Download Immunesystem - Child Early Intervention Medical Center

Autism and the
Immune System
Jane M. El-Dahr, M.D., FAAP, FAAAAI
Department of Pediatrics
Allergy/Immunology/Rheumatology
Tulane University School of Medicine
New Orleans, Louisiana, USA
Autism Around the World Conference – May 2010
The Invaders . . .
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Bacteria
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Viruses
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Parasites
fungi
worms
http://www.hhs.gov/asphep/presentation/images/bacteria.jpg
http://www.skidmore.edu/academics/biology/plant_bio/lab13.FUNGI.html
worm trichura.jpg
AN IMMUNE RESPONSE
Foreign invaders - viruses, bacteria, allergens,
toxins and parasites - constantly bombard our body.
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The response to this assault is a carefully orchestrated and
controlled interaction between immune cells with the ultimate
goal to eliminate the invaders in both pathogen-specific and 3
non-specific mechanisms.
The Department of Defense
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The immune system is the body’s
defense system, guarding against
foreign invaders.
Just as we have an army, air force, police,
jails, etc. to keep us “safe”, the immune
system has different branches which do
different things but coordinate to protect
our body.
Survival
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The “goal” of the immune system is to
keep you alive to reproduce.
There is a race between each of us and
the organisms around us – we want to
eliminate foreign organisms (pathogens)
without damaging ourselves while the
microbes try to hang around as long as
possible and reproduce themselves.
Isn’t having a child with autism
hard enough already…

Why do I have to worry about what is going
on with the immune system (or worse still,
learn biochemistry!) ???
How is that going to help me???
Traditional view of Autism

Autism is a group of behaviors caused by
some defective gene or genes which cause
structural changes in the brain. We can’t fix
brain abnormalities that you are born with, so
other than behavioral therapies, there isn’t
anything that will improve the child’s level of
functioning.
Biomedical view
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Children with autism have metabolic
problems (genetic? nutritional?) that can be
diagnosed and treated.
Fixing broken biochemical pathways also
improves the immune system and helps to
heal the gut.
By paying attention to the medical (as
opposed to psychiatric or mental) issues of
the children, we can significantly improve
their quality of life and level of functioning.
Metabolic “Gridlock”
Children with autism have biochemical/metabolic
pathways that are inefficient or blocked; “fixing” their
biochemistry is like clearing the snow for these taxis
This presentation
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Overview of immunity
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What we know about immunity in autism:
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Blood
Gut
Brain
Therapies
Immune and Nervous systems
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Sample the “outside” world
Have a memory
Communicate with chemical messages
Interact with each other
The “Ideal” Immune System
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Recognize all foreign organisms.
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Bacteria, viruses, parasites (fungi,worms)
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Efficiently and rapidly destroy invaders.
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Prevent a second infection with the
same microbe (have a memory).
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Never cause damage to self.
Acquired (specific)
Innate
(non-specific)
1st line
of defense
Innate Immunity:
Phagocytes (Macrophages) and
Natural Killer cells
Capture and kill germs –
Jailor or Executioner
Adaptive Immunity:
B cells produce
Immunoglobulins (Antibodies)
Antibodies
Antibodies
Immunoglobulins
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Antibodies are divided up into classes
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IgA: Mucosal surfaces - if low, predisposes to
respiratory and GI infections as well as
autoimmunity; often low in ASD children
IgM: Rapid response bloodstream antibody
made at the beginning of an infection; can be
high or low in ASD
IgG: Slower but longer lasting bloodstream
antibody; can be high or low in ASD
IgE: Allergy; can be high or normal in ASD
Adaptive Immunity:
T cells give orders to other cells
TH1
TH2
Adaptive Immunity:
Regulatory T cells
keep things in balance
T regs tell B cells to stop
making antibodies
when the infection is over
T regs tell other T cells to
stop “directing” and killing
when the infection is over
All cell types work together in
a healthy immune system !
Cytokines – the Language
of the Immune System
Chemical messages that are the main communication
system between cells of the immune system
(and other systems – especially the nervous system).
Cytokines – the Language
of the Immune System
Can be divided several ways:
 Th1 (adaptive/memory, cell mediated): IL-2, IFN-γ
 Th2 (adaptive/memory, antibodies):IL-4, IL-5, IL-13, IL-10,TGF-β
 Innate: TNF-α, IL-1, IL-6, IL-12
 Pro-inflammatory: TNF-α, IL-1, IL-6
 Anti-inflammatory: TGF-β, IL-10
 Regulatory: IL-10, IL-12,TGF-β
Multiple roles makes this confusing!!!!
Can do different things in different contexts.
Coordinated
“Attack” with
Feedback
Loops using
Cytokines
BALANCE !!!
Things that can go wrong…
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Immune deficiency/dysfunction: defective or
ineffective response.
Hypersensitivity: Over-reaction to innocuous
foreign material, out of proportion to potential
damage - Allergy.
Autoimmunity: Inappropriate reaction towards
self, loss of self-recognition.
Inflammation: Too vigorous attack against
invaders with “bystander” damage to normal
tissue.
Inflammation
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Acute Inflammation
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Early response to injury/infection, lasts days
Swelling, redness, heat, pain at site
Beneficial, leads to elimination of infection and tissue
healing – trying to repair damage
Innate cells and mediators
Chronic Inflammation
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Late or sustained response to intracellular pathogens
or self antigens (autoimmunity)
Harmful, results in tissue destruction
Adaptive and innate cells and mediators
Often LOCAL at specific sites
TNF
Deficiency
Th1 and/or Th2
Autoimmunity
Th1 and/or Th2
Allergy
Inflammation
Th2
Innate and/or
Th1 Th2
Immunopathology in ASD
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Dysregulation of immunity in autistic
children leads to all four problems:
Deficiency / dysfunction
Hypersensitivity / allergy
Autoimmunity
Inflammation
Immune Abnormalities in Autism
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Abnormal immune systems have been found in about
20-70% of patients with autism in a wide variety of
studies, depending on which part of the immune
system is examined.
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Studies are generally small with not-well-characterized
children or are limited to a single subgroup so it is
hard to draw firm conclusions…
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BUT few studies have demonstrated no abnormalities.
Dysregulation and Inflammation!
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Nearly every study finds that some children
have poor T regulatory function so that
immune responses do not turn “off” normally,
staying “activated” or turned on and resulting
in inflammation.
Cytokines are often “pro-inflammatory”
Dysregulated immune system with
inflammation in children with ASD
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Jyonouchi H, et al. Impact of innate immunity in a subset of
children with autism spectrum disorders: a case control study
Journal of Neuroinflammation 2008, 5:52
http://www.jneuroinflammation.com/content/5/1/52
Ashwood, P., Wakefield, A.J.,2006. Immune activation of
peripheral blood and mucosal CD3+ lymphocyte cytokine
profiles in children with autism and gastrointestinal symptoms.
J. Neuroimmunol. 173, 126–134.
Croonenberghs, J., Bosmans, E., Deboutte, D., Kenis, G., Maes, M.,
2002. Activation of the inflammatory response system in
autism. Neuropsychobiology 45, 1–6.
Zimmerman, A., Jyonouchi, H., Comi, A., Connors, S., Milstien, S.,
Varsou, A., Heyes, M., 2005. Cerebrospinal fluid and serum
markers of inflammation in autism. Pediatr.Neurol. 35, 195-201.
Blood (serum) findings in ASD
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Many studies find that ASD children have lownormal immunoglobulins (IgG, IgM, IgA) and/or
low T cell numbers and/or low-normal
functioning and/or low and poorly functional
Natural Killer cells ; a subset of children have
true immunodeficiency.
Some children have low serum IgA, predisposing
them to respiratory and GI infections.
Reduced levels of IgG and IgM are indicative of an underlying
defect in the immune system of children with autism.
Low IgG
Low IgM
M.I.N.D.
Institute
Low Normal IgA
Huge
variation
in IgE
10 Warning Signs of an
Immune Deficiency
www.jmfworld.com
Recurrent Infections if IgG, IgM, or IgA are low
Allergy
Blood (serum) findings in ASD
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Some children have allergy (atopy) with
high levels of IgE.
Traditional IgE allergies can be measured either
by blood testing (RAST) or by skin prick testing.
It is well documented that in neuro-typical
children, untreated allergies cause poor memory
and concentration as well as poor sleep.
Blood (serum) findings in ASD
Bottom line #1: A child on the autism
spectrum with recurrent infections
deserves an immune evaluation for
immunodeficiency.
Bottom line #2: A child on the autism
spectrum with eczema, chronic nasal
symptoms, asthma, significant GI
symptoms, or recurrent respiratory
infections deserves an allergy evaluation
for IgE inhalant and food allergies.
Autoimmunity
(Reaction to “self”)
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There is a tendency towards a positive family
history of autoimmunity in families –
Rheumatoid Arthritis, Thyroiditis - with an
ASD child, and a genetic tendency towards
autoimmune disorders as well.
Many, many types of autoantibodies
(against “self” tissues) have been found in
ASD children but the significance of the many
types of anti-brain antibodies is not clear.
GI Tract - Mucosal findings
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Gut inflammation in some children
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Abnormal lymphocyte profiles: lots of
T cells present where none should be.
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Abnormal cytokine profiles: pro-inflammatory
with lots of TNF-α and too little regulatory IL-10.
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Measles virus demonstrable by PCR and other
methods.
Hypotheses of Etiology of
Inflammatory Bowel Disease
1. Abnormal (dysregulated) immune system, normal gut microbes
2.Normal immune system, abnormal microbes +/- abnormal barrier
We conclude that IBD is characterized by an abnormal mucosal
immune response but that microbial factors and epithelial
cell abnormalities can facilitate this response.
Strober W, The fundamental basis of inflammatory bowel disease J. Clin. Invest. 117:514-521 (2007)
Immune Reactions to Food –
Jyonouchi 2005
(Neuropsychobiol and J. Peds)
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Immune cells from autistic children with GI
symptoms showed strong pro-inflammatory
response and a reduced ability to switch off the
immune response compared to normal children.
Immune reactivity to milk and wheat common
with or without GI symptoms. Soy and corn next
most common.
Still no test or good predictors (although a few
children did have IgE antibodies which can be
measured) - elimination and challenge best.
Yeast (Candida albicans) overgrowth also found
in the stools of some children (J. Peds May 2005).
Jyonouchi H. Food allergy and ASD: is
there a link? Cur Allergy Asthma Reports
(2009) 9(3):194-201
ASD pts with
non-IgE
mediated food
Allergy to milk had
low TGF beta
(T reg cytokine)
levels which increased
on a casein free diet.
Outgrowing milk allergy
developing T regs
Brain: Vargas 2005
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We demonstrate an active neuroinflammatory
process in the cerebral cortex, white matter, and notably
in cerebellum of autistic patients with marked microglial
activation.
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Our findings indicate that innate neuroimmune
reactions play a pathogenic role in an undefined
proportion of autistic patients, suggesting that future
therapies might involve modifying neuroglial responses
in the brain.
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Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA.
Neuroglial activation and neuroinflammation in the brain of patients
with autism. Ann Neurol. 2005 Jan;57(1):67-81.
Immune system & Autism:
An overview
[Pardo 2005]
Immune dysregulation and
increased inflammation are
frequent findings in autism
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Over-active innate inflammatory response,
especially increased pro-inflammatory cytokines,
is a consistent finding.
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There is evidence of over-activity of the immune
system in all parts of the immune system, with
inflammation in the blood, in the brain, and in the
GI tract of many of these children.
Therapies?
Many simple things support the immune system
and promote T regulation:
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Dietary intervention
Probiotics
Omega-3 fatty acids
Vitamin D
Anti-oxidants
Metabolic support with supplements such as
meB-12 and glutathione
Improving Immunity
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Diet
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Remove foods causing immune stimulation
Healthy, well balanced
Free of toxins
Supplements to support metabolism
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Vitamins
Minerals
Antioxidants
Exercise and stress
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Exercise has been shown to boost the immune response
 moderate exercise increases the immune response in all
age groups
 intensive exercise can stress the immune system
Lack of sleep and exhaustion decrease immune function
Psychological stress has also been found to decrease
immune function
Metabolic stress – Oxidative Stress – also very
detrimental to immune function and is pro-inflammatory
51
Immunomodulatory Therapies
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Probiotics
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Probiotics = dietary supplement containing live microorganisms
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Early regulation of the immune system largely dependent
on gut flora
Omega 3 Fatty Acids
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Methyl B12
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Natural anti-inflammatory agents
A crucial biochemical crossroads that helps in stabilizing
membranes and making glutathione
Glutathione
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Helps to regulate T cells and regenerate gut epithelium
Probiotics
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Probiotic bacteria can modulate abnormal
gastrointestinal immune responses:
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Suppress either antibody-mediated or T cell
mediated hypersensitivity to food so decreases
gut inflammation
Increases secretory IgA production
Decreases gut permeability
Stimulates NK cells
Increases IL-10 production so improves immune
regulatory function
Good guys in the gut
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GI tract is sterile until birth
Colonization begins immediately after birth
and is nearly complete by one week of life,
but quantity and species vary markedly over
the first 6 months of life and is “adult” by 2 yrs
More than 1000 species have been found,
each with numerous strains
Easier to detect via molecular
means than by culture
Fun facts about flora
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12
We have 10 viable bacteria/gm of large
bowel content which is more bacteria in
one person’s gut than there have ever
been humans on the planet - 10 trillion
bacteria which weigh ~ 3 lbs
There are 10 X more bacteria
in the gastrointestinal lumen than the
number of cells in the human body
There are 100 X the human genome’s
DNA content in those bacteria
The metabolic activity of the intestinal
flora is greater than that of the liver’s
Microbes in the gut – our Flora
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Neonatal, childhood, and adult flora differ
based upon environmental factors :
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Mode of delivery (C/S vs vaginal)
Hygiene measures
Maternal flora
Breast vs formula feeding
Antibiotic exposure
Diet
“Bugs” aren’t always bad
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Intestinal bacterial flora are there for a reason
Interact with the immune system of the host
Compete with pathogens for space and
resources in the intestines
We get short chain fatty acids (Vit K etc) for
our metabolic pathways
Humans get heat from the metabolism of
indigestible (to us) compounds
Old friends
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Mammalian evolution has kept us in close
contact with relatively harmless microorganisms over a long period of time
We recognize these “old friends” and they
help to educate our immune system
Decreased types of bacteria in our gut from
antibiotics similar to effect of global warming
to the planet
Hygiene Hypothesis???
Hygiene Hypothesis
Hygiene Hypothesis
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The rise in allergic conditions (TH2) and
autoimmune disorders (TH1) in Westernized
countries is from immune dysregulation due
to modern hygiene with decreased exposure
to microbes that “prime” the immune system
to develop T regulatory cells
Tolerance “has to be carefully taught”
Microbial diplomacy
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Probiotics - dead or alive - can affect
systems in the body by contributing to the
communications among the gut's native
microbes.
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The gut is the largest immune organ in the
body – so particularly important in
“orchestrating” immune response
Effects of Probiotics on the
Immune System
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Produce natural anti-microbials
Block adhesion of toxins and pathogens
Modulate immune response
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Enhanced natural killer cell activity
Increase mucosal and secretory IgA
Decrease pro-inflammatory cytokines (chemical
messages)
Increase anti-inflammatory cytokines and T regs
Barrier function
Saarela M et al, Int J Food Microbiol. 2002; 78:99-117
Proven uses of Probiotics
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Treatment of Inflammatory Bowel Disease
Treatment as well as prevention of antibioticassociated diarrhea
Reducing the duration and severity of colds
and flu-like illnesses
Treatment and prevention of pediatric atopic
dermatitis
Many different types of bacteria…
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Bifidobacterium
Lactobacillus
Escherichia
Bacteroides
Clostridium
Fusobacterium
Eubacterium
Pepto – and Peptostreptococcus
Unknowns
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Don’t know what species/brand is most beneficial
– does it vary by disease state?
Mix of strains or single strain?
Dose?
Do you have to continue to ingest them daily or do
the benefits stop when you stop taking them?
Who is at risk of severe adverse event?
How good are the marketed supplements?
Taking Probiotics
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Live-culture yogurt (for those who tolerate
milk) or fermented foods
Supplements: Want at least 10 billion
colonies (CFU’s) per day
Many good brands: see Handout
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Klaire Labs
Kirkman
Culturelle
Jarro-Dophilus
VSL3
Omega-3 Fatty Acids
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Omega-6 fatty acids (in many processed foods) are
pro-inflammatory.
Omega-3 fatty acids (fish oil, flax seed oil) are antiinflammatory - can have marked influence on both
specific and nonspecific immune responses in modifying
inflammatory precursors and replacing Omega-6 FAs in
cell membranes.
1 - 2 grams a day can be given safely. Start with a low
dose and work up.
See Handout for food content and supplement brands
Kankaanpaa P, Dietary fatty acids and allergy. Annals of Med 31(4): 282-7, 1999
Grimm H, Regulatory potential of n-3 fatty acids in immunological and
inflammatory process. Brit J Nutrition 87(sup 1): S59-67, 2002.
Vitamin A
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Research now recognizing the impact in the
immune system
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Decreases autoimmunity
Helps in regulation
Aides IgA function
Take recommended daily allowance in a multi-vitamin
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Retinoic acid-dependent regulation of immune responses by dendritic cells
and macrophages. Manicassamya, S and Pulendrana,B. Seminars in Immunology
(2009) 21:22–27.
Regulation of FoxP3+ Regulatory T Cells and Th17 Cells by Retinoids. Kim CH.
Clinical and Developmental Immunology (2008)
Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells. Mora,
J R and von Andrian U H. Seminars in Immunology. (2009) 21:28–35.
Vitamin D
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Critical role in innate immunity and
autoimmunity
Very frequently low in patients with
autoimmune disease
Low in people with darker skin or little sun
exposure – made in skin when in sunlight
Can measure 25 (OH) D3 level in the blood
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Want levels 50 – 90 ng/ml range
Immune functions of Vit D
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Nonclassic actions of Vitamin D. Bikle D. J Clin
Endocrinol Metab January 2009, 94(1): 26-34.
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Inhibits T cell proliferation
Increases IL-10 and TGF-beta (regulatory cytokines)
Increases T regs
Decreases innate inflammation
Evidence that vitamin D3 reverses age-related
inflammatory changes in the rat hippocampus.
Moore ME et al. Biochemical Society Transactions (2005) 33(4): 573- 577.
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… vitamin D3 acts as an anti-inflammatory agent and
reverses the age-related increase in microglial
activation in the brain.
Dosing Vitamin D
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Safe to give children 2000 IU per day without
checking a blood level.
If measured value is low (< 30ng/ml), can
give 4000-5000 IU daily ; don’t go above
10,000 IU per day.
Endocrinologists give adults with levels below
20 – 30 Ergocalciferol 50,000 IU once a week
for 3 months, then once a month.
Check levels and don’t let the patient get
above 90 ng/ml of 25(OH)D
Antioxidants –
Curcumin (Turmeric)
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Antioxidant and anti-inflammatory
properties of curcumin. Adv Exp Med Biol.
2007;595:105-25.
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The anti-inflammatory effect of curcumin is most
likely mediated through its ability to inhibit
cyclooxygenase-2 (COX-2), lipoxygenase
(LOX), and inducible nitric oxide synthase
(iNOS), all important enzymes that mediate
inflammatory processes.
Cook with it!
Antioxidants –
CoQ 10 and Quercetin

CoQ-10 is anti-inflammatory/anti-oxidant
 Start with 50 mg a day, can go to 100 - 200 mg

Quercetin
 Natural antihistamine (for allergies)
 Quercetin also has anti-inflammatory properties
 Dose – start with 100 mg a day, can go to 200 mg
Goal: Decrease inflammatory
stimulation
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Vaccines
 Ask for IgG vaccine antibody titers to see if
boosters are necessary or not, especially for
live viral vaccines (MMR, varicella)
Decrease Stress
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Avoid/Remove Toxins
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Depresses immunity; causes Th1 -> Th2 shift
Cause autoimmunity, promotes immune dysregulation
Decrease oxidative stress
 Activates innate immunity
Avoid overusing antibiotics
and acetaminophen
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Antibiotics are used to treat bacterial illness
that may cause your child to run a fever

MOST CHILDHOOD ILLNESSES ARE CAUSED
BY VIRUSES
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Viruses are NOT killed by antibiotics
Acetaminophen is used for fever and
inflammation
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Not all fevers need to be treated
American Academy of
Pediatrics

Management of Children With Autism Spectrum
Disorders – Pediatrics November 2007 120: 1162-1182.
http://www.pediatrics.org/cgi/content/full/120/5/1162
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Toolkit - published 2007
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Diagnosis
Treatment options
 Includes gfcf diet!
Gastrointestinal Disorders in Individuals with
Autism Spectrum Disorders – Pediatrics Jan 2010
Summary: Immune dysregulation
and increased inflammation are
frequent in autism

Over-active innate inflammatory
response


especially increased pro-inflammatory
cytokines including TNF-α
There is evidence of over-activity of the
immune system



especially the innate immune system
adaptive immune system appears to be
dysregulated as well
inflammation in the blood, in the brain, and
in the GI tract of many of these children
FIXING BROKEN BIOCHEMISTRY and
SUPPORTING IMMUNE REGULATION HELPS!
Good News - Changes in
diagnostic codes for autism
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In 2006, the official ICD-9 codes were:
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299.0 Autistic disorder
Childhood autism
Infantile psychosis
Kanner's syndrome
299.8 Other specified pervasive
developmental disorders
Asperger's disorder
299.9 Unspecified pervasive developmental
disorder
Pervasive developmental disorder NOS
Changes in diagnostic codes for
autism from 4 digits to 5 …

As of 2007, an “extra digit” had to be added:
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“0” if the Autism, Asperger’s, or PDD-NOS is
in a “current or active state” [299.00]
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“1” if the Autism, Asperger’s, or PDD-NOS is
in a “residual state”
[299.01]
Every physician who sees a child on the spectrum
now has to specify if the child is “losing” the diagnosis!