Mast Cells Disrupt The Gut-Blood-Brain Barriers and Contribute To Autism

Autism, Blood-brain-barrier and
Mast cells
T. C. Theoharides, M.S., Ph.D., M.D.
Professor of Pharmacology, Internal Medicine
and Biochemistry; Associate Professor of
Psychiatry
Director, Molecular Immunopharmacology and
Drug Discovery Laboratory
Tufts University School of Medicine
Tufts Medical Center, Boston, MA, USA
Clinical Pharmacologist, Massachusetts Drug
Formulary Commission (1986-2010)
May 1, 2009 Copyright-Dr. T.C. Theoharides 1
Pervasive Developmental Disorders
DSMIV TR Diagnostic Criteria
Pervasive Developmental Disorders
Rett's Childhood Autistic Asperger's PDD-NOS

Disorder Disintegrative Disorder Disorder
Disorder

Autism Spectrum Disorders
Nomenclature
t i s m
m Au
utis
o dA u ti sm
High Functio
ning Autism u tism
h o K a n n er’s A lA
ild NVLD c a
h
C Early Infa rome ty pi
ntile Autism er’s S yn d A
Asperg
Autism Spectrum Disorders
High-Functioning ASD
(intact intellectual capacity)
Autism spectrum disorders: concurrent
clinical disorders
Xue Ming , Brimacombe M, Chaaban J, Zimmerman-Bier B,
Wagner GC. J Child Neurol. 2008 Jan;23(1):6-13. Epub 2007 Dec 3.
• Individuals with autism spectrum disorders are heterogeneous in

clinical presentation, concurrent disorders, and developmental
outcomes. This study characterized the clinical co-occurrences and
potential subgroups in 160 children with autism spectrum disorders
who presented to The Autism Center between 1999 and 2003.
• Medical and psychiatric co-occurrences included sleep disorders,

epilepsy, food intolerance, gastrointestinal dysfunction, mood
disorder, and aggressive and self-injurious behaviors. Sleep
disorders were associated with gastrointestinal dysfunction (P < .05)
and mood disorders (P < .01). Food intolerance was associated
with gastrointestinal dysfunction (P = .001).
Immunologic Dysregulation in Autism
• Plasma from autistic patients (and their mothers) contains autoantibodies to
brain antigens, suggesting BBB disruption.
• Brain of autistic patients have higher expression of IL-6
• Maternal infection in mice increases circulating IL-6 levels that cross the
placenta at midgestation and induce the release of fetal stress hormones
resulting in fetal injury.
• Viral poly(I:C) injection increases IL-6 in the placenta and brain of mice and,
like IL-6 injection, induces autistic-like behavior in mice.
• Acute stress increases serum IL-6, absent in mast cell deficient mice.
• Autistic patient CSF has high levels of macrophage chemoattractant protein-

1 (MCP-1), which is chemotactic for mast cells
• Autistic patient plasma has reduced transforming growth factor-beta1 (TGF-

beta1), which inhibis for mast cell maturation and activation.

Mast Cell Activation Seen With
Nomarski Optics
Triggers Mediators
Allergen/IgE Histamine
Chymase
Tryptase
Neuropeptides Normal mast cells
Leukotrienes
Prostaglandins
Chemokines
IL-1, IL-6, IL-8
GM-CSF, TNF-α
Activated mast cell VEGF
Mast cell degranulation leads to the release of mediators with

potent vasodilatory, nociceptive,
May 1, 2009 and inflammatory properties
Copyright-Dr. T.C. Theoharides 7
Differential release of mast cell mediators and
the pathogenesis of inflammation.
Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D.
Immunol Rev. 2007 Jun;217:65-78.
• Mast cells can be activated by bacterial or viral antigens,

cytokines, growth factors, neuropeptides and stress hormones,
leading to selective release of distinct mediators without
degranulation.
– Trigger Mediator Implication in autism
CRH VEGF
IL-1 IL-6 High brain and serum levels
IL-33 IL-13
LPS TNF-α High CSF levels
SCF IL-6 High brain and serum levels
TLR-9 IL-6 High brain and serum levels

Evidence of “allergic” symptomatology in autism
• In a nested control study, there was over 2-fold higher risk of
children with ASD (n=407) born to mothers with diagnosis of
allergies or asthma during 2nd trimester of pregnancy as
compared to controls (n=2095).
• ASD children had a significant family history of atopy (30%) as
compared to controls (2.5%).
• ASD children had at least one manifestation of allergy and 50% of
ASD children may have two or more symptoms.
• Non-IgE-mediated food intolerance was significantly more
common in ASD children (n=133) than controls (n=81).
• Serum levels of IgG4, associated with atopic phenotype, were
increased in children with autism disorder
• A study of 362 ASD patients in Italy showed that the only
statistically significant association was with history of allergies
• ASDs and mastocytosis children share common symptoms such
as, anxiety, atopic dermatitis,“brain fog”, and food intolerance

www.tmsforacure.org

Proposed Role of Mast Cells in Autism
CNS originating mast cell activation triggers:

Adenylate cyclase activating peptide, Intestine-originating mast cell triggers
corticotropin-releasing hormone, Butyrophilin, casein, gliadin, gluten,
myelin basic protein IL-1, IL-33, reactive oxygen species,
neurotensin, substance P rotavirus, vasoactive intestinal peptide
Mast cell Blood

vessel
Mast cell-derived cytokines Mast cell-derived vasoactive

and other neurotoxic mediators
mediators Gut
Bradykinin, histamine,
IL-1, IL-6, IL-8, IL-13, IL-32, IL-6, nitric oxide, tryptase,
MCP-1, prostaglandin D2, vascular endothelial growth
serotonin, tumor necrosis factor, vasoactive intestinal
factor peptide
Increased
Gut-blood-brain barrier
permeability
ASD

Mast cells are located perivascularly close to
nerve endings
Rozniecki, Dimitriadou, Lambracht-Hall et al. (1999) Brain Res 849: 1.

May 1, Bv=blood
2009 Copyright-Dr. endings;
vessel; white arrowhead=nerve T.C. Theoharides 12
dark arrow=mast cells; g=granule; e=endothelial
Cell; er=erythrocyte; n=nucleus; p=pericyte; vl=blood vessel lumen
Mast cell are located close to
blood vessels and sensory
neurons

Preterm birth, perinatal stress, corticotropin-
releasing hormone and autism
• A retrospective study of preterm children born in Atlanta (1981-
93) who survived to 3 years of age showed that preterm birth at
<33 weeks gestation was associated with a two-fold higher risk
of autism in all infants identified through the Metropolitan Atlanta
Developmental Disabilities Surveillance Program
• A prospective follow-up assessment on 91 ex-preterm infants

(<1500 g) found 26% of these (mean age=22 months) to have a
positive Modified Checklist for Autism in the Toddlers (M-CHAT)
• Another study found that 21% of infants (212/988) born before 28

weeks gestation screened positive using M-CHAT as compared
to 5.7% of healthy children 16-30 months old
• A statistically significant association was reported between

extremely low birth weight and higher rates of autistic and
Asperger disorders

Prematurity
Maternal BBB
CRH
Disruption
Neonatal Delivery Infections

stress (Neonatal ICU)
Newborn BBB
CRH Disruption
Allergies/food
Genetics Infancy
intolerance
(Positive M-CHAT)
Environmental Brain Oxidative

toxins Inflammation stress
Autism
(Positive ADOS-G, ADI-R)

Immunocytochemistry of CRH-R in
human mast cells
4 -
R1 no IL-4
A
R1 + IL-4C
R2 no IL-4
D E
R2 + IL-4
A B BD
F
E G
F
B
C
No R1 primary DAPI
E F

CRH Induces Selective VEGF Release from
Human Mast Cells
VEGF (pg/106cells)
Mast cells were stimulated with CRH at increasing concentration for 6 hours in culture
medium with A) or without B) 10% fetal bovine serum (FBS). Secretion of VEGF in
the samples were measured with a VEGF-specific ELISA kit. VEGF release was
compared to unstimulated control samples. The values are given as mean±SD of five
independent experiments.
99
Tc-G Extravasation Study—
Experimental Design
Plasma leak
30 minutes restraint stress -99Tc-G extravasation
mouse
HPA axis activation
-Blood corticosterone
tv 99Tc-G
C57BL
+/+
W/Wv mast cell-deficient Mast cell activation
Neurokinin-1 receptor -/- -Toluidine blue
Substance P -/-
Stress-induced brain vascular permeability
is dependent on mast cells
99-Technetium-gluceptate HPA axis

extravasation activation
200 600 control
* stress
500 *p<0.05
% change from control
corticosterone (ng/ml)
150
400 *p<0.05
100 300
200
50
100
0 0
+/+ W/W v +/+ W/W v

Corticotropin-releasing hormone and the
blood-brain-barrier
Theoharides TC, Konstantinidou AD.
Front Biosci. 2007 Jan 1;12:1615-28.
• Increased BBB permeability precedes any clinical or pathologic

signs in various brain inflammatory disorders.
• Mast cell specific tryptase is elevated in the CSF of MS
patients, induces microvascular leakage and stimulates
protease-activated receptors (PAR), leading to widespread
inflammation.
• BBB permeability, appears to worsen in response to acute
stress that leads to the local release of corticotropin-releasing
hormone (CRH), which activates brain mast cells to selectively
release IL-6, IL-8 and VEGF.
• Acute stress increases BBB permeability that is dependent on
CRH and mast cells.

Summary
• Mast cells regulate gut-blood-brain barrier permeability, disrupted by acute
stress through corticotropin-releasing hormone (CRH).
• CRH can activate skin mast cells and increase vascular permeability in
rodents and humans, through activation of CRH receptor-1. Similar effects
have been shown in the bladder and the intestines, where CRH was shown
to be involved in intestinal inflammation and motility.
• CRH could increase permeability in normal human colonic biopsies through

activation of subepithelial mast cells.
• Neonatal maternal deprivation stress induced long-term alterations of

colonic nerve-mast cell interactions, while a recent review indicated that
prenatal stress could contribute to the development of autism in humans.

Interleukin-6 and mast cells
Conti P, Kempuraj D, Di Gioacchino M, Boucher W, Letourneau R, Kandere
K, Barbacane RC, Reale M, Felaco M, Frydas S, Theoharides TC.
Allergy Asthma Proc. 2002 Sep-Oct;23(5):331-5.
• IL-6 is a pleiotropic cytokine that was originally named

interferon beta 2 or B cell-stimulating factor or differentiating B
cell factor inducing immunoglobulin production.
• IL-6 mediates immune responses and inflammation
• IL-6 also is a crucial cytokine for mast cell maturation
• IL-6 also up-regulates histamine production and induces the

expression of immunoglobulin E (IgE) receptors on the surface
of mast cells

Stress-induced IL-6 release in mice is
mast cell-dependent
Huang M, Pang X, Karalis K, Theoharides TC.
Cardiovasc Res. 2003 Jul 1;59(1):241-9 .

• Acute stress increases serum IL-6 in mice
• Stress-induced IL-6 release is absent in W/Wv mast

cell-deficient mice
• Both normal and W/Wv mast cell-deficient mice

respond similarly to stress

Effect of acute stress on serum IL-6 levels in (A) stressed W/Wv mice and their +/+
controls, as well as in (B) stressed CRH k/o mice and their controls.
IL-1 induces vesicular secretion of IL-6 without
degranulation from human mast cells
Kandere-Grzybowska K, Letourneau R, Kempuraj D, Donelan J,
Poplawski S, Boucher W, Athanassiou A, Theoharides TC.
J Immunol. 2003 Nov 1;171(9):4830-6.
• IL-1 stimulates secretion of IL-6 without release of the granule-
associated protease tryptase in normal human umbilical cord
blood-derived mast cells.
• IL-6 is de novo synthesized, as its secretion is blocked by

inhibitors of transcription or protein synthesis. IL-1 does not
increase intracellular calcium ion levels in either hCBMCs or
HMC-1 cells, and IL-6 stimulation proceeds in the absence of
extracellular calcium ions.
• Ultrastructural Immunogold localization shows that IL-6 is

excluded from the secretory granules and is compartmentalized
in 40- to 80-nm vesicular structures.

IL-1 stimulates differential release of IL-6
without degranulation
8-16 wk hCBMCs + IL-1 6 hourscell free supernatants
assay IL-6 (ELISA) or tryptase (fluoroimmunoenzyme assay).
1000 125
A spont B *
MC)
*
stim Tryptase *
MC)
IL-6
100
5
750
5
Tryptase (ng/5x10
75
IL-6 (pg/5x10
500
50
250
25
0 0
IL-1 anti-IgE IL-1 anti-IgE
May 1, 2009 n=6, *p<0.05 paired t-

Copyright-Dr. T.C. Theoharides 35
test
Ultrastructural cryo-
immunocytochemistry of
IL-6 molecules released from a secretory
vesicle, 1/10th the diameter of that of
140 nm
secretory granules, of a human mast cell
stimulated with IL-1
140 nm
190 nm
nm
140 nm
190 nm
70 nm
140 nm
Serum IL-6 reflects disease severity and
osteoporosis in mastocytosis patients
Theoharides TC, Boucher W, Spear K.
Int Arch Allergy Immunol. 2002 Aug;128(4):344-50.
• Mastocytosis is characterized by an increased number of mast

cells in the bone marrow or in skin areas known as urticaria
pigmentosa (UP)
• Patients may present with flushing, itching, food intolerance, but

also anxiety, headaches, lack of concentration (“brain fog”)
• Serum IL-6 is elevated in mastocytosis patients and correlates

with severity of symptoms and the presence of osteoporosis.
• High serum IL-6 may not only signify disease progression, but
may also participate in the pathophysiology of mastocytosis

Double Immunocytochemistry
for c-kit and CRH-R

Novel therapeutic targets for autism
Theoharides TC, Doyle R, Francis K, Conti P, Kalogeromitros D.
Trends Pharmacol Sci. 2008 Aug;29(8):375-82. Epub 2008 Jul 6.
• Children with mastocytosis often have ADD, learning

difficulties and “brain fog”
• Data were obtained in response to the question

listed below that was sent by the Mastocytosis
Society to a database of 400 patients
• “Could you please let us know if you or any of your

children have been diagnosed with Autism or an
Autistic Spectrum Disorder (e.g.Asperger’s
disorder). Please include yours and your child’s sex,
current age, age at time of diagnosis, and how/where
diagnosis was made”

Mastocytosis patients with ASD*
Patient Age ‘08 Sex ASD Mast cell diagnosis
1 (BN) 4 M Stuttering, high functioning Mastocytoma, solitary

2 (SH) 15 M ASD, poor speech UP, asthma
3 (RC) 11 M Asperger’s UP, NF1
4 (BL) 18 M+ ASD, dyslexia SM
5 (?) 44 M+ Asperger’s Mastocytosis, UP?
6 (EC) 21 F SID UP
7 (ESC) 21 F SID Mastocytosis
8 (?) 18 M Asperger’s Mastocytosis
26 (BN) 7.5 M Autism Mastocytoma, solitary
10 (CJP) 4 M ASD, ADHD, SID Mastocytosis, UP?, flushing, GI
11 (EA) 9 M Asperger’s UP, hives, rash, GI (brother with masto)
12 (NP) 3.5 M PDD-NOS Mastocytosis
13 (MH) 46 (father) M# Asperger’s Hives, asthma
14 (MH) 10 (daughter) F# Asperger’s Diarrhea, hives, itching
15 (MH) 8 (son) M# Mood problems, ADD Mastocytosis

16 (AB) 2.5 F Autism spectrum, PDD-NOS UP, SM?
17(SMMcC) 17 F Asperger’s Mast cell disease, food intolerance
18 (DA) 9 M Asperger’s UP
19(JDPH) 15 M Asperger’s Mast cell disease, asthma
20 (ME) 23 F Mild autism, ADD Mast cell disease
21 (AC) 4 M Asperger’s Mastocytosis
Mastocytosis patients with ASD*
Patient Age ‘08 Sex ASD Mast cell diagnosis
22 (ND) 7 M Asperger’s (mild) UP
23 (AS) 2 M ASD, SID Mastocytosis, Celiac disease
24 (GC) 21 F Asperger’s SM
25 (AL) 4.5 M ASD, moderate Mastocytoma, solitary
26 (SS) 8 F Asperger’s UP
27 (EAIS) 5 F PDD-NOS Mast cell disease, flushing, milk intolerance, anxiety
28 (JT) 2.5 M Regressive autism Mast cell disease, flushing, food intolerance, acute
lymphocytic anemia
29 (CJM) 3.5 M& PDD-NOS UP, GI symptoms
30 (TDM) 6.6 M& DID Food hypersensitivities
31 (JRM) 10.5 M& ADD, Asperger’s ? Food hypersensitivities
*Data obtained in response to the question listed below that was sent by the Mastocytosis Society (www.tmsforacure.org) to a database of 400
patients. + Same family (uncle); #Same family; &Same family (brothers)
“Could you please let us know if you or any of your children have been diagnosed with
Autism or an Autistic Spectrum Disorder (e.g. Asperger’s disorder). Please include yours
and your child’s sex, current age, age at time of diagnosis, and how/where diagnosis was made.”
ADD=Attention Deficit Disorder; PDD-NOS=Pervasive developmental disorder-not otherwise specified;
NF1=Neurofibromatosis-1; SID=Sensory Integration Dysfunction; SM=systemic mastocytosis; UP=Urticaria Pigmentosa

Mastocytosis parents with children with ASD
Patient Age Sex Mast cell diagnosis Child with ASD-Sex, Age at Dx
1 (CB) 48 F Systemic mastocytosis ADD, Asperger’s-M, 5 y/o
2 (LA) 43 F Mast cell disease Autism, FCAS-F triplets, 2 y/o
3 (?) 45 F Systemic mastocytosis Asperger’s, Mast cell disease
4 (SH) ? F UP, Systemic Asperger’s, ADD, asthma, M
mastocytosis
5 (LK) 45 F Systemic mastocytosis Mild autism, ADD, Mast cell disease, F
6 (CH) ? F Systemic mastocytosis Asperger’s, ADD, M
7 (RK) ? F Mastocytosis Asperger’s, 15 y/o
8 (CS) ? F Systemic mastocytosis Niece with Asperger’s, F
9 (MH) 42 F Mast cell disease Asperger’s F 10 y/o, ADD M 8 y/o
10 (SS) ? F UP Rett syndrome, F
11 (LLMcC) 56 F Mast cell disease Asperger’s, F, 5 y/o
12 (RDK) 49 M Indolent mastocytosis Asperger’s, M, 14 y/o
*Data obtained in response to the question listed below that was sent by the Mastocytosis Society
(www.tmsforacure.org) to a database of 400 patients. + Same family (uncle); #Same family;
“Could you please let us know if you or any of your children have been diagnosed with Autism or an Autistic
Spectrum Disorder (e.g. Asperger’s disorder). Please include yours and your child’s sex, current age, age at time
of diagnosis, and how/where diagnosis was made.”
ADD=Attention Deficit Disorder; PDD-NOS=Pervasive developmental disorder-not otherwise specified;
NF1=Neurofibromatosis-1; SID=Sensory Integration Dysfunction; SM=systemic mastocytosis; UP=Urticaria
Pigmentosa
Serum levels of a mast cell trigger and a
mast cell mediator are increased in
young children with autism
• Serum Neurotensin is significantly elevated in
autistic children (n=28, <4 years old) as
compared to healthy, normally maturing controls
(n=8, <4 years old)
• Serum IL-6 is significantly elevated in autistic

children (n=29, <4 years old) as compared to
healthy, normally maturing controls (n=7, <5
years old)
Serum levels of neurotensin
p=0.0356
2500
2500
2000
Serum NT (pg/ml)
2000
1500
1500
1000
1000
500
500
00
Control Autism
n=8 n=28

Serum levels of IL-6
p=0.0128
1200
1000
Serum IL-6 (pg/ml)
800
600
400
200
0
Control Autism
n=7 n=29

Effect
Effectof
ofmercury
mercury on
on intracellular
histamine calcium
release ion
from
Effect of mercury on intracellular calcium ion
level
LAD2in human
LAD 2 mast
mast cells
cells
level in LAD 2 mast cells
*
Histamine release (%)

100
*
90
80
70
60
50
40
30
20
10
0
Spontaneous
SP (0.1 µM)
SP (2 µM)
HgCl2(0.1 µM)
HgCl2 (1 µM)
HgCl2(10 µM)
µ + HgCl2(0.1 µM)
µ + HgCl2(0.1 µM)
SP (0.1M)
May 1, 2009 Copyright-Dr. T.C. Theoharides SP (2 M) 47

Effect of mercury on intracellular calcium ion
level in LAD2 mast cells
2.5
2
Intracellular calcium
(arbitrary unit)
1.5 Control
1 HgCl2
0.5
0
1 3 5 7 9 11 13 15 17 19 21
Time (min)

Effect of mercury on VEGF release from LAD2
human mast cells
1400
cells)
*
1200 *
6
1000 *
VEGF release (pg/10
800
600
400
200
0
HgCl 2 (1 µ M)
HgCl 2 ( 1 0 µ M)
HgCl 2 (0.1 µ M)
HgCl 2 ( 1 0 0 µ M)
Control

May 1, 2009
6
VEGF release (pg/10
cells)
0
250
500
750
1000
Spontaneous
*
*
SP (0.1µM)
SP (2µM)
HgCl
2 (0.1µM)
HgCl
2 (1 µM)
HgCl
2 (10µM)
µM)
HgCl2 (0.1µ M) + SP (0.1
Copyright-Dr. T.C. Theoharides

human mast cells
µM)
HgCl2 (0.1µ M) + SP (2
.1 µM)
HgCl2 (1µ M) + SP (0
µM)
HgCl2 (1µ M) + SP (2
µM)
HgCl2 (10 µ M) + SP (2
Effect of mercury and SP on VEGF release from LAD2
50
Effect of thimerosal on VEGF release from
Umbilical cord human mast cells
1200
hCBMCs - VEGF release

*
1000
(pg/106 cells)
800
600
400
200
0
Control
Thimerosal (1µ M)
Thimerosal (10µ M)
Thimerosal (100µ M)
May 1, 2009
Cell viability (%)
20
40
60
80
100
0
Control
HgCl
2 (0.1µM)
HgCl
2 (1µM)
HgCl
2 (10µM)
HgCl M)
2 (100 µ
Copyright-Dr. T.C. Theoharides

Thimerosal (0.1
µM)
M)
Thimerosalµ(1
human mast cell viability
Thimerosal (10
µM)
*
Thimerosal (100
µM)
Effect of mercury and thimerosal on LAD2
52
Brain Inflammation
Autism and Oxidative Stress
• One study of 305 autistic children and 205 controls

showed that the ratio of S-adenosylhomocysteine,
used as an indicator of methylation ability, was
significantly reduced in autistic children
• Reduced plasma levels of S-adenosylmethionine

(SAMe), the main endogenous antioxidant. Both of
these studies and a recent review imply that autistic
patients may have excessive free radical production
• Reactive oxygen species are generated during mast

cell activation and further stimulate mast cells

Beneficial Effect of Flavonoids in Brain
Inflammation
Middleton E Jr, Kandaswami C, Theoharides TC.
Pharmacol Rev. 2000 52(4):673-751. Review.
• Flavonoids are potent anti-oxidant and anti-

inflammatory compounds.
• Select flavonoids inhibit mast cell activation.
• Flavonoids inhibit glia IL-6 release.
• The most potent flavonoids are luteolin and

quercetin, but need to be given in a liposomal
formulation to increase absorption.

Flavonols inhibit proinflammatory mediator release,
intracellular calcium ion levels and protein kinase C
theta phosphorylation in human mast cells
Kempuraj D, Madhappan B, Christodoulou S, Boucher W, Cao J, Papadopoulou N, Cetrulo CL, Theoharides TC.
Br J Pharmacol. 2005 Aug;145(7):934-44.
•Allergic stimulation of human mast cells results in

secretion of histamine, the proteolytic enzyme
tryptase, and the pro-inflammatory cytokines IL-6, IL-8
and TNF-α
•Quercetin inhibits histamine release by 52-77%,
tryptase release by 79-96%, and cytokines release by
82-93%

Inhibition of inflammatory molecules by quercetin
from human mast cells
100 * *
*
90 *
80
Pe rce nt inhibition
70
*
60
50
40
30
20
10
0
Histamine Tryptase IL-6 IL-8 TNF-alpha

Regulation of IL-1-induced selective IL-6 release
from human mast cells and inhibition by quercetin
Kandere-Grzybowska K, Kempuraj D, Cao J, Cetrulo CL, Theoharides TC.
Br J Pharmacol. 2006 May;148(2):208-15.
•IL-1-stimulates IL-6 production from human mast cells
•Quercetin inhibits IL-6 secretion induced by IL-1 in a

dose-dependent manner

Inhibitory effect of quercetin on tryptase and MCP-1
chemokine release, and histidine decarboxylase mRNA
transcription by human mast cell-1 cell line
Castellani ML, Kempuraj D, Frydas S, Theoharides TC, Simeonidou
I, Conti P, Vecchiet J.
Neuroimmunomodulation. 2006;13(3):179-86. Epub 2006 Dec 21.
• Quercetin, is a potent antioxidant, cytoprotective

and anti-inflammatory compound capable of
inhibiting histamine and cytokines release from mast
cells. In this study quercetin inhibits, in a dose-
response manner, tryptase and MCP-1
• Quercetin inhibited the transcription of histidine

decarboxylase using RT-PCR

Luteolin inhibits myelin basic protein-induced
human mast cell activation and mast cell-
dependent stimulation of Jurkat T cells
Kempuraj D, Tagen M, Iliopoulou BP, Clemons A, Vasiadi M,
Boucher W, House M, Wolfberg A, Theoharides TC.
Br J Pharmacol. 2008 Sep 22. [Epub ahead of print]
• Addition of mast cells to Jurkat T cells activated by

anti-CD3/anti-CD28 increases IL-2 release by 30-fold
(n=3, P<0.05). SP-stimulated mast cells and their
supernatant fluid further increase Jurkat cell IL-2
release (n=3, P<0.05)
• Luteolin pretreatment inhibits mast cell activation

(n=3-6, P<0.05), Jurkat cell activation and mast cell-
dependent Jurkat cell stimulation (n=3, P<0.05)
Quercetin protects against acute immobilization
stress-induced behaviors and biochemical
alterations in mice
Kumar A, Goyal R.
J Med Food. 2008 Sep;11(3):469-73.
• Acute immobilization stress for 6 hours causes severe

anxiety, analgesia, and impaired motor activity in
mice, accompanied by partial depletion of brain levels
of reduced glutathione and catalase activity
• Pretreatment with quercetin reversed immobilized

stress-induced anxiety and analgesia and reduced
locomotor activity; it also restored the depleted brain
glutathione and catalase activity

Conclusions
• It is important to investigate food intolerance and
introduce appropriate diets
• The flavonoids quercetin and luteolin inhibit IL-6 and

TNF-α release from mast cells
• Luteolin inhibits IL-6 release from microglia, as well as

IL-1 mediated release of IL-6, IL-8 and MCP-1 from
astrocytes
• The dietary supplement NeuroProtek contains

quercetin and luteolin, along with other antioxidants

NeuroProtek Label

Mast Cells Disrupt The Gut-Blood-Brain Barriers and Contribute To Autism

Загружено:

Сведения о документе

Исходное описание:

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Mast Cells Disrupt The Gut-Blood-Brain Barriers and Contribute To Autism

Загружено:

Авторское право:

Доступные форматы

Autism, Blood-brain-barrier and

Pervasive Developmental Disorders

Rett's Childhood Autistic Asperger's PDD-NOS

May 1, 2009 Copyright-Dr. T.C. Theoharides 3

Autism Spectrum Disorders

• Individuals with autism spectrum disorders are heterogeneous in

• Medical and psychiatric co-occurrences included sleep disorders,

• Brain of autistic patients have higher expression of IL-6

• Autistic patient CSF has high levels of macrophage chemoattractant protein-

• Autistic patient plasma has reduced transforming growth factor-beta1 (TGF-

May 1, 2009 Copyright-Dr. T.C. Theoharides 6

Mast cell degranulation leads to the release of mediators with

Immunol Rev. 2007 Jun;217:65-78.

• Mast cells can be activated by bacterial or viral antigens,

May 1, 2009 Copyright-Dr. T.C. Theoharides 8

May 1, 2009 Copyright-Dr. T.C. Theoharides 9

May 1, 2009 Copyright-Dr. T.C. Theoharides 10

CNS originating mast cell activation triggers:

Mast cell Blood

Mast cell-derived cytokines Mast cell-derived vasoactive

May 1, 2009 Copyright-Dr. T.C. Theoharides 11

Rozniecki, Dimitriadou, Lambracht-Hall et al. (1999) Brain Res 849: 1.

May 1, 2009 Copyright-Dr. T.C. Theoharides 13

• A prospective follow-up assessment on 91 ex-preterm infants

• Another study found that 21% of infants (212/988) born before 28

• A statistically significant association was reported between

May 1, 2009 Copyright-Dr. T.C. Theoharides 17

Neonatal Delivery Infections

Environmental Brain Oxidative

May 1, 2009 Copyright-Dr. T.C. Theoharides 19

May 1, 2009 Copyright-Dr. T.C. Theoharides 21

99-Technetium-gluceptate HPA axis

May 1, 2009 Copyright-Dr. T.C. Theoharides 26

Front Biosci. 2007 Jan 1;12:1615-28.

• Increased BBB permeability precedes any clinical or pathologic

May 1, 2009 Copyright-Dr. T.C. Theoharides 27

• CRH could increase permeability in normal human colonic biopsies through

• Neonatal maternal deprivation stress induced long-term alterations of

May 1, 2009 Copyright-Dr. T.C. Theoharides 28

• IL-6 is a pleiotropic cytokine that was originally named

• IL-6 mediates immune responses and inflammation

• IL-6 also is a crucial cytokine for mast cell maturation

• IL-6 also up-regulates histamine production and induces the

May 1, 2009 Copyright-Dr. T.C. Theoharides 31

Cardiovasc Res. 2003 Jul 1;59(1):241-9 .

• Stress-induced IL-6 release is absent in W/Wv mast

• Both normal and W/Wv mast cell-deficient mice

May 1, 2009 Copyright-Dr. T.C. Theoharides 32

• IL-6 is de novo synthesized, as its secretion is blocked by

• Ultrastructural Immunogold localization shows that IL-6 is

May 1, 2009 Copyright-Dr. T.C. Theoharides 34

May 1, 2009 n=6, *p<0.05 paired t-

• Mastocytosis is characterized by an increased number of mast

• Patients may present with flushing, itching, food intolerance, but

• Serum IL-6 is elevated in mastocytosis patients and correlates

May 1, 2009 Copyright-Dr. T.C. Theoharides 37

May 1, 2009 Copyright-Dr. T.C. Theoharides 38

• Children with mastocytosis often have ADD, learning

• Data were obtained in response to the question

• “Could you please let us know if you or any of your

May 1, 2009 Copyright-Dr. T.C. Theoharides 39

1 (BN) 4 M Stuttering, high functioning Mastocytoma, solitary