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4/8/2016 Copyright by Dr. TC Theoharides 1
Theoharis C. Theoharides, MS, MPhil, PhD, MD, FAAAAI
Professor of Pharmacology, Internal Medicine and Psychiatry
Director, Molecular Immunopharmacology and Drug DiscoveryTufts University School Medicine, Boston, MA, USA
drtheoharides@gmail.comwww.mastcellmaster.comwww.autismfreebrain.org
www.brain-gate.org
14/8/2016 Copyright by Dr. TC Theoharides
An Autism Subgroup With Brain Inflammation
Is Treatable
Disclosures
• Scientific Director and shareholder of Algonot, LLC
• Medical Advisory Board, The Mastocytosis Society
4/8/2016 Copyright by Dr. TC Theoharides 2
Autism Spectrum Disorders
Rett Syndrome
Autistic Disorder
Childhood Disintegrative
Disorder
PDD-NOS* Asperger’s SyndromePDD‐NOS, pervasive
developmental disorder not otherwise specified.
• ADD/ADHD• Allergies/Food intolerance• Gastrointestinal problems• Mitochondrial dysfunction• PANDAS (Pediatric Autoimmune Neuropsychiatric
Disorders Associated With Streptococcal Infections)• PTEN mutations (large skull, headaches)• Seizures
Subgroups
K. Weintraub, Nature 479, Nov. 3 2011, 22-24.
Deficits in communication and sociability together with repetitive movements
Now 1 in 45 children
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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
4/8/2016 5Copyright by Dr. TC Theoharides
Gestational and Perinatal Factors Increasing Autism Risk
Gestational
• Allergies/Asthma• Autoimmune diseases• Diabetes• Infection• Low Vitamin D• Pre-eclampsia• Psoriasis• Psychotropic drug use • Stress
Perinatal• Excessive oxytocin to induce labor
• High fever
• Incubation/maternal separation stress
• Infection
• Low birth weight
• Perinatal anoxia
• Preterm birth
3
Diencephalon(coordinates sensory input and emotions)
Mast Cell Activation
Dysfunctional social behavior, communication and stereotypic
movements
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There was significant association with food intolerance (P = 0.001).
9Copyright Dr. T.C. Theoharides4/8/2016
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Croen et al. Arch Pediatr Adolesc Med 2005;159:151-7.
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Autism Spectrum Disorders and MastocytosisTheoharides 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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Copyright by Dr. TC Theoharides
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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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IL-6, TNFMicroglia
Neuron
Mast cell
8
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
9
tv 99Tc-G
30 minutes restraint stress
C57BL +/+ normalW/Wv mast cell-deficient
mouse
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0
50
100
150
200
*
+/+ W/Wv%
ch
ang
e fr
om
co
ntr
ol
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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)
Culture with SCF (100 ng/ml) and IL-6 (50 ng/ml) for 8-16 wk yields 100% tryptase-positive mast cells
CD34+ cells
mast cellsKempuraj D., Saito H. et al. Blood 93: 3338-3346, 1999.
RBCs
MNCs
AC133 mAb
MACs
10
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Immunocytochemistry of CRH-R in human mast cells
F G
B
-
R1 no IL-4
DCA E
E F
B
R1 + IL-4
A B
R2 no IL-4 R2 + IL-4
DB
No R1 primary DAPI
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Effect of Mast Cells on the HPA Axis
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11
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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01020304050
control 1nM 10nM 100nM 1uMCRH
VE
GF
A) B)
C) D)
Figure 3 Microglia Express NTR3/Sortilin, which is Elevated in the Serum of Children with ASD
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Neurotensin Stimulates Human Microglia IL1 Gene Expression and Release
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Treatment
Beaudet. Science; 338:342-3, 2012
14
Wong AY et al., Autism Res. 2014 Oct;7(5):543-54
Most Countries Use Psychotropic Drugs in Children with ASDs
Luteolin (3′,4′,5,7-tetrahydroxyflavone)
Methoxyluteolin (3′,4′,5,7-tetramethoxyluteolin)
Properties of Luteolin Useful in Autism
• Reduces oxidative stress• Inhibits inflammation• Inhibits mast cell activation• Inhibits microglia activation• Inhibits neurotoxicity• Is weak metal chelator• Increases memory• Prevents autism-like behavior in mice
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0
10
20
30
40
50
60
70
80
90
100
Histamine Tryptase IL-6 IL-8 TNF-alpha
Per
cen
t in
hib
itio
n
*
** *
*
Inhibition of inflammatory molecules by quercetin from human mast cells
Effect of luteolin on SP-induced human mast cell secretion
15
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Jang et al. Proc Natl Acad Sci USA, 2008;105:7534-9
Luteolin significantly inhibitedIL-6-induced behavioral deficits in social interactions in mice
17
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
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Mast Cell Triggers
PI3K
AKT
mTORC1
PTENMast cell number
mast cell activation
Mast cell number
Rapamycin
Luteolin
Calcium influx via receptor
Methoxyuteolin inhibits mTOR activation
1-Control 2-Rapamycin 3-Methoxyluteolinteolin
MAST CELL SECRETION
18
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A novel, hypoallergenic, anti-oxidant, flavonoid lotion for dry, irritated or sensitive skin
Hydrates-Nourishes–Soothes-Rejuvenates-RepairsLet Nature Calm Your SkinTM
Net weight 2 oz (56.7 gm)
Ingredients: Water, organic aloe barbadensis leaf juice, olea europea (olive) fruit oil, glycerin, organic helianthus annuus (sunflower) seed oil, steareth-21, stereath-2, cetyl
alcohol, stearyl alcohol, glyceryl stearate, lanolin, tetramethoxyflavone, sodium benzoate, quaternium-15, disodium EDTA, magnesium chloride, honey, sodium chloride, potassium
chloride, tetrahexyldecyl ascorbate, origanum vulgare oil, disodium phosphate
Made for Algonot, LLC, 5111 Ocean Bvd-Suite J Sarasota, FL 34242, USA-Toll Free 1-800-254-6668
www.gentlederm.com
GentleDermTM
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.
Mast Cell
Microglia
Inflammatory
mediators
Neurons
Neuronal damage and impaired connectivity
H
No trigger Triggers +Atopy + CRH +Neurotensin + mTOR activation
Triggers +Atopy
Triggers
INSCREASED RISK OR AUTISMTriggers +Atopy + CRH+Neurotensin
Lut & Methlut
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.
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drtheoharides@gmail.comwww.mastcellmaster.comwww.autismfreebrain.org
www.brain-gate.org
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