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Review Article
Is a Subtype of Autism an Allergy of the Brain?
Theoharis C. Theoharides, MS, MPhil, PhD, MD
Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and
Pharmacology, Tufts University School of Medicine, Boston, Massachusetts; Departments of Biochemistry,
Tufts University School of Medicine, Boston, Massachusetts; Department of Internal Medicine, Tufts
University School of Medicine and Tufts Medical Center, Boston, Massachusetts; and Department of
Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts
ABSTRACT
Background: Autism spectrum disorders (ASDs) are
characterized by deficits in social communication and
language and the presence of repetitive behaviors that
affect as many as 1 in 50 US children. Perinatal stress
and environmental factors appear to play a significant
role in increasing the risk for ASDs. There is no defin-
itive pathogenesis, which therefore significantly hin-
ders the development of a cure.
Objective: We aimed to identify publications using
basic or clinical data that suggest a possible associ-
ation between atopic symptoms and ASDs, as well as
evidence of how such an association could lead to
brain disease, that may explain the pathogenesis of
ASD.
Methods: PubMed was searched for articles published
since 1995 that reported any association between autism
and/or ASDs and any one of the following terms: allergy,
atopy, brain, corticotropin-releasing hormone, cytokines,
eczema, food allergy, food intolerance, gene mutation, in-
flammation, mast cells, mitochondria, neurotensin, pheno-
type, stress, subtype,ortreatment.
Results: Children with ASD respond disproportion-
ally to stress and also present with food and skin allergies
that involve mast cells. Brain mast cells are found primar-
ily in the hypothalamus, which participates in the regula-
tion of behavior and language. Corticotropin-releasing
hormone is secreted from the hypothalamus under
stress and, together with neurotensin, stimulates brain
mast cells that could result in focal brain allergy and
neurotoxicity. Neurotensin is significantly increased in
serum of children with ASD and stimulates mast cell
secretion of mitochondrial adenosine triphosphate and
DNA, which is increased in these children; these mito-
chondrial components are misconstrued as innate
pathogens, triggering an autoallergic response in the
brain. Gene mutations associated with higher risk of
ASD have been linked to reduction of the phosphatase
and tensin homolog, which inhibits the mammalian
target of rapamycin (mTOR). These same mutations
also lead to mast cell activation and proliferation. Cor-
ticotropin-releasing hormone, neurotensin, and envi-
ronmental toxins could further trigger the already ac-
tivated mTOR, leading to superstimulation of brain
mast cells in those areas responsible for ASD symp-
toms. Preliminary evidence indicates that the flavonoid
luteolin is a stronger inhibitor of mTOR than rapamy-
cin and is a potent mast cell blocker.
Conclusion: Activation of brain mast cells by aller-
gic, environmental, immune, neurohormonal, stress,
and toxic triggers, especially in those areas associated
with behavior and language, lead to focal brain allergies
and subsequent focal encephalitis. This possibility is more
likely in the subgroup of patients with ASD susceptibility
genes that also involve mast cell activation. (Clin Ther.
2013;35:584–591) © 2013 Elsevier HS Journals, Inc. All
rights reserved.
Key words: allergy, autism, brain, inflammation,
mast cells, mitochondria.
INTRODUCTION
Autism spectrum disorders (ASDs) are neurodevelop-
mental disorders that affect almost 1 in 50 children
1–3
and, according to the fifth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-5) due to
Accepted for publication April 19, 2013.
http://dx.doi.org/10.1016/j.clinthera.2013.04.009
0149-2918/$ - see front matter
© 2013 Elsevier HS Journals, Inc. All rights reserved.
Clinical Therapeutics/Volume 35, Number 5, 2013 · Atopic Clinical Entities Update
584 Volume 35 Number 5
be published in May 2013, are characterized by 2 com-
ponents: deficits in social communication and social in-
teraction and restricted, repetitive behaviors and interests
Allergies and asthma have also reached epidemic propor-
tions in the last 10 years.
4
There is new evidence that the
environment contributes significantly to ASD pathogen-
esis.
5–7
Many patient with ASD also have food allergies
8
and allergic-like symptoms
9
but often without positive
objective test results, suggesting mast cell activation by
nonallergic triggers.
10,11
A recent epidemiologic study of
92,642 children reported a strong correlation between
atopic dermatitis (eczema), attention-deficit/hyperactiv-
ity disorder, and autism.
12
Moreover, children with mas-
tocytosis, a spectrum of diseases that present with skin
allergies, hyperactivity, and difficulty focusing (brain
fog),
13,14
appear to have a 5-fold higher prevalence of
ASD (1 in 10 children) than that reported for the gen-
eral population.
15
We propose that brain mast cells in critical brain
areas, such as those regulating the autonomic nervous
system and emotions (eg. diencephalon) and language
(Broca area) are activated by environmental, infec-
tious, or stress triggers, resulting in local brain allergies
and focal encephalitis (Figure).
16
METHODS
PubMed was searched for articles published since 1995
that reported any association between autism and/or
ASD and anyone of the following terms: allergy, atopy,
brain, corticotropin-releasing hormone, cytokines, ec-
zema, food allergy, food intolerance, gene mutation,
inflammation, mast cells, mitochondria, neurotensin,
The genesis of brain allergies and autism
Mast Cell Activation
Diencephalon
(coordinates sensory input
and emotions) Dysfunctional social behavior,
communication and stereotypic
movements
Figure. Brain allergies. Brain mast cells are located close to blood vessels and nerve endings, especially in the
hypothalamus of the diencephalon, which participates in the regulation of emotions. On stimulation
by allergic, environmental (mercury), infectious (viruses), mitochondrial (adenosine triphosphate
and/or DNA), stress (corticotropin-releasing hormone or neurotensin), and toxic (propionic acid)
triggers, mast cells release inflammatory and neurotoxic molecules (eg, interleukin 6, tumor necrosis
factor, and tryptase), triggering focal brain allergies, while they also increase blood brain barrier
permeability, permitting entry of circulating lymphocytes in the brain, and activate microglia cells,
leading to focal encephalitis. The microphotograph of the mast cell shown was taken from the rat
hypothalamus after staining with toluidine blue (original magnification ⫻1000; arrow indicates area
of degranulation). The photograph of the young, autistic female patient is shown with the parents’
permission before improvement with the use of the flavonoid-containing dietary formulation men-
tioned in the discussion.
T.C. Theoharides
May 2013 585
phenotype, stress, subtype, treatment, or therapy. Ar-
ticles were chosen for relevance, human data, and use
of the English language. Any contradictory results are
discussed. Articles were excluded if they were pub-
lished as hypotheses or if they were repetitive.
RESULTS
ASD and Brain Inflammation
Substances that originate in the gut or the brain can
trigger mast cells to release mediators that could dis-
rupt the blood brain barrier (BBB) and cause allergies
in specific brain areas, thus contributing to the patho-
genesis of autism.
17
Such mediators include interleukin
(IL) 6,
18
which can be released from mast cells selec-
tively.
19
IL-6 expression was elevated in the brains of
patients with ASD,
20
and increased serum IL-6 level
was linked to the expression of an autistic phenotype in
mice.
21,22
Interestingly, patients with mastocytosis,
characterized by increased number of activated mast
cells, also have high serum IL-6 levels.
23,24
Offspring of
maternal immune activation in mice developed in-
creased IL-6 and IL-17, which contributed to ASD-
related behaviors.
25
Tumor necrosis factor (TNF) lev-
els were also increased in the cerebrospinal fluid (CSF)
of patients with ASD.
20
Brain mast cells were reported
to produce TNF.
26
Interestingly, mast cells are the only
cell type that stores preformed TNF in secretory gran-
ules.
27
A recent diagnosis of mast cell activation syn-
drome in fact includes the statement “accompanied by
neurologic complaints,”
28
implying that brain mast
cells could be involved.
Patients with ASD exhibit neuroimmune dysfunc-
tion.
29
We reported that neurotensin (NT) was in-
creased in young children with autism
30
and was
proposed as a possible therapeutic target for autism
also due to its ability to induce neurotoxicity.
31
We
also reported that NT and corticotropin-releasing
hormone (CRH), secreted under stress, synergisti-
cally stimulate mast cells, leading to increase vascu-
lar permeability
32
and contributing to BBB disrup-
tion.
33
We further found that NT stimulates mast
cell secretion of vascular endothelial growth fac-
tor.
34
In addition, NT increases expression of CRH
receptor 1 (CRHR-1),
35
activation of which by CRH
increases allergic stimulation of human mast cells.
36
Furthermore, NT is increased in the skin after acute
stress, stimulates skin mast cells, and increases vas-
cular permeability in rodents.
37
Finally, NT stimu-
lates rodent peritoneal mast cells to secrete hista-
mine and elevates histamine plasma levels through
activation of specific NTR.
38–40
Brain Mast Cells
Mast cells are considered the “immune gate to the
brain.”
41
The richest source of mast cells in the brain is
the hypothalamus,
42
part of the diencephalon that re-
lays sensory information among brain regions, con-
nects structures of the endocrine and nervous systems,
and communicates with the limbic system to regulate
emotions. Moreover, the highest concentration of NT
receptors is in the hypothalamus,
43
and Broca area,
44
which regulates language, known to be lost in many
children with ASD. Stress activates brain mast cells,
leading to BBB disruption,
45
which is important in
brain inflammation.
46
Patients with ASD are suscepti-
ble to stress,
47
and prenatal stress has been linked to an
increased risk of autism.
48–50
Moreover, CRH, se-
creted under stress, can activate mast cells
33
and is
responsible for mast cell–dependent BBB
42
disrup-
tion.
33,45
This process could worsen by activation of
Fc
␥
receptors (Fc
␥
RI) on neurons that could contribute
to brain cell death after injection of the kainic acid.
51
Moreover, Fcreceptors (FcRI), typically thought to
be expressed only by mast cells and basophils, were
recently identified on neurons,
52
implying that allergic
triggers may even affect the neurons directly once the
BBB has been disrupted to permit entry of immuno-
globulins. We had found that rat brain mast cells did
not synthesized FcRI until induction of experimental
allergic encephalomyelitis.
53
Mast cell–microglial interactions are important in
neuroinflammatory diseases.
54,55
Microglia are the in-
nate brain immune cells that are increasingly impli-
cated in a number of neuropsychiatric diseases.
56
In
fact, abnormal microglial growth and activation were
recently reported in the brain of patients with
ASD.
57,58
It is therefore of interest that mast cell tryp-
tase induced microglia activation.
59
Mast cells are re-
sponsible for eliciting neutrophil infiltration that pro-
motes inflammation.
60
Increasing evidence indicates
that mast cells participate in innate and acquired im-
munity
61
and inflammation.
62
Extracellular Mitochondrial Components
Brain gene clusters associated with increased in-
flammation and mitochondrial dysfunction appear
to be the main findings in neuropsychiatric disor-
ders.
63
We recently found that mast cell activation
Clinical Therapeutics
586 Volume 35 Number 5
leads to mitochondrial translocation to the cell sur-
face.
64
and secretion of extracellular mitochondrial
adenosine triphosphate (ATP) and DNA.
35
We also
found that serum of children with autism had in-
creased levels of extracellular mitochondrial
DNA,
65
and such extracellular mitochondrial com-
ponents could augment allergies and eczema.
36
Ex-
tracellular mitochondrial ATP and DNA are miscon-
strued by the body as innate pathogens and induce a
strong autoinflammatory response
35
because mito-
chondria were bacteria that became symbiotic with
eukaryotic cells.
66
Neurotensin triggers mast cells to
secrete mitochondrial DNA that acts as innate
pathogen to stimulate mast cells and other immune
cells, leading to autoinflammation and contributing
to autism pathogenesis.
67
Mast cells also express Toll-like receptors (TLRs),
including TLR-9, which can be activated by bacterial
DNA sequences, leading to release of different cyto-
kines,
68
and allow mast cells to participate in immu-
nity against bacteria.
69
Extracellular ATP has been
found to trigger and maintain inflammation in asth-
matic airways.
70
Moreover, extracellular ATP was
recently considered a universal alarm signal released
from cells under stress and capable of affecting
neighboring cells.
71
Mitochondrial DNA was also
reported to be directly neurotoxic and alter behavior
in mice.
72
Extracellular nucleic acids are now considered as
sensors of cell damage and are involved in autoimmu-
nity.
73
However, our findings are different from those
of damaged associated molecular patterns, which in-
clude mitochondrial DNA and are released after major
trauma in humans
74
or shock-injured rat tissues
75
and
can activate TLR-9 receptors on human peripheral
polymorphonuclear cells, leading to inflammation.
74
In both these cases, the damaged associated molecu-
lar patterns came from dying cells. A recent study
reported that treatment with the antitrypanosomia-
sis, nonspecific, antipurinergic drug suramin re-
versed ASD-like behavior in offspring of mice
treated with the polyinosinic-polycytidylic acid dur-
ing pregnancy.
76
They concluded that this drug
blocked ATP released due to the viral infection. This
was not a novel theory
35
as it was claimed, and the
natural flavonoid luteolin had previously been re-
ported to inhibit ASD-like behavior and brain oxi-
dative changes in the same mouse model.
77
Possible Treatment Targets
Activation of susceptibility genes is being increas-
ingly invoked to explain ASD.
78,79
High risk of devel-
oping ASD has been associated with gene mutations,
leading to decreased phosphatase and tensin ho-
molog.
80,81
This protein is an upstream inhibitor of the
mammalian target of rapamycin, which leads to micro-
glial and mast cell proliferation
82,83
, as well as mast
cell chemotaxis
84
and activation.
85
Rapamycin and its analogues are mammalian target
of rapamycin inhibitors
86
and are being tried for treat-
ment of ASD.
87–89
Our preliminary results indicate
that the natural flavonoid luteolin,
90
with potent anti-
oxidant, free radical scavenger and antiinflammatory
effects, is more potent that rapamycin that inhibits hu-
man mast cell TNF release.
16
Obviously, luteolin is not
specific for mast cell inhibitory activity.
91
However,
luteolin inhibits microglia IL-6 release,
92,93
microglial-
induced hippocampal neuron apoptosis,
94
and also de-
creased cognitive decline in rats.
95
Luteolin inhibited
mast cell–dependent stimulation of activated T cells
96
and activated peripheral blood mononuclear cells from
patients with multiple sclerosis.
97
Recently, a luteolin-
containing formulation was found to have consider-
able benefits in children with ASD.
98,99
DISCUSSION
Many recent studies stress the importance of mast cells
in both innate and acquired immunity
100
and inflam-
mation
.62
Brain mast cells can be activated by a num-
ber of neurohormonal, infectious, and environmental
triggers, leading to secretion of numerous molecules
that could cause brain allergy in key brain regions.
Extracellular mitochondrial components could also act
as innate pathogens, turning brain allergy into focal
encephalitis. Detecting increased serum or CSF levels
of mitochondrial DNA and/or ATP could be used for
diagnosis. Preventing brain mast cell activation and
secretion of TNF and extracellular mitochondrial com-
ponents may serve as a novel therapeutic approach.
Unfortunately, no drugs are clinically available that
can block mast cell secretion. The so-called mast cell
stabilizer disodium cromoglycate (cromolyn) is effec-
tive in rats
101
but has been recently reported not to
inhibit human mast cells.
102–104
Luteolin may be a rea-
sonable alternative.
Even though luteolin is not specific, it certainly
inhibits microglia and mast cells, the main immune
cells involved in neuroinflammation, and is more tol-
T.C. Theoharides
May 2013 587
erable that nonsteroidal anti-inflammatory drugs.
105
Our unpublished findings indicate that a structural
analogue of luteolin particularly rich in a specific
natural source is more potent than luteolin with par-
ticular affinity for mast cells.
CONCLUSIONS
Activation of brain mast cells by allergic, environmen-
tal, immune, neurohormonal, stress, and toxic triggers,
especially in those areas associated with behavior and
language, could lead to focal brain allergies and subse-
quent focal encephalitis. This possibility is more likely
in the subgroup of patients with ASD with susceptibil-
ity genes that also involve mast cell activation.
ACKNOWLEDGMENTS
Aspects of our work were funded by National Insti-
tutes of Health grants NS38326 and AR47652, as well
as the Autism Collaborative, the Autism Research In-
stitute, National Autism Association, Safe Minds, and
Theta Biomedical Consulting and Development Co,
Inc (Brookline, Massachusetts). Many thanks are due
to Smaro Panagiotidou for her excellent word process-
ing skills. Dr. Theoharides was the sole author respon-
sible for the literature search, data interpretation, fig-
ure creation, and writing of the manuscript.
CONFLICTS OF INTEREST
Dr. Theoharides is the inventor of US patent No.
8,268,365 for treatment of neuroinflammatory condi-
tions, as well as US patent applications No. 12/
534,571 and No. 13/009,282 for the diagnosis and
treatment of ASD. Dr Theoharides is also the inventor
of the dietary supplement NeuroProtek®, which has
the US trademark No. 3,225,924.
REFERENCES
1. Kogan MD, Blumberg SJ, Schieve LA, et al. Prevalence of
parent-reported diagnosis of autism spectrum disorder
among children in the US, 2007. Pediatrics. 2009;5:1395–
1403.
2. Fombonne E. Epidemiology of pervasive developmental
disorders. Pediatr Res. 2009;65:591–598.
3. Volkmar FR, State M, Klin A. Autism and autism spectrum
disorders: diagnostic issues for the coming decade. J Child
Psychol Psychiatry. 2009;50:108 –115.
4. Douwes J, Brooks C, van DC, et al. Importance of allergy in
asthma: an epidemiologic perspective. Curr Allergy Asthma
Rep. 2011;11:434 –444.
5. Angelidou A, Asadi S, Alysandratos KD, et al. Perinatal
stress, brain inflammation and risk of autism: review and
proposal. BMC Pediatr. 2012;12:89.
6. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritabil-
ity and shared environmental factors among twin pairs
with autism. Arch Gen Psychiatry. 2011;68:1095–1102.
7. Herbert MR. Contributions of the environment and
environmentally vulnerable physiology to autism spec-
trum disorders. Curr Opin Neurol. 2010;23:103–110.
8. Jyonouchi H. Autism spectrum disorders and allergy:
observation from a pediatric allergy/immunology clinic.
Expert Rev Clin Immunol. 2010;6:397– 411.
9. Angelidou A, Alysandratos KD, Asadi S, et al. Brief report:
“allergic symptoms” in children with autism spectrum
disorders: more than meets the eye? J Autism Dev Disord.
2011;41:1579–1585.
10. Theoharides TC, Angelidou A, Alysandratos KD, et al.
Mast cell activation and autism. Biochim Biophys Acta.
2012;1822:34– 41.
11. Kempuraj D, Asadi S, Zhang B, et al. Mercury induces
inflammatory mediator release from human mast cells.
J Neuroinflammation. 2010;7:20.
12. Yaghmaie P, Koudelka CW, Simpson EL. Mental health
comorbidity in patients with atopic dermatitis. J Allergy
Clin Immunol. 2013;131:428 –433.
13. Valent P, Akin C, Escribano L, et al. Standards and
standardization in mastocytosis: consensus statements
on diagnostics, treatment recommendations and re-
sponse criteria. Eur J Clin Invest. 2007;37:435– 453.
14. Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;
112:946–956.
15. Theoharides TC. Autism spectrum disorders and mastocy-
tosis. Int J Immunopathol Pharmacol. 2009;22:859 –865.
16. Theoharides TC, Asadi S, Pate AB. Focal brain inflamma-
tion and autism. J Neuroinflammation. 2013;10:1– 46.
17. Theoharides TC, Doyle R, Francis K, et al. Novel therapeutic
targets for autism. Trends Pharmacol Sci. 2008;29:375–382.
18. Kandere-Grzybowska K, Letourneau R, Kempuraj D, et al. IL-1
induces vesicular secretion of IL-6 without degranulation from
human mast cells. J Immunol. 2003;171:4830 – 4836.
19. Theoharides TC, Kempuraj D, Tagen M, et al. Differential
release of mast cell mediators and the pathogenesis of
inflammation. Immunol Rev. 2007;217:65–78.
20. Li X, Chauhan A, Sheikh AM, et al. Elevated immune
response in the brain of autistic patients. J Neuroimmunol.
2009;207:111–116.
21. Dahlgren J, Samuelsson AM, Jansson T, et al. Interleukin-6
in the maternal circulation reaches the rat fetus in
mid-gestation. Pediatr Res. 2006;60:147–151.
22. Smith SE, Li J, Garbett K, et al. Maternal immune
activation alters fetal brain development through interleu-
kin-6. J Neurosci. 2007;27:10695–10702.
Clinical Therapeutics
588 Volume 35 Number 5
23. Brockow K, Akin C, Huber M, et al.
IL-6 levels predict disease variant and
extent of organ involvement in pa-
tients with mastocytosis. Clin Immu-
nol. 2005;115:216 –223.
24. Theoharides TC, Boucher W, Spear
K. Serum interleukin-6 reflects dis-
ease severity and osteoporosis in
mastocytosis patients. Int Arch Al-
lergy Immunol. 2002;128:344–350.
25. Hsiao EY, McBride SW, Chow J, et
al. Modeling an autism risk factor
in mice leads to permanent im-
mune dysregulation. Proc Natl Acad
SciUSA. 2012;109:12776 –12781.
26. Cocchiara R, Bongiovanni A, Albeg-
giani G, et al. Evidence that brain
mast cells can modulate neuroin-
flammatory responses by tumor
necrosis factor-
␣
production. Neu-
roreport. 1998;9:95–98.
27. Olszewski MB, Groot AJ, Dastych J,
et al. TNF trafficking to human
mast cell granules: mature chain-
dependent endocytosis. J Immunol.
2007;178:5701–5709.
28. Akin C, Valent P, Metcalfe DD.
Mast cell activation syndrome: pro-
posed diagnostic criteria. J Allergy
Clin Immunol. 2010;126:1099–
1104.
29. Theoharides TC, Kempuraj D, Red-
wood L. Autism: an emerging ‘neu-
roimmune disorder’ in search of
therapy. Expert Opin Pharmacother.
2009;10:2127–2143.
30. Angelidou A, Francis K, Vasiadi M, et
al. Neurotensin is increased in serum
of young children with autistic disor-
der. J Neuroinflam. 2010;7:48.
31. Ghanizadeh A. Targeting neuroten-
sin as a potential novel approach
for the treatment of autism. J Neuro-
inflammation. 2010;7:58.
32. Donelan J, Boucher W, Papado-
poulou N, et al. Corticotropin-
releasing hormone induces skin vas-
cular permeability through a
neurotensin-dependent process.
Proc Natl Acad SciUSA. 2006;103:
7759–7764.
33. Theoharides TC, Konstantinidou
A. Corticotropin-releasing hor-
mone and the blood-brain-barrier.
Front Biosci. 2007;12:1615–1628.
34. Vasiadi M, Therianou A, Alysandra-
tos KD, et al. Serum neurotensin
(NT) is increased in psoriasis and
NT induces VEGF release from hu-
man mast cells. Br J Dermatol. 2012;
166:1349–1352.
35. Zhang B, Asadi S, Weng Z, et al.
Stimulated human mast cells se-
crete mitochondrial components
that have autocrine and paracrine
inflammatory actions. PLoS One.
2012;7:e49767.
36. Asadi S, Theoharides TC. Cortico-
tropin-releasing hormone and ex-
tracellular mitochondria augment
IgE-stimulated human mast-cell
vascular endothelial growth factor
release, which is inhibited by luteo-
lin. J Neuroinflam. 2012;9:85.
37. Singh LK, Pang X, Alexacos N, et al.
Acute immobilization stress trig-
gers skin mast cell degranulation
via corticotropin-releasing hor-
mone, neurotensin and substance
P: a link to neurogenic skin disor-
ders. Brain Behav Immun. 1999;13:
225–239.
38. Carraway R, Cochrane DE, Lans-
man JB, et al. Neurotensin stimu-
lates exocytotic histamine secre-
tion from rat mast cells and elevates
plasma histamine levels. J Physiol.
1982;323:403–414.
39. Feldberg RS, Cochrane DE, Car-
raway RE, et al. Evidence for a
neurotensin receptor in rat serosal
mast cells. Inflamm Res. 1998;47:
245–250.
40. Barrocas AM, Cochrane DE, Car-
raway RE, et al. Neurotensin stimu-
lation of mast cell secretion is
receptor-mediated, pertussis-toxin
sensitive and requires activation of
phospholipase C. Immunopharmacol-
ogy. 1999;41:131–137.
41. Theoharides TC. Mast cells: the
immune gate to the brain. Life Sci.
1990;46:607–617.
42. Pang X, Letourneau R, Rozniecki JJ,
et al. Definitive characterization of
rat hypothalamic mast cells.
Neuroscience. 1996;73:889 –902.
43. Goedert M, Lightman SL, Mantyh
PW, et al. Neurotensin-like immu-
noreactivity and neurotensin recep-
tors in the rat hypothalamus and in
the neurointermediate lobe of the
pituitary gland. Brain Res. 1985;
358:59– 69.
44. Fassio A, Evans G, Grisshammer R,
et al. Distribution of the neurotensin
receptor NTS1 in the rat CNS studied
using an amino-terminal directed an-
tibody. Neuropharmacology. 2000;
39:1430–1442.
45. Esposito P, Chandler N, Kandere-
Grzybowska K, et al. Corticotropin-
releasing hormone (CRH) and
brain mast cells regulate blood-
brain-barrier permeability induced
by acute stress. J Pharmacol Exp Ther.
2002;303:1061–1066.
46. Banks WA, Erickson MA. The
blood-brain barrier and immune
function and dysfunction. Neuro-
biol Dis. 2010;37:26 –32.
47. Gillott A, Standen PJ. Levels of
anxiety and sources of stress in
adults with autism. J Intellect Disabil.
2007;11:359–370.
48. Kinney DK, Munir KM, Crowley DJ,
et al. Prenatal stress and risk for
autism. Neurosci Biobehav Rev. 2008;
32:1519–1532.
49. Ronald A, Pennell CE, Whitehouse
AJ. Prenatal maternal stress associ-
ated with ADHD and autistic traits
in early childhood. Front Psychol.
2010;1:223.
50. Hao GJ, Xue SA, Ki JCY, de Schep-
per L. A preliminary investigation of
prenatal stress and risk factors of
autism spectrum disorder. J Autism
Insights. 2012;4:15–30.
51. Suemitsu S, Watanabe M, Yoko-
bayashi E, et al. Fcgamma recep-
tors contribute to pyramidal cell
death in the mouse hippocampus
following local kainic acid injec-
tion. Neuroscience. 2010;166:819–
831.
52. van der KH, Charles N, Karimi K et
al. Evidence for neuronal expres-
T.C. Theoharides
May 2013 589
sion of functional Fc (epsilon and
gamma) receptors. J Allergy Clin
Immunol. 2010;125:757–760.
53. Dimitriadou V, Pang X, Theoharides
TC. Hydroxyzine inhibits experi-
mental allergic encephalomyelitis
(EAE) and associated brain mast
cell activation. Int J Immunopharma-
col. 2000;22:673– 684.
54. Skaper SD, Giusti P, Facci L. Micro-
glia and mast cells: two tracks on
the road to neuroinflammation.
FASEB J. 2012;26:3103–3117.
55. Skaper SD, Facci L. Mast cell-glia
axis in neuroinflammation and
therapeutic potential of the anand-
amide congener palmitoylethanol-
amide. Philos Trans R Soc Lond B Biol
Sci. 2012;367:3312–3325.
56. Nagai A, Nakagawa E, Hatori K, et
al. Generation and characteriza-
tion of immortalized human micro-
glial cell lines: expression of cyto-
kines and chemokines. Neurobiol
Dis. 2001;8:1057–1068.
57. Morgan JT, Chana G, Abramson I,
et al. Abnormal microglial-neuro-
nal spatial organization in the dor-
solateral prefrontal cortex in au-
tism. Brain Res. 2012;1456:72–81.
58. Rodriguez JI, Kern JK. Evidence of
microglial activation in autism and
its possible role in brain undercon-
nectivity. Neuron Glia Biol. 2011;7:
205–213.
59. Zhang S, Zeng X, Yang H, et al.
Mast cell tryptase induces micro-
glia activation via protease-acti-
vated receptor 2 signaling. Cell
Physiol Biochem. 2012;29:931–940.
60. Walker ME, Hatfield JK, Brown
MA. New insights into the role of
mast cells in autoimmunity: evi-
dence for a common mechanism of
action? Biochim Biophys Acta. 2012;
1822:57–65.
61. Gordon JR, Galli SJ. Mast cells as a
source of both preformed and im-
munologically inducible TNF-
␣
/
cachectin. Nature. 1990;346:274–
276.
62. Theoharides TC, Alysandratos KD,
Angelidou A, et al. Mast cells and
inflammation. Biochim Biophys Acta.
2010;1822:21–33.
63. Theoharides TC, Zhang B, Conti P.
Decreased mitochondrial function
and increased brain inflammation
in bipolar disorder and other neuro-
psychiatric diseases. J Clin Psychop-
harmacol. 2011;31:685– 687.
64. Zhang B, Alysandratos KD, Angeli-
dou A, et al. Human mast cell
degranulation and preformed TNF
secretion require mitochondrial
translocation to exocytosis sites:
relevance to atopic dermatitis. J
Allergy Clin Immunol. 2011;127:
1522–1531.
65. Zhang B, Angelidou A, Alysandra-
tos KD, et al. Mitochondrial DNA
and anti-mitochondrial antibodies
in serum of autistic children. J Neu-
roinflammation. 2010;7:80.
66. Margulis L. Symbiotic theory of the
origin of eukaryotic organelles; cri-
teria for proof. Symp Soc Exp Biol.
1975;29:21–38.
67. Theoharides A. Extracellular mito-
chondrial components secreted
from activated live mast cells act as
innate pathogens and contribute
to autism pathogenesis. Int Trends
Immun. 2013;1:5–10.
68. Bischoff SC, Kramer S. Human
mast cells, bacteria, and intestinal
immunity. Immunol Rev. 2007;217:
329–337.
69. Abraham SN, St John AL. Mast
cell-orchestrated immunity to
pathogens. Nat Rev Immunol. 2010;
10:440– 452.
70. Kouzaki H, Iijima K, Kobayashi T,
et al. The danger signal, extracellu-
lar ATP, is a sensor for an airborne
allergen and triggers IL-33 release
and innate Th2-type responses. J Im-
munol. 2011;186:4375– 4387.
71. Corriden R, Insel PA. Basal release
of ATP: an autocrine-paracrine
mechanism for cell regulation. Sci
Signal. 2010;3:re1.
72. Lauritzen KH, Moldestad O, Eide
L, et al. Mitochondrial DNA toxic-
ity in forebrain neurons causes
apoptosis, neurodegeneration, and
impaired behavior. Mol Cell Biol.
2010;30:1357–1367.
73. Stander S, Siepmann D, Herrgott I,
et al. Targeting the neurokinin re-
ceptor 1 with aprepitant: a novel
antipruritic strategy. PloS One.
2010;5:e10968.
74. Zhang Q, Raoof M, Chen Y, et al.
Circulating mitochondrial DAMPs
cause inflammatory responses to
injury. Nature. 2010;464:104 –107.
75. Zhang Q, Itagaki K, Hauser CJ.
Mitochondrial DNA is released by
shock and activates neutrophils via
p38 map kinase. Shock. 2010;34:
55–59.
76. Naviaux RK, Zolkipli Z, Wang L, et
al. Antipurinergic therapy corrects
the autism-like features in the
poly(IC) mouse model. PloS One.
2013;8:e57380.
77. Parker-Athill E, Luo D, Bailey A, et
al. Flavonoids, a prenatal prophy-
laxis via targeting JAK2/STAT3 sig-
naling to oppose IL-6/MIA associ-
ated autism. J Neuroimmunol.
2009;217:20–27.
78. Williams SC. Genetics: searching for
answers. Nature. 2012;491:S4 –S6.
79. Weiss LA, Arking DE, Daly MJ, et al.
A genome-wide linkage and asso-
ciation scan reveals novel loci for
autism. Nature. 2009;461:802–
808.
80. Aldinger KA, Plummer JT, Qiu S, et
al. SnapShot: genetics of autism.
Neuron. 2011;72:418.
81. Hoeffer CA, Klann E. mTOR signal-
ing: at the crossroads of plasticity,
memory and disease. Trends Neuro-
sci. 2010;33:67–75.
82. Smrz D, Kim MS, Zhang S, et al.
mTORC1 and mTORC2 differen-
tially regulate homeostasis of neo-
plastic and non-neoplastic human
mast cells. Blood. 2011;118:6803–
6813.
83. Shang YC, Chong ZZ, Wang S, et al.
Erythropoietin and Wnt1 govern
pathways of mTOR, Apaf-1, and
XIAP in inflammatory microglia.
Curr Neurovasc Res. 2011;8:270–
285.
Clinical Therapeutics
590 Volume 35 Number 5
84. Halova I, Draberova L, Draber P.
Mast cell chemotaxis: chemoattrac-
tants and signaling pathways. Front
Immunol. 2012;3:119.
85. Kim MS, Kuehn HS, Metcalfe DD,
et al. Activation and function of the
mTORC1 pathway in mast cells.
J Immunol. 2008;180:4586 –4595.
86. Zhou H, Luo Y, Huang S. Updates
of mTOR inhibitors. Anticancer
Agents Med Chem. 2010;10:571–
581.
87. Ehninger D, Silva AJ. Rapamycin
for treating tuberous sclerosis and
autism spectrum disorders. Trends
Mol Med. 2011;17:78 –87.
88. de Vries PJ. Targeted treatments for
cognitive and neurodevelopmental
disorders in tuberous sclerosis com-
plex. Neurotherapeutics. 2010;7:275–
282.
89. Hampson DR, Gholizadeh S, Pacey
LK. Pathways to drug development
for autism spectrum disorders. Clin
Pharmacol Ther. 2012;91:189–200.
90. Middleton E Jr, Kandaswami C.
The impact of plant flavonoids on
mammalian biology: implications
for immunity, inflammation and
cancer, in the flavonoids. In: Bar-
borne JB, ed. The Flavonoids. Lon-
don, England: Chapman & Hall;
1993:619– 652.
91. Kimata M, Shichijo M, Miura T, et
al. Effects of luteolin, quercetin
and baicalein on immunoglobulin
E-mediated mediator release from
human cultured mast cells. Clin Exp
Allergy. 2000;30:501–508.
92. Jang S, Kelley KW, Johnson RW.
Luteolin reduces IL-6 production in
microglia by inhibiting JNK phos-
phorylation and activation of AP-1.
Proc Natl Acad SciUSA. 2008;105:
7534–7539.
93. Meyer U, Feldon J, Dammann O.
Schizophrenia and autism: both
shared and disorder-specific patho-
genesis via perinatal inflamma-
tion? Pediatr Res. 2011;69:26R–
33R.
94. Zhu LH, Bi W, Qi RB, et al. Luteolin
inhibits microglial inflammation
and improves neuron survival
against inflammation. Int J Neurosci.
2011;121:329–336.
95. Liu Y, Tian X, Gou L, et al. Luteolin
attenuates diabetes-associated
cognitive decline in rats. Brain Res
Bull. 2013;94C:23–29.
96. Kempuraj D, Tagen M, Iliopoulou
BP, et al. Luteolin inhibits myelin
basic protein-induced human mast
cell activation and mast cell depen-
dent stimulation of Jurkat T cells.
Br J Pharmacol. 2008;155:
1076–1084.
97. Sternberg Z, Chadha K, Lieberman
A, et al. Immunomodulatory re-
sponses of peripheral blood mono-
nuclear cells from multiple sclero-
sis patients upon in vitro incubation
with the flavonoid luteolin: addi-
tive effects of IFN-beta. J Neuroin-
flammation. 2009;6:28.
98. Theoharides TC, Asadi S, Panagioti-
dou S. A case series of a luteolin
formulation (NeuroProtek(R)) in
children with autism spectrum dis-
orders. Int J Immunopathol Pharmacol.
2012;25:317–323.
99. Taliou A, Zintzaras E, Lykouras L, et
al. A pilot, open-label study of a
formulation containing the anti-
inflammatory flavanoid luteolin on
behavior of children with autism
spectrum disorders. Clin Therap. In
press.
100. Galli SJ, Nakae S, Tsai M. Mast
cells in the development of adap-
tive immune responses. Nat Immu-
nol. 2005;6:135–142.
101. Theoharides TC, Sieghart W,
Greengard P, et al. Antiallergic drug
cromolyn may inhibit histamine
secretion by regulating phosphory-
lation of a mast cell protein. Sci-
ence. 1980;207:80 –82.
102. Oka T, Kalesnikoff J, Starkl P, et al.
Evidence questioning cromolyn’s
effectiveness and selectivity as a
‘mast cell stabilizer’ in mice. Lab
Invest. 2012;92:1472–1482.
103. Vieira Dos SR, Magerl M, Martus
P, et al. Topical sodium cromogli-
cate relieves allergen- and hista-
mine-induced dermal pruritus.
Br J Dermatol. 2010;162:674–
676.
104. Weng Z, Zhang B, Asadi S, et al.
Quercetin is more effective than
cromolyn in blocking human mast
cell cytokine release and inhibits
contact dermatitis and photosensi-
tivity in humans. PloS One. 2012;7:
e33805.
105. Conti P, Varvara G, Murmura G,
et al. Comparison of beneficial
actions of non-steroidal anti-
inflammatory drugs to flavonoids.
J Biol Regul Homeost Agents. 2013;
27:1–7.
Address correspondence to: Theoharis C. Theoharides, MS, PhD, MD,
Molecular Immunopharmacology and Drug Discovery Laboratory, De-
partment of Molecular Physiology and Pharmacology, Tufts University
School of Medicine, 136 Harrison Avenue, Boston, MA 02111. E-mail:
theoharis.theoharides@tufts.edu
T.C. Theoharides
May 2013 591
