This document discusses the immune system in individuals with autism. It begins by outlining the different components of the innate and adaptive immune system. It then discusses how the immune system can become dysregulated in autism, leading to issues like immune deficiency, hypersensitivity, autoimmunity, and inflammation. Several studies are cited that found abnormal immune responses and inflammation in the blood, gut, and brain of individuals with autism. The document concludes by discussing potential therapies like dietary changes, probiotics, vitamins, and supplements that may help support the immune system.

1. 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

2. The Invaders . . .
 Bacteria
 Viruses
 Parasites
fungi
worms
worm trichura.jpg
http://www.hhs.gov/asphep/presentation/images/bacteria.jpg
http://www.skidmore.edu/academics/biology/plant_bio/lab13.FUNGI.html

3. 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 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.

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. 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???

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 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.

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. Children with autism have biochemical/metabolic
pathways that are inefficient or blocked; “fixing” their
biochemistry is like clearing the snow for these taxis
Metabolic “Gridlock”

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. Innate
(non-specific)
Acquired (specific)
1st line
of defense

14. Innate Immunity:
Phagocytes (Macrophages) and
Natural Killer cells
Capture and kill germs –
Jailor or Executioner

15. Adaptive Immunity:
B cells produce
Immunoglobulins (Antibodies)
Antibodies
Antibodies

16.  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
Immunoglobulins

17. Adaptive Immunity:
T cells give orders to other cells
TH1 TH2

18. 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

19. All cell types work together in
a healthy immune system !

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-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.

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. Allergy
Autoimmunity
Deficiency
Inflammation
Th2 Innate and/or
Th1 Th2
Th1 and/or Th2 Th1 and/or Th2

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, 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.

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.
M.I.N.D.
Institute
Low IgG Low IgM
Low Normal IgA
Huge
variation
in IgE

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-α and too little regulatory IL-10.
 Measles virus demonstrable by PCR and other
methods.

42. 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)

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 Jan;57(1):67-81.

46. Immune system & Autism:
An 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.

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. 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
 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
12

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” aren’t 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; 78:99-117

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
 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?

68. Taking Probiotics
 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
 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) 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.

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 (< 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

74. Antioxidants –
Curcumin (Turmeric)
 Antioxidant and anti-inflammatory
properties of curcumin. Adv Exp Med Biol.
2007;595:105-25.
 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 -> 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/full/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-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

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 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

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, Asperger’s, or PDD-NOS is
in a “current or active state” [299.00]
 “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!