An Autism Subgroup With Brain Inflammation

Is Treatable

Theoharis C. Theoharides,
MS, MPhil, PhD, MD, FAAAAI
Professor of Pharmacology, Internal Medicine and Psychiatry
Director, Molecular Immunopharmacology and Drug Discovery
Tufts University School Medicine, Boston, MA, USA

drtheoharides@gmail.com
www.mastcellmaster.com
www.autismfreebrain.org
www.brain-gate.org

4/8/2016 Copyright by Dr. TC Theoharides 1

Disclosures

Scientific Director and shareholder of Algonot, LLC

Medical Advisory Board, The Mastocytosis Society

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K. Weintraub, Nature 479, Nov. 3 2011, 22-24.

Now 1 in 45 children

Autism Spectrum Disorders

Deficits in communication and sociability
together with repetitive movements
Rett Autistic Childhood PDD-NOS* Aspergers
Syndrome Disorder Disintegrative PDDNOS,pervasive Syndrome
developmentaldisordernot
Disorder otherwisespecified.

ADD/ADHD
Allergies/Food intolerance
Gastrointestinal problems
Subgroups Mitochondrial dysfunction
PANDAS (Pediatric Autoimmune Neuropsychiatric
Disorders Associated With Streptococcal Infections)
PTEN mutations (large skull, headaches)
Seizures

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 Presenting Behavior
Suggestive of Autism
No response when calling name
Isolation
No group play
Loss of vocabulary
Rigid routines
Lack of imaginative play
Inability to follow directions
Anxiety
Intolerance to stress
Repetitive non-purposeful
movements
Hyperactivity
Tantrums
Tip-toeing
Hand flapping
Intolerance to sensory overload
Strange food habits
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Gestational and Perinatal Factors Increasing Autism Risk

Gestational Perinatal
Excessive oxytocin to induce labor
Allergies/Asthma
Autoimmune diseases High fever
Diabetes Incubation/maternal separation stress
Infection Infection
Low Vitamin D Low birth weight
Pre-eclampsia
Perinatal anoxia
Psoriasis
Psychotropic drug use Preterm birth
Stress

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 Mast Cell Activation

Diencephalon
(coordinates sensory input and emotions)

Dysfunctional social behavior,

communication and stereotypic
movements

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There was significant association with food intolerance (P = 0.001).

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 Croen et al. Arch Pediatr Adolesc Med 2005;159:151-7.

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Autism Spectrum
Disorders and
Mastocytosis
Theoharides TC. Int J Immunopathol Pharmacol.

2009 Oct-Dec;22(4):859-65.
The risk of autism was 10 times
higher than in the general population
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Is There Evidence of Inflammation in

the Brain?

Activation and proliferation of

microglia, the brain immune cells,
causes local inflammation and
choking of neuronal connectivity

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Mast cell

Neuron

Microglia
IL-6, TNF

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 How Can Stress Contribute to
Inflammation of the Brain?

Disrupts the gut-blood barrier

Opens up the blood-brain barrier
Stimulates mast cells
Triggers microglia cells

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Prenatal Stress Has Been Associated With

High Risk of Developing Autism

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 30 minutes restraint stress

mouse 200
*

% change from control

150

100

tv 99Tc-G
50

C57BL +/+ normal

W/Wv mast cell-deficient
0
+/+ W/W v

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Intradermal CRH Injection Induces Skin Vascular

Permeability, but not in W/Wv Mast Cell Deficient Mice

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Culture of human umbilical cord blood-

derived mast cells (hCBMCs)
CD34+ cells

MNCs

AC133 mAb
RBCs

Culture with SCF (100

ng/ml) and IL-6 (50
ng/ml) for 8-16 wk
MACs yields 100% tryptase-
positive mast cells

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mast cells 27
Kempuraj D., Saito H. et al. Blood 93: 3338-3346, 1999.

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Immunocytochemistry of CRH-R in human
mast cells
-
A C D E
A B BD

F
E F
G

R1 no IL-4 R1 + IL-4 R2 no IL-4 R2 + IL-4 No R1 primary DAPI

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Effect of Mast Cells on the HPA Axis

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 The Peptide Neurotensin Can Trigger
Inflammation of the Brain

Is increased in the blood of children with ASD

Is found in the brain and gut
Stimulates mast cells and microglia
Has synergistic action with CRH
Opens up the blood-brain barrier
Is neurotoxic

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What Triggers Inflammation in the Brain?

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 50
40
VEGF

30
20
10
0
control 1nM 10nM 100nM 1uM
CRH

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Figure 3 Microglia Express NTR3/Sortilin, which is Elevated in the

A) Serum of Children
B) with ASD

C) D)

Neurotensin Stimulates Human Microglia

IL1 Gene Expression and Release

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Treatment

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Beaudet. Science; 338:342-3, 2012

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 Most Countries Use Psychotropic Drugs in
Children with ASDs

Wong AY et al., Autism Res. 2014 Oct;7(5):543-54

Luteolin
(3,4,5,7-tetrahydroxyflavone)

Properties of Luteolin Useful in Autism

Reduces oxidative stress

Inhibits inflammation
Inhibits mast cell activation
Methoxyluteolin Inhibits microglia activation
(3,4,5,7-tetramethoxyluteolin)
Inhibits neurotoxicity
Is weak metal chelator
Increases memory
Prevents autism-like behavior in mice

Inhibition of inflammatory molecules by quercetin

Effect of luteolin on SP-induced
fromhuman mast cells
human mast cell secretion
100 * *
*
90 *
80
Percent inhibition

70
*
60
50
40
30
20
10
0
Histamine Tryptase IL-6 IL-8 TNF-alpha

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Jang et al. Proc Natl Acad Sci USA, 2008;105:7534-9

Luteolin significantly inhibited

IL-6-induced behavioral deficits
in social interactions in mice

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 Methoxyluteolin Inhibits Inflammatory
Molecule Release from Human Microglia

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Methoxyluteolin Inhibits IL-33/SP-Induced

TNF Secretion and NFB Activation in Mast Cells

Mast Cell Triggers

Calcium
influx via
receptor
mast cell PI3K PTEN
Mast cell
activation
number
AKT 1-Control 2-Rapamycin 3-Methoxyluteolinteolin

Rapamycin
mTORC1
Mast cell Luteolin
number

MAST CELL SECRETION

Methoxyuteolin inhibits
mTOR activation
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Net weight 2 oz (56.7 gm) www.gentlederm.com

A B C D

Photos of lesional skin areas. Areas were photographed before (upper panels) and after (lower panels)
using GentleDerm twice daily for two weeks. (A,B) eczema: (A) face of a 51 year-old female patient with
mast cell activation syndrome and (B) abdomen of 43 year-old female patient with mast cell activation syndrome;
(C,D) psoriasis: (C) leg of a 47 year-old male patient with indolent systemic mastocytosis and (D) hand of
39 year-old female patient with mast cell activation syndrome.

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Mast Cell
Lut & Methlut

Neurons
Inflammatory
H mediators

Microglia Neuronal damage

and impaired
connectivity

INSCREASED RISK OR AUTISM

No trigger Triggers Triggers + Triggers + Triggers +
Atopy Atopy + CRH+ Atopy + CRH +
Neurotensin Neurotensin +
mTOR activation

Treatment Approaches
Reduce anxiety/pressure
Limit sensory overload
Start speech, music and work support
Correct vitamin deficiencies
Supplement methyl donors (glutathione, SAMe, NAC)
Eliminate food intolerances
Reduce allergies
Add anti-oxidants (Omega-3, sulforaphane)
Address inflammation (luteolin, methoxyluteolin)

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 Research Funding:

DK62861
AR47652
NS071361
NS55681
AR60951
NS66205

Autism Research
Collaborative
National Autism
Association
Safe Minds
Autism Research
Institute
Jane B Johnson Fnd.

drtheoharides@gmail.com
www.mastcellmaster.com
www.autismfreebrain.org
www.brain-gate.org
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