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Autism and the Immune System

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Title: Autism and the Immune System


1
Autism and the Immune System
  • Jane M. El-Dahr, M.D., FAAP, FAAAAI
  • Department of Pediatrics Allergy/Immunology/Rheuma
    tology
  • Tulane University School of Medicine
  • New Orleans, Louisiana, USA

Autism Around the World Conference May 2010
2
The Invaders . . .
  • Bacteria
  • Viruses
  • Parasites
    fungi

    worms

3
AN IMMUNE RESPONSE
Foreign invaders - viruses, bacteria, allergens,
toxins and parasites - constantly bombard our
body.
? ? ?
?
?
?
?
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
non-specific mechanisms.
4
The Department of Defense
  • The immune system is the bodys 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.

5
Survival
  • 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.

6
Isnt 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???

7
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 cant fix brain
    abnormalities that you are born with, so other
    than behavioral therapies, there isnt anything
    that will improve the childs level of
    functioning.

8
Biomedical view
  • 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.

9
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
10
This presentation
  • Overview of immunity
  • What we know about immunity in autism
  • Blood
  • Gut
  • Brain
  • Therapies

11
Immune and Nervous systems
  • Sample the outside world
  • Have a memory
  • Communicate with chemical messages
  • Interact with each other

12
The Ideal Immune System
  • Recognize all foreign organisms.
  • Bacteria, viruses, parasites (fungi,worms)
  • Efficiently and rapidly destroy invaders.
  • Prevent a second infection with the same microbe
    (have a memory).
  • Never cause damage to self.

13
Acquired (specific)
Innate (non-specific)
1st line of defense
14
Innate ImmunityPhagocytes (Macrophages) and
Natural Killer cells
Capture and kill germs Jailor or Executioner
15
Adaptive ImmunityB cells produce
Immunoglobulins (Antibodies)
Antibodies
Antibodies
16
Immunoglobulins
  • Antibodies are divided up into classes
  • 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

17
Adaptive ImmunityT cells give orders to other
cells
TH2
TH1
18
Adaptive ImmunityRegulatory 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
19
All cell types work together in a healthy immune
system !
20
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21
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).
22
Cytokines the Language of the Immune
System
  • Can be divided several ways
  • Th1 (adaptive/memory, cell mediated) IL-2, IFN-?
  • Th2 (adaptive/memory, antibodies)IL-4, IL-5,
    IL-13, IL-10,TGF-ß
  • Innate TNF-a, IL-1, IL-6, IL-12
  • Pro-inflammatory TNF-a, IL-1, IL-6
  • Anti-inflammatory TGF-ß, IL-10
  • Regulatory IL-10, IL-12,TGF-ß

Multiple roles makes this confusing!!!! Can do
different things in different contexts.
23
Coordinated Attack with Feedback Loops using
Cytokines
BALANCE !!!
24
Things that can go wrong
  • 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.

25
Inflammation
  • Acute Inflammation
  • 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
  • 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

26
TNF
27
Autoimmunity
Deficiency
Th1 and/or Th2
Th1 and/or Th2
Allergy
Inflammation
Th2
Innate and/or Th1 Th2
28
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29
Immunopathology in ASD
  • Dysregulation of immunity in autistic children
    leads to all four problems
  • Deficiency / dysfunction
  • Hypersensitivity / allergy
  • Autoimmunity
  • Inflammation

30
Immune Abnormalities in Autism
  • 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.
  • Studies are generally small with
    not-well-characterized children or are limited to
    a single subgroup so it is hard to draw firm
    conclusions
  • BUT few studies have demonstrated no
    abnormalities.

31
Dysregulation and Inflammation!
  • 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

32
Dysregulated immune system with inflammation in
children with ASD
  • 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, 552 http//www.jneuroin
    flammation.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, 126134.
  • Croonenberghs, J., Bosmans, E., Deboutte, D.,
    Kenis, G., Maes, M., 2002. Activation of the
    inflammatory response system in autism.
    Neuropsychobiology 45, 16.
  • 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.

33
Blood (serum) findings in ASD
  • Many studies find that ASD children have
    low-normal 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.

34
Reduced levels of IgG and IgM are indicative of
an underlying defect in the immune system of
children with autism.
Low IgM
Low IgG
M.I.N.D. Institute
Huge variation in IgE
Low Normal IgA
35
10 Warning Signs of an Immune Deficiency
www.jmfworld.com
Recurrent Infections if IgG, IgM, or IgA are low
36
Allergy
37
Blood (serum) findings in ASD
  • 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.

38
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.

39
Autoimmunity (Reaction to self)
  • 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.

40
GI Tract - Mucosal findings
  • Gut inflammation in some children
  • Abnormal lymphocyte profiles lots of
  • T cells present where none should be.
  • Abnormal cytokine profiles pro-inflammatory
    with lots of TNF-a and too little regulatory
    IL-10.
  • Measles virus demonstrable by PCR and other
    methods.

41
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42
Hypotheses of Etiology of Inflammatory Bowel
Disease
  • 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. 117514-521
(2007)
43
Immune Reactions to Food Jyonouchi 2005
(Neuropsychobiol and J. Peds)
  • 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).

44
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
45
Brain Vargas 2005
  • We demonstrate an active neuroinflammatory
    process in the cerebral cortex, white matter, and
    notably in cerebellum of autistic patients with
    marked microglial activation.
  • 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.
  • Vargas DL, Nascimbene C, Krishnan C, Zimmerman
    AW, Pardo CA. Neuroglial activation and
    neuroinflammation in the brain of patients with
    autism. Ann Neurol. 2005 Jan57(1)67-81.

46
Immune system AutismAn overview Pardo
2005
47
Immune dysregulation and increased inflammation
are frequent findings in autism
  • Over-active innate inflammatory response,
    especially increased pro-inflammatory cytokines,
    is a consistent finding.
  • 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.

48
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49
Therapies?
  • Many simple things support the immune system and
    promote T regulation
  • Dietary intervention
  • Probiotics
  • Omega-3 fatty acids
  • Vitamin D
  • Anti-oxidants
  • Metabolic support with supplements such as
    meB-12 and glutathione

50
Improving Immunity
  • Diet
  • Remove foods causing immune stimulation
  • Healthy, well balanced
  • Free of toxins
  • Supplements to support metabolism
  • Vitamins
  • Minerals
  • Antioxidants

51
Exercise and stress
  • 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

52
Immunomodulatory Therapies
  • Probiotics
  • Probiotics dietary supplement containing live
    micro- organisms
  • Early regulation of the immune system largely
    dependent on gut flora
  • Omega 3 Fatty Acids
  • Natural anti-inflammatory agents
  • Methyl B12
  • A crucial biochemical crossroads that helps in
    stabilizing membranes and making glutathione
  • Glutathione
  • Helps to regulate T cells and regenerate gut
    epithelium

53
Probiotics
  • Probiotic bacteria can modulate abnormal
    gastrointestinal immune responses
  • 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

54
Good guys in the gut
  • 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

55
Fun facts about flora

12
  • We have 10 viable bacteria/gm of large bowel
    content which is more bacteria in one persons
    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 genomes DNA
    content in those bacteria
  • The metabolic activity of the intestinal flora
    is greater than that of the livers

56
Microbes in the gut our Flora
  • Neonatal, childhood, and adult flora differ based
    upon environmental factors
  • Mode of delivery (C/S vs vaginal)
  • Hygiene measures
  • Maternal flora
  • Breast vs formula feeding
  • Antibiotic exposure
  • Diet

57
Bugs arent always bad
  • 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

58
Old friends
  • Mammalian evolution has kept us in close contact
    with relatively harmless micro-organisms 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

59
Hygiene Hypothesis???
60
Hygiene Hypothesis
61
Hygiene Hypothesis
  • 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

62
Microbial diplomacy
  • Probiotics - dead or alive - can affect systems
    in the body by contributing to the communications
    among the gut's native microbes.
  • The gut is the largest immune organ in the body
    so particularly important in orchestrating
    immune response

63
Effects of Probiotics on the Immune System
  • Produce natural anti-microbials
  • Block adhesion of toxins and pathogens
  • Modulate immune response
  • 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

64
Saarela M et al, Int J Food Microbiol. 2002
7899-117
65
Proven uses of Probiotics
  • Treatment of Inflammatory Bowel Disease
  • Treatment as well as prevention of
    antibiotic-associated diarrhea
  • Reducing the duration and severity of colds and
    flu-like illnesses
  • Treatment and prevention of pediatric atopic
    dermatitis

66
Many different types of bacteria
  • Bifidobacterium
  • Lactobacillus
  • Escherichia
  • Bacteroides
  • Clostridium
  • Fusobacterium
  • Eubacterium
  • Pepto and Peptostreptococcus

67
Unknowns
  • Dont 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?

68
Taking Probiotics
  • Live-culture yogurt (for those who tolerate milk)
    or fermented foods
  • Supplements Want at least 10 billion colonies
    (CFUs) per day
  • Many good brands see Handout
  • Klaire Labs
  • Kirkman
  • Culturelle
  • Jarro-Dophilus
  • VSL3

69
Omega-3 Fatty Acids
  • Omega-6 fatty acids (in many processed foods) are
    pro-inflammatory.
  • Omega-3 fatty acids (fish oil, flax seed oil) are
    anti-inflammatory - 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.
70
Vitamin A
  • Research now recognizing the impact in the immune
    system
  • Decreases autoimmunity
  • Helps in regulation
  • Aides IgA function
  • Take recommended daily allowance in a
    multi-vitamin
  • Retinoic acid-dependent regulation of immune
    responses by dendritic cells and macrophages.
    Manicassamya, S and Pulendrana,B. Seminars in
    Immunology (2009) 212227.
  • 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)
    212835.

71
Vitamin D
  • 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
  • Want levels 50 90 ng/ml range

72
Immune functions of Vit D
  • Nonclassic actions of Vitamin D. Bikle D. J Clin
    Endocrinol Metab January 2009, 94(1) 26-34.
  • 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.
  • vitamin D3 acts as an anti-inflammatory agent
    and reverses the age-related increase in
    microglial activation in the brain.

73
Dosing Vitamin D
  • Safe to give children 2000 IU per day without
    checking a blood level.
  • If measured value is low (lt 30ng/ml), can give
    4000-5000 IU daily dont 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 dont let the patient get above
    90 ng/ml of 25(OH)D

74
Antioxidants Curcumin (Turmeric)
  • Antioxidant and anti-inflammatory properties of
    curcumin. Adv Exp Med Biol. 2007595105-25.
  • 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!

75
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

76
Goal Decrease inflammatory stimulation
  • Vaccines
  • Ask for IgG vaccine antibody titers to see if
    boosters are necessary or not, especially for
    live viral vaccines (MMR, varicella)
  • Decrease Stress
  • Depresses immunity causes Th1 -gt Th2 shift
  • Avoid/Remove Toxins
  • Cause autoimmunity, promotes immune dysregulation
  • Decrease oxidative stress
  • Activates innate immunity

77
Avoid overusing antibiotics and acetaminophen
  • Antibiotics are used to treat bacterial illness
    that may cause your child to run a fever
  • MOST CHILDHOOD ILLNESSES ARE CAUSED BY VIRUSES
  • Viruses are NOT killed by antibiotics
  • Acetaminophen is used for fever and inflammation
  • Not all fevers need to be treated

78
American Academy of Pediatrics
  • Management of Children With Autism Spectrum
    Disorders Pediatrics November 2007 120
    1162-1182. http//www.pediatrics.org/cgi/content/f
    ull/120/5/1162
  • Toolkit - published 2007
  • Diagnosis
  • Treatment options
  • Includes gfcf diet!
  • Gastrointestinal Disorders in Individuals with
    Autism Spectrum Disorders Pediatrics Jan 2010

79
Summary Immune dysregulation and increased
inflammation are frequent in autism
  • Over-active innate inflammatory response
  • especially increased pro-inflammatory cytokines
    including TNF-a
  • 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

80
  • FIXING BROKEN BIOCHEMISTRY and
  • SUPPORTING IMMUNE REGULATION HELPS!

81
Good News - Changes in diagnostic codes for autism
  • In 2006, the official ICD-9 codes were
  • 299.0 Autistic disorderChildhood
    autismInfantile psychosisKanner's syndrome
  • 299.8 Other specified pervasive
    developmental disordersAsperger's disorder
  • 299.9 Unspecified pervasive developmental
    disorderPervasive developmental disorder NOS

82
Changes in diagnostic codes for autism from 4
digits to 5
  • As of 2007, an extra digit had to be added
  • 0 if the Autism, Aspergers, or PDD-NOS is
    in a current or active state 299.00
  • 1 if the Autism, Aspergers, 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!
83

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