a mechanism by which gluten-free and casein-free
diets might be beneficial for substantial subgroups of autistic
children.
i) Gliadin and gluten have long been known to induce TNFa (eg,
18-20).
ii) Pathologies labeled as celiac disease are realized to have a wider
range of symptomatology than were specified by the original criteria
(21-27).
iii) Casein increases TNFa in children hypersensitive to milk (31-32,
see also 33).
Speculation: The finding that GF diet alters intestinal microbiota
profiles in healthy adults may need be set aside for some children with
intestinal inflammation and elevated TNFa, especially for children who
respond well to a GF and/or a CF diet. Many studies document skewed
TNFa (previous cites) and/or intestinal inflammation in subgroups of
autistic children (28-30). Lowering TNFa (even somewhat) via GF or CF
diet may be beneficial for some of those children. Thus we ask, which
is the more serious pathology - skewed microbiota (1) or elevated TNFa
(3), especially given the finding that intestinal inflammation alters
CNS excitability via increased TNFa (17)?
Since Riazi et al's finding that intestinal inflammation alters
in-brain TNFa and CNS excitability emerged from a rat study (17), the
results do not necessarily apply to children with autism. Nonetheless,
there is consistency between the Riazi et al findings and parent
descriptions of GF and CF diets (2). Furthermore, the many descriptions
of altered TNFa in autistic subgroups (3-9,11-15) suggest that the GF
or CF diet's alteration of TNFa, in the very least, may be a
contributing factor in the mechanism by which the GF or CF diet helps
some children (2).
References:
1: Effects of a gluten-free diet
on gut microbiota and immune function in healthy adult human
subjects
De Palma G et al. Br J Nutr. 2009 May 18:1-7. [Epub ahead of print]
Diet influences the composition of the gut microbiota and host's
health, particularly in patients suffering from food-related diseases.
Coeliac disease (CD) is a permanent intolerance to cereal gluten
proteins and the only therapy for the patients is to adhere to a
life-long gluten-free diet (GFD). In the present preliminary study, the
effects of a GFD on the composition and immune function of the gut
microbiota were analysed in ten healthy subjects (mean age 30.3 years)
over 1 month. Faecal microbiota was analysed by fluorescence in situ
hybridisation (FISH) and quantitative PCR (qPCR). The ability of faecal
bacteria to stimulate cytokine production by peripheral blood
mononuclear cells (PBMC) was determined by ELISA. No significant
differences in dietary intake were found before and after the GFD
except for reductions (P = 0.001) in polysaccharides. Bifidobacterium,
Clostridium lituseburense and Faecalibacterium prausnitzii proportions
decreased (P = 0.007, P = 0.031 and P = 0.009, respectively) as a
result of the GFD analysed by FISH. Bifidobacterium, Lactobacillus and
Bifidobacterium longum counts decreased (P = 0.020, P = 0.001 and P =
0.017, respectively), while Enterobacteriaceae and Escherichia coli
counts increased (P = 0.005 and P = 0.003) after the GFD assessed by
qPCR. TNF-alpha, interferon-gamma, IL-10 and IL-8 production by PBMC
stimulated with faecal samples was also reduced (P = 0.021, P = 0.037,
P = 0.002 and P = 0.007, respectively) after the diet. Therefore, the
GFD led to reductions in beneficial gut bacteria populations and the
ability of faecal samples to stimulate the host's immunity. Thus, the
GFD may constitute an environmental variable to be considered in
treated CD patients for its possible effects on gut health.
2. Parent Ratings of Behavorial Effects of
Biomedical Interventions
http://www.autism.com/treatable/form34qr.htm
3. Elevated immune response in the brain of
autistic patients
Li X et al. J Neuroimmunol. 2009 Feb 15;207(1-2):111-6.
This study determined immune activities in the brain of ASD patients
and matched normal subjects by examining cytokines in the brain tissue.
Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and
GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were
significantly increased in the brains of ASD patients compared with the
controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no
significant difference. The Th1/Th2 ratio was also significantly
increased in ASD patients. Conclusion: ASD patients displayed an
increased innate and adaptive immune response through the Th1 pathway,
suggesting that localized brain inflammation and autoimmune disorder
may be involved in the pathogenesis of ASD.
4. Elevation of tumor necrosis factor-alpha
in cerebrospinal fluid of autistic children
Chez MG et al. Pediatr Neurol. 2007 Jun;36(6):361-5.
Recent reports implicating elevated cytokines in the central nervous
system in a small number of patients studied with autism have reported
clinical regression. These studies have not focused on tumor necrosis
factor-alpha as a possible marker for inflammatory damage. A series of
10 children with autism had clinical evaluation of their serum and
spinal fluid for inflammatory changes and possible metabolic disease as
part of their neurological evaluation. Elevation of cerebrospinal fluid
levels of tumor necrosis factor-alpha was significantly higher (mean =
104.10 pg/mL) than concurrent serum levels (mean = 2.78 pg/mL) in all
of the patients studied. The ratio of the cerebrospinal fluid levels to
serum levels averaged 53.7:1. This ratio is significantly higher than
the elevations reported for other pathological states for which
cerebrospinal fluid and serum tumor necrosis factor-alpha levels have
been simultaneously measured. This observation may offer a unique
insight into central nervous system inflammatory mechanisms that may
contribute to the onset of autism and may serve as a potential clinical
marker. More controlled study of this potentially important observation
may prove valuable.
5. Immune activation of peripheral blood
and mucosal CD3+ lymphocyte cytokine profiles in children with autism
and gastrointestinal symptoms
Ashwood P, Wakefield AJ. J Neuroimmunol. 2006 Apr;173(1-2):126-34.
Gastrointestinal pathology, characterized by lymphoid nodular
hyperplasia and entero-colitis, has been demonstrated in a cohort of
children with autistic spectrum disorder (ASD). Systemic and intestinal
mucosal immune dysregulation was assessed in ASD children with
gastrointestinal (GI) symptoms (n = 18), and typically developing
controls (n = 27), including non-inflamed controls (NIC) and inflamed
GI control children with Crohn's disease (CD), by analysis of
intracellular cytokines in CD3+ lymphocytes. In both peripheral blood
and mucosa, CD3+ TNFalpha+ and CD3+ IFNgamma+ were increased in ASD
children compared with NIC (p < 0.004) and reached levels similar to
CD. In contrast, peripheral and mucosal CD3+ IL-10+ were markedly lower
in ASD children with GI symptoms compared with both NIC and CD controls
(p < 0.02). In addition, mucosal CD3+ IL-4+ cells were increased (p
< 0.007) in ASD compared with NIC. There is a unique pattern of
peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines,
which is consistent with significant immune dysregulation, in this ASD
cohort.
6. Cerebrospinal fluid and serum markers of
inflammation in autism
Zimmerman AW et al. Pediatr Neurol. 2005 Sep;33(3):195-201.
Systemic immune abnormalities have no known relevance to brain
dysfunction in autism. In order to find evidence for neuroinflammation,
we compared levels of sensitive indicators of immune activation:
quinolinic acid, neopterin, and biopterin, as well as multiple
cytokines and cytokine receptors, in cerebrospinal fluid and serum from
children with autism, to control subjects with other neurologic
disorders. In cerebrospinal fluid from 12 children with autism,
quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased,
and biopterin (P = 0.040) was elevated, compared with control subjects.
In sera from 35 persons with autism, among cytokines, only tumor
necrosis factor receptor II was elevated compared with controls (P <
0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid
are paradoxical and suggest dysmaturation of metabolic pathways and
absence of concurrent infection, respectively, in autism.
Alternatively, they may be produced by microglia but remain localized
and not expressed in cerebrospinal fluid.
7. Evaluation of an association between
gastrointestinal symptoms and cytokine production against common
dietary proteins in children with autism spectrum disorders
Jyonouchi H et al. J Pediatr. 2005 May;146(5):605-10.
OBJECTIVE: To evaluate an association between cytokine production with
common dietary proteins as a marker of non-allergic food
hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young
children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral
blood mononuclear cells (PBMCs) were obtained from 109 ASD children
with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N =
34], from children with NFH (N = 15), and control subjects (N = 19).
Diarrhea and constipation were the major GI symptoms. We measured
production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2),
and regulatory cytokines by PBMCs stimulated with whole cow's milk
protein (CMP), its major components (casein, beta-lactoglobulin, and
alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI
(+) ASD children produced more tumor necrosis factor-alpha
(TNF-alpha)/interleukin-12 (IL-12) than those obtained from control
subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin,
irrespective of objective GI symptoms. They also produced more
TNF-alpha with gliadin, which was more frequently observed in the group
with loose stools. PBMCs obtained from GI (-) ASD children produced
more TNF-alpha/IL-12 with CMP than those from control subjects, but not
with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine
production with casein and soy were unremarkable. CONCLUSION: A high
prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs
with CMP and its major components indicates a role of NFH in GI
symptoms observed in children with ASD.
8. Dysregulated innate immune responses in
young children with autism spectrum disorders: their relationship to
gastrointestinal symptoms and dietary intervention
Jyonouchi H et al. Neuropsychobiology. 2005;51(2):77-85.
OBJECTIVE: Our previous study indicated an association between cellular
immune reactivity to common dietary proteins (DPs) and excessive
proinflammatory cytokine production with endotoxin (lipopolysaccharide,
LPS), a major stimulant of innate immunity in the gut mucosa, in a
subset of autism spectrum disorder (ASD) children. However, it is
unclear whether such abnormal LPS responses are intrinsic in these ASD
children or the results of chronic gastrointestinal (GI) inflammation
secondary to immune reactivity to DPs. This study further explored
possible dysregulated production of proinflammatory and
counter-regulatory cytokines with LPS in ASD children and its
relationship to GI symptoms and the effects of dietary intervention
measures. METHODS: This study includes ASD children (median age 4.8
years) on the unrestricted (n = 100) or elimination (n = 77) diet
appropriate with their immune reactivity. Controls include children
with non-allergic food hypersensitivity (NFH; median age 2.9 years) on
the unrestricted (n = 14) or elimination (n = 16) diet, and typically
developing children (median age 4.5 years, n = 13). The innate immune
responses were assessed by measuring production of proinflammatory
(TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra,
IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells
(PBMCs) with LPS. The results were also compared to T-cell responses
with common DPs and control T-cell mitogens assessed by measuring
T-cell cytokine production. RESULTS: ASD and NFH PBMCs produced higher
levels of TNF-alpha with LPS than controls regardless of dietary
interventions. However, only in PBMCs from ASD children with positive
gastrointestinal (GI(+)) symptoms, did we find a positive association
between TNF-alpha levels produced with LPS and those with cow's milk
protein (CMP) and its major components regardless of dietary
interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced
higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with
LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less
counter-regulatory cytokines with LPS in the unrestricted diet group
than in the elimination diet group. There was no significant difference
among the study groups with regard to cytokine production in responses
to T-cell mitogens and other recall antigens. Conclusion: Our results
revealed that there are findings limited to GI(+) ASD PBMCs in both the
unrestricted and elimination diet groups. Thus our findings indicate
intrinsic defects of innate immune responses in GI(+) ASD children but
not in NFH or GI(-) ASD children, suggesting a possible link between GI
and behavioral symptoms mediated by innate immune abnormalities.
9. Spontaneous mucosal lymphocyte cytokine
profiles in children with autism and gastrointestinal symptoms: mucosal
immune activation and reduced counter regulatory
interleukin-10
Ashwood P et al. J Clin Immunol. 2004 Nov;24(6):664-73.
A lymphocytic enterocolitis has been reported in a cohort of children
with autistic spectrum disorder (ASD) and gastrointestinal (GI)
symptoms. This study tested the hypothesis that dysregulated intestinal
mucosal immunity with enhanced pro-inflammatory cytokine production is
present in these ASD children. Comparison was made with developmentally
normal children with, and without, mucosal inflammation. Duodenal and
colonic biopsies were obtained from 21 ASD children, and 65
developmentally normal paediatric controls, of which 38 had signs of
histological inflammation. Detection of CD3+ lymphocyte staining for
spontaneous intracellular TNFalpha, IL-2, IL-4, IFNgamma, and IL-10,
was performed by multicolor flow cytometry. Duodenal and colonic
mucosal CD3+ lymphocyte counts were elevated in ASD children compared
with noninflamed controls (p<0.03). In the duodenum, the proportion
of lamina propria (LP) and epithelial CD3(+)TNFalpha+ cells in ASD
children was significantly greater compared with noninflamed controls
(p<0.002) but not coeliac disease controls. In addition, LP and
epithelial CD3(+)IL-2+ and CD3(+)IFNgamma+, and epithelial CD3(+)IL-4+
cells were more numerous in ASD children than in noninflamed controls
(p<0.04). In contrast, CD3(+)IL-10+ cells were fewer in ASD children
than in noninflamed controls (p<0.05). In the colon, LP
CD3(+)TNFalpha+ and CD3(+)IFNgamma+ were more frequent in ASD children
than in noninflamed controls (p<0.01). In contrast with Crohn's
disease and non-Crohn's colitis, LP and epithelial CD3(+)IL-10+ cells
were fewer in ASD children than in nondisease controls (p<0.01).
There was a significantly greater proportion of CD3(+)TNFalpha+ cells
in colonic mucosa in those ASD children who had no dietary exclusion
compared with those on a gluten and/or casein free diet (p<0.05).
There is a consistent profile of CD3+ lymphocyte cytokines in the small
and large intestinal mucosa of these ASD children, involving increased
pro-inflammatory and decreased regulatory activities. The data provide
further evidence of a diffuse mucosal immunopathology in some ASD
children and the potential for benefit of dietary and immunomodulatory
therapies.
10. High nitric oxide production in
autistic disorder: a possible role for interferon-gamma
Sweeten TL et al. Biol Psychiatry. 2004 Feb 15;55(4):434-7.
BACKGROUND: Neuroimmune regulation abnormalities have been implicated
in the pathophysiology of autistic disorder. Nitric oxide (NO) is
involved in immune reactivity and is known to affect brain
neurodevelopmental processes. Recent evidence indicates that NO, and
cytokines involved in NO production, may be high in children with
autism. The purpose of this study was to verify that plasma NO is high
in children with autism and determine whether this elevation is related
to plasma levels of cytokines involved in NO production. METHODS: The
metabolites of NO, nitrite, and nitrate (NOx), along with the cytokines
interferon-gamma (IFN-gamma), tumor necrosis factor-alpha, and
interleukin-1beta, were measured in plasma of 29 children with autism
(mean age +/- SD = 6.1 +/- 2.8 years) and 27 age- and gender-matched
healthy comparison subjects using commercially available assay kits.
RESULTS: Plasma levels of NOx were significantly higher in the autistic
subjects (p =.006); plasma levels of the cytokines did not differ
between groups. NOx and IFN-gamma levels were positively correlated in
the autistic subjects (r =.51; p =.005). CONCLUSIONS: These results
confirm that plasma NO is high in some children with autism and suggest
that this elevation may be related to IFN-gamma activity.
11. Innate immunity associated with
inflammatory responses and cytokine production against common dietary
proteins in patients with autism spectrum disorder
Jyonouchi H, Sun S, Itokazu N. Neuropsychobiology. 2002;46(2):76-84.
OBJECTIVES: Children with autism spectrum disorder (ASD) frequently
reveal various gastrointestinal (GI) symptoms that may resolve with an
elimination diet along with apparent improvement of some of the
behavioral symptoms. Evidence suggests that ASD may be accompanied by
aberrant (inflammatory) innate immune responses. This may predispose
ASD children to sensitization to common dietary proteins (DP), leading
to GI inflammation and aggravation of some behavioral symptoms.
METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against
representative DPs [gliadin, cow's milk protein (CMP), and soy] by
peripheral blood mononuclear cells (PBMCs) from ASD and control
children [those with DP intolerance (DPI), ASD siblings, and healthy
unrelated children]. We evaluated the results in association with
proinflammatory and counter-regulatory cytokine production with
endotoxin (LPS), a microbial product of intestinal flora and a
surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs
produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs
at high frequency as observed in DPI PBMCs. ASD PBMCs revealed
increased proinflammatory cytokine responses with LPS at high frequency
with positive correlation between proinflammatory cytokine production
with LPS and IFN-gamma and TNF-alpha production against DPs. Such
correlation was less evident in DPI PBMCs. CONCLUSION: Immune
reactivity to DPs may be associated with apparent DPI and GI
inflammation in ASD children that may be partly associated with
aberrant innate immune response against endotoxin, a product of the gut
bacteria.
12. Activation of the inflammatory response
system in autism
Croonenberghs J et al. Neuropsychobiology. 2002;45(1):1-6.
BACKGROUND/AIM: There is now some evidence that autism may be
accompanied by abnormalities in the inflammatory response system (IRS).
Products of the IRS, such as proinflammatory cytokines, may induce some
of the behavioral symptoms of autism, such as social withdrawal,
resistance to novelty and sleep disturbances. The main aim of the
present study was to examine whether autism is accompanied by an
activation of the IRS. METHODS: We measured the production of
interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA),
interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by whole
blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R)
and IL-1RA. RESULTS: This study showed a significantly increased
production of IFN-gamma and IL-1RA and a trend toward a significantly
increased production of IL-6 and TNF-alpha by whole blood of autistic
children. There were no significant differences in the serum
concentrations of IL-6, IL-2R and IL-1RA between autistic and normal
children. CONCLUSIONS: These results suggest that autism may be
accompanied by an activation of the monocytic (increased IL-1RA) and
Th-1-like (increased IFN-gamma) arm of the IRS. It is hypothesized that
increased production of proinflammatory cytokines could play a role in
the pathophysiology of autism.
13. Proinflammatory and regulatory cytokine
production associated with innate and adaptive immune responses in
children with autism spectrum disorders and developmental
regression
Jyonouchi H, Sun S, Le H. J Neuroimmunol. 2001 Nov 1;120(1-2):170-9.
We determined innate and adaptive immune responses in children with
developmental regression and autism spectrum disorders (ASD, N=71),
developmentally normal siblings (N=23), and controls (N=17). With
lipopolysaccharide (LPS), a stimulant for innate immunity, peripheral
blood mononuclear cells (PBMCs) from 59/71 (83.1%) ASD patients
produced >2 SD above the control mean (CM) values of TNF-alpha,
IL-1beta, and/or IL-6 produced by control PBMCs. ASD PBMCs produced
higher levels of proinflammatory/counter-regulatory cytokines without
stimuli than controls. With stimulants of phytohemagglutinin (PHA),
tetanus, IL-12p70, and IL-18, PBMCs from 47.9% to 60% of ASD patients
produced >2 SD above the CM values of TNF-alpha depending on
stimulants. Our results indicate excessive innate immune responses in a
number of ASD children that may be most evident in TNF-alpha
production.
14. An infection-based model of
neurodevelopmental damage
Hornig M et al. Proc Natl Acad Sci U S A. 1999 Oct
12;96(21):12102-7.
http://www.pnas.org/content/96/21/12102.long
Perinatal exposure to infectious agents and toxins is linked to the
pathogenesis of neuropsychiatric disorders, but the mechanisms by which
environmental triggers interact with developing immune and neural
elements to create neurodevelopmental disturbances are poorly
understood. We describe a model for investigating disorders of central
nervous system development based on neonatal rat infection with Borna
disease virus, a neurotropic noncytolytic RNA virus. Infection results
in abnormal righting reflexes, hyperactivity, inhibition of open-field
exploration, and stereotypic behaviors. Architecture is markedly
disrupted in hippocampus and cerebellum, with reduction in granule and
Purkinje cell numbers. Neurons are lost predominantly by apoptosis, as
supported by increased mRNA levels for pro-apoptotic products (Fas,
caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in
situ labeling of fragmented DNA. Although inflammatory infiltrates are
observed transiently in frontal cortex, glial activation (microgliosis
> astrocytosis) is prominent throughout the brain and persists for
several weeks in concert with increased levels of proinflammatory
cytokine mRNAs (interleukins 1alpha, 1beta, and 6 and tumor necrosis
factor alpha) and progressive hippocampal and cerebellar damage. The
resemblance of these functional and neuropathologic abnormalities to
human neurodevelopmental disorders suggests the utility of this model
for defining cellular, biochemical, histologic, and functional outcomes
of interactions of environmental influences with the developing central
nervous system.
15. Preliminary evidence of the in vitro
effects of BDE-47 on innate immune responses in children with autism
spectrum disorders
Ashwood P et al. J Neuroimmunol. 2009 Mar 31;208(1-2):130-5.
Autism spectrum disorders (ASD) are complex neurodevelopmental
disorders that manifest in childhood. Immune dysregulation and
autoimmune reactivity may contribute to the etiology of ASD and are
likely the result of both genetic and environmental susceptibilities. A
common environmental contaminant, 2,2',4,4'-tetrabrominated biphenyl
(BDE-47), was tested for differential effects on the immune response of
peripheral blood mononuclear cells (PBMC) isolated from children with
ASD (n=19) and age-matched typically developing controls (TD, n=18).
PBMC were exposed in vitro to either 100 nM or 500 nM BDE-47, before
challenge with bacterial lipopolysaccharide (LPS), an innate immune
activator, with resultant cytokine production measured using the
Luminex multiplex platform. The cytokine responses of LPS stimulated
PBMC from ASD and TD subjects diverged in the presence of 100 nM BDE.
For example, cells cultured from the TD group demonstrated
significantly decreased levels of the cytokines IL-12p40, GM-CSF, IL-6,
TNFalpha, and the chemokines MIP-1alpha and MIP-1beta following LPS
stimulation of PBMC pretreated with 100 nM BDE-47 compared with samples
treated with vehicle control (p<0.05). In contrast, cells cultured
from subjects with ASD demonstrated an increased IL-1beta response to
LPS (p=0.033) when pretreated with 100 nM BDE-47 compared with vehicle
control. Preincubation with 500 nM BDE-47 significantly increased the
stimulated release of the inflammatory chemokine IL-8 (p<0.04) in
cells cultured from subjects with ASD but not in cells from TD
controls. These data suggest that in vitro exposure of PBMC to BDE-47
affects cell cytokine production in a pediatric population. Moreover,
PBMC from the ASD subjects were differentially affected when compared
with the TD controls suggesting a biological basis for altered
sensitivity to BDE-47 in the ASD population.
16. Plasma increase of interleukin-12 and
interferon-gamma. Pathological significance in autism
Singh VK. J Neuroimmunol. 1996 May;66(1-2):143-5.
Immune factors such as autoimmunity have been implicated in the genesis
of autism, a neurodevelopmental disorder. Since autoimmune response
involves immune activation, the plasma levels of interferon-alpha
(IFN-alpha), interferon-gamma (IFN-gamma), interleukin-12 (IL-12),
interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and
soluble intercellular adhesion molecule-1 (sICAM-1) were measured in
autistic patients and age-matched normal controls. The levels of IL-12
and IFN-gamma were significantly (P < or = 0.05) higher in patients
as compared to controls. However, IFN-alpha, IL-6, TNF-alpha, and
sICAM-1 levels did not significantly differ between the two groups.
Because macrophage-derived IL-12 is known to selectively induce
IFN-gamma in T helper type-1 (Th-1) cells, it is suggested that IL-12
and IFN-gamma increases may indicate antigenic stimulation of Th-1
cells pathogenetically linked to autoimmunity in autism.
17. Microglial activation and TNFalpha
production mediate altered CNS excitability following peripheral
inflammation
Riazi K et al. Proc Natl Acad Sci U S A. 2008 Nov
4;105(44):17151-6.
http://www.pnas.org/content/105/44/17151.long
Peripheral inflammation leads to a number of centrally mediated
physiological and behavioral changes. The underlying mechanisms and the
signaling pathways involved in these phenomena are not yet well
understood. We hypothesized that peripheral inflammation leads to
increased neuronal excitability arising from a CNS immune response. We
induced inflammation in the gut by intracolonic administration of
2,4,6-trinitrobenzene sulfonic acid (TNBS) to adult male rats. To
examine the excitability of the brain in vivo, we administered
pentylenetetrazole (PTZ; a GABAergic antagonist) intravenously to evoke
clonic seizures. Rats treated with TNBS showed increased susceptibility
to PTZ seizures that was strongly correlated with the severity and
progression of intestinal inflammation. In vitro hippocampal slices
from inflamed, TNBS-treated rats showed increased spontaneous
interictal burst firing following application of 4-aminopyridine,
indicating increased intrinsic excitability. The TNBS-treated rats
exhibited a marked, reversible inflammatory response within the
hippocampus, characterized by microglial activation and increases in
tumor necrosis factor alpha (TNFalpha) levels. Central antagonism of
TNFalpha using a monoclonal antibody or inhibition of microglial
activation by i.c.v. injection of minocycline prevented the increase in
seizure susceptibility. Moreover, i.c.v. infusion of TNFalpha in
untreated rats for 4 days also increased seizure susceptibility and
thus mimicked the changes in seizure threshold observed with intestinal
inflammation. Our finding of a microglia-dependent TNFalpha-mediated
increase in CNS excitability provides insight into potential mechanisms
underlying the disparate neurological and behavioral changes associated
with chronic inflammation.
18. Gliadin stimulates human monocytes
to production of IL-8 and TNF-alpha through a mechanism involving
NF-kappaB
Jelínková L et al. FEBS Lett. 2004 Jul 30;571(1-3):81-5.
Wheat gliadin is the triggering agent in coeliac disease. In this
study, we documented that proteolytic fragments of gliadin, in contrast
to other food antigens, induced interleukin (IL)-8 and tumour necrosis
factor-alpha (TNF-alpha) production and significantly increased
interferon (IFN)-gamma-induced cytokine secretion in human monocytic
line THP-1 cells. Stimulation with gliadin resulted in elevated
phosphorylation of the IkappaBalpha molecule and increased
NF-kappaB/DNA binding activity that was inhibited by sulfasalazine,
l-1-tosylamido-2-phenylethyl chloromethyl ketone and pyrrolidine
dithiocarbamate (PDTC). The activation pathway was shown to be
independent of the CD14 molecule. Less mature U-937 monocytes responded
to gliadin stimulation by low IL-8 secretion, TNF-alpha production was
not detectable. We propose that gliadin-induced activation of
monocytes/macrophages can participate in mechanisms leading to the
impairment of intestinal mucosa in coeliac patients.
19. Inflammatory cytokines in small
intestinal mucosa of patients with potential coeliac disease
Westerholm-Ormio M et al. Clin Exp Immunol. 2002 Apr;128(1):94-101.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1906370&blobtype=pdf
T helper cell type 1 (Th1) response to gluten has been implicated in
the pathogenesis of coeliac disease (CD). To characterize immunological
activation and mild inflammations leading to overt CD in potential
coeliac patients, jejunal biopsies were obtained from family members of
patients with CD or dermatitis herpetiformis (DH). Nine family members
and one latent CD, eight CD patients and eight normal controls
furnished jejunal biopsy specimens. Immunohistochemical staining of
sections for interleukin-1alpha (IL-1alpha), IL-2, IL-4,
interferon-gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha),
CD3, gammadelta-T cell receptor (gammadelta-TCR), and alphabeta-TCR was
carried out with monoclonal antibodies. Further, expression of IL-4 and
IFN-gamma messenger RNA was detected by radioactive in situ
hybridization in these same samples. In lamina propria, CD patients and
potential CD patients had higher densities of IL-2 (P = 0.028, P =
0.043), IL-4 (P = 0.021, P = 0.034) and IFN-gamma positive cells (P =
0.000, P = 0.009) than did controls. Moreover, CD patients showed a
higher density of TNF-alpha positive cells (P = 0.012, P = 0.001) than
the other two groups, and expression of IFN-gamma mRNA (P = 0.035) was
higher in them than in the other two study groups. Additionally, higher
densities of TNF-alpha and IFN-gamma positive cells occurred in
potential CD patients with high gammadelta-TCR+ intraepithelial
lymphocytes (IELs). Our findings support the hypothesis that lamina
propria T cells and macrophages, through their secretion of cytokines,
play a central role in the pathogenesis of coeliac disease. The
inflammatory cytokines found in potential CD specimens strongly suggest
that these inflammatory markers can be identified long before visible
villous changes have occurred.
20. Activation of macrophages by food
antigens: enhancing effect of gluten on nitric oxide and cytokine
production
Tucková L et al. J Leukoc Biol. 2000 Mar;67(3):312-8.
http://www.jleukbio.org/cgi/reprint/67/3/312
Macrophages play an important role in effector mechanisms of various
chronic inflammatory diseases. We studied the effect of gluten, the
agent inducing celiac disease, and other food antigens on the
activation of macrophages. Nitric oxide (NO) and cytokine production
were followed as markers of activation, using cultured murine
peritoneal macrophages. None of the food antigens tested caused direct
inducible nitric oxide synthase (iNOS) activation in macrophages.
Unlike other food antigens gluten, gliadin, and their proteolytic
fragments significantly enhanced NO production when applied together
with interferon-gamma (IFN-gamma), the most efficient being fragments
originating from 25- to 45-min peptic digestion. The activation pathway
was mediated via direct stimulation of tumor necrosis factor alpha
(TNF-alpha) secretion. The NO-enhancing effect was confirmed at the
level of iNOS mRNA transcription. In case of sustained local
inflammatory reaction connected with increase of IFN-gamma, gluten and
its proteolytic fragments may thus elevate NO production. Increased NO
level could consequently participate in the development of mucosal
lesions in the gut of celiac patients.
22. Clinical and pathological spectrum of
coeliac disease--active, silent, latent, potential
Ferguson A et al. Gut. 1993 Feb;34(2):150-1.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1373959&blobtype=pdf
22. Celiac disease and the spectrum of
gluten sensitivity
Frick TJ, Olsen WA. Gastroenterologist. 1994 Dec;2(4):285-92.
Celiac disease is a well-known entity in which intolerance to wheat
gluten and related proteins from barley, rye, and oats (collectively
known as prolamins) damage intestinal mucosa. New insights into the
pathology of the celiac intestinal lesion point to a wider spectrum of
gluten sensitivity than previously thought. Recent advances in
immunology and genetics have shed light on the underlying mechanisms
and risks associated with the disease. Although the classical
manifestations are well known, the wide variety of clinical
presentations make celiac disease often difficult to diagnose, and the
ubiquitous presence of prolamins in the Western diet make treatment
challenging.
23. The spectrum of coeliac disease in
children
Catassi C, Fabiani E. Baillieres Clin Gastroenterol. 1997
Sep;11(3):485-507.
Coeliac disease is the life-long intolerance to dietary gluten, usually
characterized by severe damage to the small-intestinal mucosa. The
widespread use of sensitive diagnostic tools, such as the serum
anti-gliadin and the anti-endomysial antibodies, has shown not only
that coeliac disease is one of the commonest disorders in Western
countries but also that this condition is characterized by a higher
degree of clinical variability than previously thought (typical,
atypical and silent forms). The existence of a latent-potential coeliac
disease and even a gluten-sensitive disease with immunological
activation of an otherwise normal small-intestinal mucosa has recently
been postulated. An increased prevalence of coeliac disease in a number
of other disorders has also been reported in both children and adults.
The reasons for such a wide clinical heterogeneity are still poorly
understood but are likely to depend on both genetic and environmental
factors. Further investigations are required to evaluate the impact of
undiagnosed, clinically milder forms of coeliac disease on the
well-being of the population.
24. The widening spectrum of celiac
disease
Murray JA. Am J Clin Nutr. 1999 Mar;69(3):354-65.
http://www.ajcn.org/cgi/content/full/69/3/354
Celiac disease is a permanent intolerance to ingested gluten that
results in immunologically mediated inflammatory damage to the
small-intestinal mucosa. Celiac disease is associated with both human
leukocyte antigen (HLA) and non-HLA genes and with other immune
disorders, notably juvenile diabetes and thyroid disease. The classic
sprue syndrome of steatorrhea and malnutrition coupled with multiple
deficiency states may be less common than more subtle and often
monosymptomatic presentations of the disease. Diverse problems such as
dental anomalies, short stature, osteopenic bone disease, lactose
intolerance, infertility, and nonspecific abdominal pain among many
others may be the only manifestations of celiac disease. The rate at
which celiac disease is diagnosed depends on the level of suspicion for
the disease. Although diagnosis relies on intestinal biopsy findings,
serologic tests are useful as screening tools and as an adjunct to
diagnosis. The treatment of celiac disease is lifelong avoidance of
dietary gluten. Gluten-free diets are now readily achievable with
appropriate professional instruction and community support. Both benign
and malignant complications of celiac disease occur but these can often
be avoided by early diagnosis and compliance with a gluten-free
diet.
25. Current approaches to diagnosis and
treatment of celiac disease: an evolving spectrum
Fasano A, Catassi C. Gastroenterology. 2001 Feb;120(3):636-51.
Celiac disease (CD) is a syndrome characterized by damage of the small
intestinal mucosa caused by the gliadin fraction of wheat gluten and
similar alcohol-soluble proteins (prolamines) of barley and rye in
genetically susceptible subjects. The presence of gluten in these
subjects leads to self-perpetuating mucosal damage, whereas elimination
of gluten results in full mucosal recovery. The clinical manifestations
of CD are protean in nature and vary markedly with the age of the
patient, the duration and extent of disease, and the presence of
extraintestinal pathologic conditions. In addition to the classical
gastrointestinal form, a variety of other clinical manifestations of
the disease have been described, including atypical and asymptomatic
forms. Therefore, diagnosis of CD is extremely challenging and relies
on a sensitive and specific algorithm that allows the identification of
different manifestations of the disease. Serologic tests developed in
the last decade provide a noninvasive tool to screen both individuals
at risk for the disease and the general population. However, the
current gold standard for the diagnosis of CD remains histologic
confirmation of the intestinal damage in serologically positive
individuals. The keystone treatment of CD patients is a lifelong
elimination diet in which food products containing gluten are
avoided.
26. Range of neurologic disorders in
patients with celiac disease
Zelnik N et al. Pediatr Neurol. 2008 Dec;39(6):392-8.
OBJECTIVE: During the past 2 decades, celiac disease (CD) has been
recognized as a multisystem autoimmune disorder. A growing body of
distinct neurologic conditions such as cerebellar ataxia, epilepsy,
myoclonic ataxia, chronic neuropathies, and dementia have been
reported, mainly in middle-aged adults. There still are insufficient
data on the association of CD with various neurologic disorders in
children, adolescents, and young adults, including more common and
"soft" neurologic conditions, such as headache, learning disorders,
attention-deficit/hyperactivity disorder (ADHD), and tic disorders. The
aim of the present study is to look for a broader spectrum of
neurologic disorders in CD patients, most of them children or young
adults. METHODS: Patients with CD were asked to fill in a questionnaire
regarding the presence of neurologic disorders or symptoms. Their
medical charts were reviewed, and those who were reported as having
neurologic manifestations underwent neurologic examination and brain
imaging or electroencephalogram if required. Their neurologic data were
compared with that of a control group matched for age and gender.
RESULTS: Patients with CD were more prone to develop neurologic
disorders (51.4%) in comparison with control subjects (19.9%). These
disorders include hypotonia, developmental delay, learning disorders
and ADHD, headache, and cerebellar ataxia. Epileptic disorders were
only marginally more common in CD. In contrast, no difference was found
in the prevalence of tic disorders in both groups. Therapeutic benefit,
with gluten-free diet, was demonstrated only in patients with transient
infantile hypotonia and migraine headache. CONCLUSION: This study
suggests that the variability of neurologic disorders that occur in CD
is broader than previously reported and includes "softer" and more
common neurologic disorders, such as chronic headache, developmental
delay, hypotonia, and learning disorders or ADHD. Future longitudinal
prospective studies might better define the full range of these
neurologic disorders and their clinical response to a gluten-free
diet.
27. Plasma cytokine profiles in patients
with celiac disease and selective IgA deficiency
Cataldo F et al. Pediatr Allergy Immunol. 2003 Aug;14(4):320-4.
Celiac disease (CD) and selective IgA deficiency (IgAD) are frequently
associated, and share the same genetic background. The aim of the
present study was to evaluate both Type 1 and 2 plasma cytokine levels
in CD and in CD-IgAD. IL-2, TNF-alpha, IL-10, IL-4 and IL-13 plasma
levels were measured both at diagnosis and after a gluten-free diet
(GFD) in 32 CD patients, in 27 CD-IgAD patients and in 30 healthy
controls. IFN-gamma levels were significantly higher in CD and CD-IgAD
than in controls, TNF-alpha displayed significantly higher levels in
CD-IgAD when compared both with controls and with CD, and IL-2 was in
CD-IgAD significantly increased respect to controls. Kinetics of the
Type 1 cytokine plasma levels did not show a clear relationship with
the GFD in both groups of CD patients, and particularly in those with
IgAD. IL-4 and IL-13, both at diagnosis and after a GFD, were not
significantly different in controls and in celiac patients (with and
without IgAD). IL-10, whose production is stimulated by the TNF-alpha,
had significantly higher plasma levels in CD-IgAD, but not in CD
patients, with a significant decrease after a GFD. CD and especially
CD-IgAD patients display persistently higher pro-inflammatory cytokine
levels, suggesting a persistent state of activation of pro-phlogistic
signals in CD, particularly when IgAD coexists. Serial measurement of
serum IL-10 may be an adjunctive evaluating criterion in the follow-up
of CD-IgAD patients.
28. Gastrointestinal symptoms in children
with an autism spectrum disorder and language regression
Valicenti-McDermott MD et al. Pediatr Neurol. 2008 Dec;39(6):392-8.
Few studies have compared gastrointestinal problems in children with an
autism spectrum disorder with and without a history of language
regression. A cross-sectional study was conducted with structured
interviews in 100 children with autism spectrum disorder, using a
gastrointestinal questionnaire and a familial autoimmune questionnaire.
By parental report, children with language regression more frequently
exhibited an abnormal stool pattern (40% vs 12%, P = 0.006) and had an
increased family history of celiac disease or inflammatory bowel
disease (24% vs 0%, P = 0.001) and of rheumatoid arthritis (30% vs 11%,
P = 0.03). Among 35 children with a family history of autoimmune
disease, an abnormal stool pattern was reported more frequently in
those with language regression (78% vs 15%, P = 0.001) than in those
without. An association was observed between children with language
regression, a family history of autoimmune disease, and
gastrointestinal symptoms. Additional studies are needed to examine a
possible shared autoimmune process.
29. The significance of ileo-colonic
lymphoid nodular hyperplasia in children with autistic spectrum
disorder
Wakefield AJ et al. Eur J Gastroenterol Hepatol. 2005
Aug;17(8):827-36.
BACKGROUND: Intestinal mucosal pathology, characterized by ileo-colonic
lymphoid nodular hyperplasia (LNH) and mild acute and chronic
inflammation of the colorectum, small bowel and stomach, has been
reported in children with autistic spectrum disorder (ASD). AIM: To
assess ileo-colonic LNH in ASD and control children and to test the
hypothesis that there is an association between ileo-colonic LNH and
ASD in children. PATIENTS AND METHODS: One hundred and forty-eight
consecutive children with ASD (median age 6 years; range 2-16; 127
male) with gastrointestinal symptoms were investigated by
ileo-colonoscopy. Macroscopic and histological features were scored and
compared with 30 developmentally normal (non-inflammatory bowel
disease, non-coeliac disease) controls (median age 7 years; range 1-11;
25 male) showing mild non-specific colitis in 16 cases (13 male) and
normal colonic histology in 14 cases (12 male). Seventy-four ASD
children and 23 controls also underwent upper gastrointestinal
endoscopy. The influence on ileal LNH of dietary restriction, age at
colonoscopy, and co-existent LNH elsewhere in the intestine, was
examined. RESULTS: The prevalence of LNH was significantly greater in
ASD children compared with controls in the ileum (129/144 (90%) vs.
8/27 (30%), P < 0.0001) and colon (88/148 (59%) vs. 7/30 (23%), P =
0.0003), whether or not controls had co-existent colonic inflammation.
The severity of ileal LNH was significantly greater in ASD children
compared with controls, with moderate to severe ileal LNH present in 98
of 144 (68%) ASD children versus 4 of 27 (15%) controls (P <
0.0001). Severe ileal LNH was associated with co-existent colonic LNH
in ASD children (P = 0.01). The presence and severity of ileal LNH was
not influenced by either diet or age at colonoscopy (P = 0.2). Isolated
ileal LNH without evidence of pathology elsewhere in the intestine was
a rare event, occurring in less than 3% of children overall. On
histopathological examination, hyperplastic lymphoid follicles are
significantly more prevalent in the ileum of ASD children (84/138; 61%)
compared with controls (2/23; 9%, P = 0.0001). CONCLUSION: Ileo-colonic
LNH is a characteristic pathological finding in children with ASD and
gastrointestinal symptoms, and is associated with mucosal inflammation.
Differences in age at colonoscopy and diet do not account for these
changes. The data support the hypothesis that LNH is a significant
pathological finding in ASD children.
30. Intestinal lymphocyte populations in
children with regressive autism: evidence for extensive mucosal
immunopathology
Ashwood P et al. J Clin Immunol. 2003 Nov;23(6):504-17.
Inflammatory intestinal pathology has been reported in children with
regressive autism (affected children). Detailed analysis of intestinal
biopsies in these children indicates a novel lymphocytic enterocolitis
with autoimmune features; however, links with cognitive function remain
unclear. To characterize further, the nature and extent of this disease
we examined the mucosal infiltrate using flow cytometry. Duodenal,
ileal, and colonic biopsies were obtained from 52 affected children, 25
histologically normal, and 54 histologically inflamed, developmentally
normal controls. Epithelial and lamina propria lymphocyte populations
were isolated and examined by multicolor flow cytometry. Adjacent
biopsies were assessed by semiquantitative histopathology. At all
sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were
significantly increased in affected children compared with
developmentally normal noninflamed control groups (p<0.01) reaching
levels similar to inflamed controls. In addition, two populations --
CD3(+)CD4(+) IEL and LP CD19(+) B cells -- were significantly increased
in affected children compared with both noninflamed and inflamed
control groups including IBD, at all sites examined (p<0.01).
Histologically there was a prominent mucosal eosinophil infiltrate in
affected children that was significantly lower in those on a gluten-
and casein-free diet, although lymphocyte populations were not
influenced by diet. The data provide further evidence of a pan-enteric
mucosal immunopathology in children with regressive autism that is
apparently distinct from other inflammatory bowel diseases.
31. Defective tumour necrosis factor-alpha
production in mother's milk is related to cow's milk allergy in
suckling infants
Järvinen KM et al. Clin Exp Allergy. 2000 May;30(5):637-43.
BACKGROUND: The precise role of leucocytes in human milk is still
unresolved. OBJECTIVE: To assist in clarifying the immune mechanisms
involved in the development of CMA in suckling infants, we studied the
role of immunoregulatory leucocytes and their mediators in human breast
milk. METHODS: The study population consisted of 43 lactating mothers
and their infants, aged 0.25-8.0 months, followed-up prospectively from
birth. Of these mothers, 27 had an infant with challenge-proven cow's
milk allergy manifested with either skin (n = 23), gastrointestinal (n
= 2) or skin and gastrointestinal symptoms (n = 3). Sixteen mothers
with a healthy infant served as controls. We evaluated the spontaneous
and mitogen-induced tumour necrosis factor-alpha (TNFalpha) and
interferon-gamma (IFNgamma) production of human milk leucocytes and
isolated peripheral blood lymphocytes in vitro with a commercial ELISA
kit. RESULTS: TNFalpha production of breast milk leucocytes was
significantly lower in the mothers with a cow's milk-allergic infant,
whereas IFNgamma production of these cells was comparable in the two
groups. CONCLUSION: Our results suggest that in the breast milk of
mothers having an infant with cow's milk allergy, the number and
function of TNFalpha-producing cells is defective. This might lead to a
disturbance in the development of oral tolerance and thereby to the
development of CMA in suckling infants. These novel results may help in
clarifying the etiopathogenesis of CMA.
32. Cow's milk stimulated lymphocyte
proliferation and TNFalpha secretion in hypersensitivity to cow's milk
protein
Motrich RD et al. Clin Immunol. 2003 Nov;109(2):203-11.
Although there is no reliable single laboratory test available for the
diagnosis of cow's milk allergy, if an allergic mechanism is suspected,
a number of laboratory studies may be useful in delineating specific
proteins responsible for these disorders. In the current study we
analyzed in vitro lymphocyte proliferation assays, specific secretion
of TNFalpha in supernatant cultures and specific IgE, IgG, and IgA in a
group of patients with hypersensitivity to cow's milk antigens. The
stimulation index against a cow's milk antigen mixture,
alpha-lactalbumin, beta-lactoglobulin, and casein was significant
higher in the group of patients maintained on cow's milk-free diet for
less than 4 months compared with the values observed in the control
group and in the group of patients without a close contact to cow's
milk proteins. A significant increase in TNF-alpha secretion was
observed in supernatants from patients with close contact to cow's milk
(CM). Specific IgE was detected in 59.3% of the patients, with higher
specific IgE levels in patients who were not positive for the
proliferation assay, suggesting a clear difference in the two
mechanisms proposed as effectors in this disease. No differences in
specific IgG and IgA levels were observed between the patient group and
the control group, with a great dispersion among individuals in all
groups tested. We conclude that a combination of the assays tested in
this study, such as proliferative assay of peripheral blood mononuclear
cells to CM, the quantitation of TNFalpha in culture supernatants, and
serum specific IgE determination, are useful laboratory tests to
identify cow's milk allergy among patients with immediate and non
immediate adverse reactions, reducing the need for food allergen
challenges in young children.
33. Fetal sensitization to cow's milk
protein and wheat: cow's milk protein and wheat-specific TNF-alpha
production by umbilical cord blood cells and subsequent decline of
TNF-alpha production by peripheral blood mononuclear cells following
dietary intervention
Ward CM, Geng L, Jyonouchi H. Pediatr Allergy Immunol. 2007
Jun;18(4):276-80.
We present a case of fetal sensitization to cow's milk protein (CMP)
and wheat, resulting in non-IgE mediated food allergy (NFA). Fetal
sensitization was indicated by onset of NFA symptoms shortly after
birth and CMP/wheat-specific tumor necrosis factor-alpha (TNF-alpha)
production by cord blood mononuclear cells. Following dietary
intervention, we observed a decline of TNF-alpha production by
peripheral blood mononuclear cells with stimuli of these dietary
proteins (DPs) but recurrence of reactivity was observed following
viral gastroenteritis, while interleukin-10 production with these DPs
persisted during his first 5 yr of life. This finding may indicate
active suppressive mechanisms for maintaining oral tolerance.
Contact Teresa
Binstock by email
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