Академический Документы
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Factors in Autism
Aristo Vojdani, Ph.D., M.T.
Immunosciences Lab., Inc.
822 S Robertson Blvd, Ste 312
Los Angeles, California 90035
Tel: 310-657-1077
E-mail: drari@msn.com
Autism One
May 20-24, 2009
Chicago, Illinois
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Understanding The Puzzle of Complex
Diseases
♦ Understanding mechanisms
of action responsible for the
development of complex
diseases including
gastrointestinal,
cardiovascular and
autoimmune diseases.
♦ These diseases cannot be
ascribed to mutation in a
single gene; rather they
arise from the combined
action of many genes,
environmental factors and
risk-conferring behavior.
2
Autism’s Cause May Reside in Abnormalities at the Synapse
New genetic evidence is leading researchers to home in on the cleft
Separating neurons as the site where the disorder may originate.
Autism’s origin? Neuroligins and neurexins, proteins crucial for aligning and activat-
ing synapses, have now been implicated in autism, along with the Shank3 scaffolding
protein. An altered balance between excitatory synapses (left) and inhibitory (right)
could affect learning and memory during development. Science, 317:190-191, 20073
N Engl J Med 2008;358
Background
Autism spectrum disorder is a heritable developmental disorder in which
chromosomal abnormalities are thought to play a role.
Conclusions
We have identified a novel, recurrent microdeletion and a reciprocal
microduplication that carry substantial susceptibility to autism and appear to
account for approximately 1% of cases. We did not identify other regions
with similar aggregations of large de novo mutations.
4
nervous system 5
Gastrointestinal microflora studies
in late-onset autism
Finegold S.M. et al., Clin Infect Dis, 2002 Sep 1;35(Suppl 1):S6-S16
8
Science, 2002, 298:1424-1427
Isolated
lymphoid
follicles
11
11
Prenatal viral infection leads to pyramidal cell
atrophy and macrocephaly in adulthood:
implications for genesis of autism and
schizophrenia
Fatemi S. H., Earle J., Kamodia R., Kist D., Emamian E. S., Patterson, P.
H., Shi L., Sidewell R., Cell. Mol. Neurobiol., 2002, 22:25-33.
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Infectious
Agents Maternal
Exposure
to Infection
Abnormal
Brain
Development
Child
Child with
with
Schizophrenia
Autism
80
6
70
5
60
4 50
Normal 40.0
3 40
30
Normal 2.0
2
20
1
10
0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
20
IgG IgM 130
Patient #2 1- B. b. 9 - B. gar.
120
9 2- C2+C6 10 - Babe
3- LFA 11 - Bart
4 - OspA+OspC 12 - Ehr 110
8 5 - OspE 13 - Un Spir
6 - VMP 14 - MBP 100
7- B. afz. 15 - Nf
7 8 - B. s. s. 16 - BBB 90
80
6
70
5
60
4
50
Normal 40.0
3 40
30
Normal 2.0
2
20
1
10
0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
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Polyreactive myelin oligodendrocyte
glycoprotein antibodies: Implications for
systemic autoimmunity in progressive
experimental autoimmune encephalomyelitis
Peterson LK et al., J Neuroimmunol, 2007; 183:69-80
nervous system 18
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Immunogenicity of Metals by Interaction
with Amino Acids of Proteins
Haptens comprise organic compounds and metal ions, and bind to proteins
forming either covalent bonds (a) or coordination complexes (b).
a. Organic haptens forming covalent bonds bind to a single amino acid side-
chain; the covalent binding of trinitrophenyl (TNP) to lysine is shown.
b. Metal complexes consist of a central metal ion and a set of atoms, ions or
small molecules, regarded as ligands. These ligands are aligned in a character-
istic geometric form, e.g. a plane square or an octagon. The interactions
between a metal ion and ligands allow the electron-rich ligands to transfer part
of their electron density to the positively charged metal ion (coordination
bond) in order to increase complex stability; a square planar complex of nickel
with three histidines and one cysteine is shown.
c. Alternatively, certain reactive chemicals can irreversibly oxidize protein side-
chains, such as those of cysteine and methionine; a methionine sulfoxide is
shown.
Hg
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THE PROTOTYPIC Th2 AUTOIMMUNITY INDUCED BY MERCURY IS
DEPENDENT ON IFN-γ AND NOT Th1/Th2 IMBALANCE
Kono et al., Journal of Immunology 161: 234-240 (July 1998)
NO
AUTOIMMUNE AUTOIMMUNE
AUTOIMMUNE
DISEASE DISEASE
DISEASE
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Analysis of the Autoantibody Response to
Fibrillarin in Human Disease and Murine
Models of Autoimmunity
Takeuchi et al., The Journal of Immunology, 1995, 154:961-971.
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nervous system 26
27
The Humoral Response in the
Pathogenesis of Gluten Ataxia
Hadjivassiliou et al., Neurology 2002;58:1221-1226.
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Immune Response to Dietary Proteins, Gliadin and
Cerebellar Peptides in Children with Autism
Nutritional Neuroscience, 7(3):151-161, June 2004
40
PERCENT POSITIVE FOR GLIADIN AND
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CEREBELLAR ANTIBODIES
30
25
20
15
10
0
IgG IgM IgA
Percent positive sera from patients with Autism for IgG, IgM, and IgA
antibodies against gliadin and cerebellar peptides .
30
Percent Binding of Different Antibodies to Gliad
120
100
80
Peptide
60
40
20
0
Anti- Anti- Anti- Anti- Anti-Milk Anti- Anti- Anti-
Gliadin Crude Brain Cerebellar Proteins Egg Corn Soy
Peptide Gliadin MBP
100
80
Peptide
60
40
20
0
Anti- Anti- Anti- Anti- Anti-Milk Anti- Anti- Anti-
Cerebellar Brain Crude Gliadin Proteins Egg Corn Soy
MBP Gliadin Peptide
34
FUNCTION OF TISSUE ENZYMES AND
LYMPHOCYTE RECEPTORS
♦ CD 69 – is a lymphocyte activation marker involved in
apoptosis of autoreactive T-cells and hence autoimmunity
♦ Peptidases- Dipeptidylpeptidase (DPPIV) or CD 26
Aminopeptidase - N or CD 13
Aminopeptidase I (DPPI)
♦ Peptidases function as:
1. Cleaving Peptides
2. Receptors
3. Adhesion Molecules
4. Signal transduction molecules
5. Immune regulators
6. T-cell mediators of immune response
7. Inducers of cytokine production
8. Proenzymes in cytotoxic lymphocytes
35
Characterization of Human Serum Dipeptidyl
Peptidase IV (CD26) and Analysis of its
Autoantibodies in Patients with Rheumatoid
Arthritis and other Autoimmune Diseases
Cuchanovich et al., Clinical and Experimental Rheumatology
19:673, 2001.
36
Searching for a mechanism underlying autoimmunity in autism, we
postulated that gliadin peptides, heat shock protein (HSP-60) and
streptokinase (SK) bind to different peptidases. Binding results in
autoantibody production against gliadin peptides, HSP-60, SK and tissue
peptidases. We assessed this hypothesis in patients with autism and in
those with mixed connective tissue diseases. Concomitant with the
appearance of anti-gliadin and anti-HSP antibodies, children with autism and
patients with autoimmune disease developed anti-DPP I, anti-DPP IV and
anti-CD13 autoantibodies… Furthermore, addition of anti-SK, anti-HSP-60
and anti-gliadin to DPP IV+ peptides caused 18-20% enhancement of
antigen-antibody reaction. These results further support binding of SK,
gliadin and HSP to DPP IV. We propose that superantigens (e.g. SK, HSP-
60), dietary proteins (eg. gliadin peptides) in individuals with predisposing
HLA molecules bind to aminopeptidases and induce autoantibodies against
peptides and tissue antigens.
37
Percent Elevation of Antibodies Against DPP IV, DPPI,
CD13, Gliadin Peptidase and HSP-60 in
Controls and Patients with Autism and Autoimmune
Disease
% IgG Elevation in:
Antigens Children Adults Auto-
Autism
Control Control immune
DPP IV 10 54 14 64
DPP I 8 56 14 60
CD13 8 40 6 28
Gliadin
12 42 18 62
Peptide
HSP-60 16 36 22 52
38
Accumulation of peptides and
opening of the tight junctions 39
Conclusions:
♦ Autism is a disorder of the immune system and the nervous
system, induced by the combination of genes plus
environmental factors such as infections, toxic chemicals
and certain dietary proteins and peptides.
♦ Since the gut maintains an extensive and highly active
immune system, environmental factors can induce
dysregulation of the immune system and potentially
damage the tissue.
♦ In the healthy gut, Th1 and Th2 responses are carefully
regulated by regulatory T cells (CD4+CD25+) expressing IL-
10 and TGF-β.
♦ Depletion of IL-10- and TGF-β-producing regulatory T cells,
or homing of CD4+CD25RBHIGH T cells in the GI tissue of
children with autism, may be responsible for GI pathology
reported by different investigators in autism.
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Conclusions:
♦ Regulatory T cells and TGF-β production measured in the
blood of children with autism were found to be elevated in
one subgroup and low in the second subgroup.
♦ Immune function abnormalities, in particular, low natural
killer cell activity, low glutathione and abnormal cytokine
production, is part of the illness in autism, with a potential
for becoming a biological test for autism at birth.
♦ Abnormal levels of neurotransmitters such as serotonin,
dopamine, epinephrine, and norepinephrine are detected in
children with autism.
♦ A gluten- and casein-free diet, with omega-3 oil probiotics,
and high doses of vitamin-A can be extremely helpful
towards recovery for a subgroup of children with autism.
41