Immunology of Autism
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Aristo Vojdani, Ph.D., M.T. Immunosciences Lab., Inc. 822 S. Robertson Blvd., Ste. 312 Los Angeles, California 90035 Phone (310) 657-1077 Fax (310) 657-1053 E-mail: drari@msn.com Autism One May 20-24, 2009 Chicago, Illinois
Immunology of Autism
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
A model for the multifactorial nature of autoimmune disease. Sex hormones represent an important modulatory factor in the immune and autoimmune response. Sex hormones include the gonadal sex steroids as well as other hormones that indicate differences between men and women. Whitacre CC, Nature Immunol , 2:777-780, 2001
3
4
Infections, Toxic Chemicals and Dietary Peptides Binding to Lymphocyte Receptors and Tissue Enzymes are Major Instigators of Autoimmunity in Autism
Aristo Vojdani, Jon B. Pangborn, Elroy Vojdani, Edwin L. Cooper; International Journal of Immunopathology and Pharmacology, Vol. 16, 189-199 (2003)
“This study is the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with Autism.”
5
Fig. 2. Scattergram of serum titer of IgG, IgM and IgA antobodies against Gliadin peptides in healthy control subjects and autistic patients and CD69 in healthy control subjects and autistic patients expressed as optical density in ELISA test.
6
Fig. 3. Scattergram of serum titer of IgG, IgM and IgA antobodies against Streptokinase in healthy control subjects and autistic patients and CD69 in healthy control subjects and autistic patients expressed as optical density in ELISA test.
7
Aristo Vojdani, Ph.D., M.T. (310) 657-1077
8
“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.”
9
120
Gliadin
Percent Positive Gliadin or HSP 60 Peptide Antibodies
HSP 60
Gliadin
HSP 60
Gliadin
HSP 60
100
80
60
40
20
0
Elevated DPP IV Antibodies
Elevated DPPI Antibodies
Elevated CD 13 Antibodies
Percent Positive Sera From Patients with Autoimmune Disease for IgA , IgG , and IgM Antibodies against Gliadin and HSP 60 Peptides who are positive for DPP IV, DPPI, or CD 13 Antibodies.
10
100
Gliadin HSP 60 Gliadin HSP 60 Gliadin HSP 60
90
Percent Positive Gliadin or HSP 60 Peptide Antibodies
80 70 60 50 40 30 20 10 0
DPP IV Antibodies
DPPI Antibodies
CD 13 Antibodies
Percent Positive Sera From Patients with Autism for IgA , IgG , and IgM Antibodies against Gliadin and HSP 60 Peptides who are positive for DPP IV, DPPI, or CD 13 Antibodies. 11
12
13
Stem Cell
Primitive cell produced in the bone marrow and transformed into T cells in the thymus and B cells in the bone marrow. All blood cells (the entire WBC family, RBC’s, and platelets) are produced from stem cell transformation.
14
Macrophage
Housekeeper and frontline defender, this cell engulfs and digests debris that washes into the bloodstream. Encountering a foreign organism, it summons helper T cells to the scene.
15
16
17
18
19
20
T-Cell Newly formed in the thymus and ready for further specific instruction and development in the spleen and lymph nodes.
21
Mature T-Cell
Programmed with exquisite specificity, the mature T cell enters systemic circulation to “read” a specific antigen and orchestrate the body’s defenses against it.
22
Memory Cell
Generated from an initial infection, this defense cell may circulate in the blood or lymph for years, enabling the body to respond more quickly to subsequent infections.
23
24
Antibody
Engineered to target a specific invader, this Y-shaped protein molecule is rushed to the infection site, where it either neutralizes the enemy or tags it far attack by other cells or chemicals.
25
Interactions of cellular and humoral immunity as defense against invaders
26
27
60
% ABNORMAL NK, T AND B CELL FUNCTION
50
40
38 34 31
30
20 15 10
8
6 3
*
2
0 NK T-CELL FUNCTION B-CELL FUNCTION CYTOKINES AND CHILDREN % ABNORMAL LYMPHOCYTE FUNCTION AND CYTOKINE LEVELS IN CONTROLS WITH AUTISM
28
NK Cell Cytotoxic Activity
29
Neuroimmunolog y
Journal of Neuroimmunology 205 (2008) 148-154
journal of
Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15
A. Vojdani, et al.
Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p < 0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16+/CD56+ cells. When the NK “The induction of NK cell activity by IL-2, IL-15 and glutathione was more cytotoxic activity was expressed based on activity/100 CD16+/CD56+ cells, several patients who had displayed NK cell activity below a LU exhibited normal NK cell activity. Overall, after this correction that 45% of pronounced in 15 subgroup with very low NK cell activity. We concludefactor, 45%of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. a subgroup of children with autism suffers from low NK cell activity, and that low Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 intracellular levels of glutathione, IL-2 and IL-15 may be responsible.” and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible. 30
120
n = 113
n = 289 n = 189 n = 226 n = 129 n = 49 n = 21 n = 37 n = 36 n = 25
NK Cell Activity in Lytic Units
100 80 60 40
32.5
n = 26
20 0
0
18.8 13.8
22.2
23.3
22.4
24.4 16.8 20 16.8 9.6
C
0.5 1
2
1 3
4
1.5 5
6
2 7
8
2.5 9
10
Figure 1 Distribution of NK cell activity activity measured with autism from 10 with Figure 1 -– Distribution of NK cellmeasured in 1027 patientsin 1027 patientsdifferent clinics (1-10) in comparison to Controls (C). n = number of subjects in each group; box point autism from 10 different clinics (1-10) in comparison to Controls (C). shows mean value. n = number of subjects in each group; box point shows mean value.
31
100 90 80 70 60 50 40 30 20 10 0 Controls 1 2 3 4 5 6 7 8 9 10 Figure 2 - % NK cell activity below 15 lytic units in controls and patients with autism obtained from 10 different clinics
81% 70% 56% 50% 53% 46% 41% 56% 71% 64%
8%
Figure 2 – Percentage of NK cell activity below 15 lytic units in controls and patients with autism obtained from 10 different clinics.
32
33
70% 60%
6-12
% regulatory T cells
50% 40% 30% 20% 10% 0%
0-5 13-25
Classification of controls and children with autism based on % regulatory T cells (CD4+CD25+) in blood.
34
% with different levels of TGF-β
60%
50%
40%
30%
20%
10%
0% 10-30 ng/mL 31-60 ng/mL 61-100 ng/mL
Classification of controls and children with autism based on TGF-β production by PMBC.
35
Levels of cytokine production in controls and in children with autism.
36
37
38
80
50% Individuals w/ IL-17 greater than RR of 57 µg/mL 45% 40% 35% 30% 25% 20%
47.50%
70
60 Interleukin-17 Level (Pg/mL)
51+29
50
40
36+21
30
15%
15% 10% 5% 0%
20
10
0 Healthy Controls Children w/ Autism
Healthy Controls
Children w/ Autism
PBMCs from healthy controls and children with autism were stimulated with 10 µg/mL PHA and incubated for 48 hours at 37C. Aliquots of cell culture supernatant were removed and assayed for level of IL-17. The percentage of IL-17 elevation above the reference range is calculated.
39
40
Neuroimmunolog y
♦ We measured autoantibodies against nine different neuron-specific antigens and three crossreactive peptides in the sera of autistic subjects and healthy controls by means of enzymelinked immunosorbent assay (ELISA) testing. ♦ The antigens were myelin basic protein (MBP), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), α-B-crystallin (α-B-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), Streptococcal M protein (STM6P) and milk butyrophilin (BTN). ♦ Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. ♦ These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. ♦ These results suggest a mechanism by which bacterial infection and milk antigens may modulate autoimmune responses in autism.
journal of
“These results suggest a mechanism by which bacterial infection and milk antigens may modulate autoimmune responses in autism.”
41
42
43
Chapter 19, Neuropsychiatric Disorders and Infection, pp 171-186, S.H. Fatemi (ed.) Taylor & Francis Ltd., London, 2005
44
Immune Response to Dietary Proteins, Gliadin and Cerebellar Peptides in Children with Autism
Vojdani et al. Nutritional Neuroscience, 2004; vol. 7: 151-161 ♦ A significant percentage of autism patients showed elevations in antibodies agaisnt gliadin and cerebellar peptides simultaneously. ♦ The reaction of anti-cerebellar peptide to gliadin peptide was 22%. ♦ Binding of anti-myelin basic protein, anti-milk, anti-egg and anti-soy to gliadin was less than 10%.
♦ We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.
45
46
O.D. FOR ANTIBODY BINDING TO GLIADI CEREBELLAR PEPTIDE
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Rabbit Anti-Gliadin 8 A.A. Peptide Rabbit Anti-Cerebellar 8 A.A. Peptide
(EQVPLVQQ)
(EDVPLLED)
Reaction of rabbit anti-gliadin or anti-cerebellar 8 amino acid (A.A.) peptides with non-specific protein (HSA) non-specific peptide and specific peptides gliadin 18 A. A. and cerebellar 22 A.A. peptides measured by O.D. in 47 ELISA.
Science, 2002, 298:1424-1427
Activation-induced cytidine deaminase (AID) plays an essential role in class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Deficiency in AID results in the development of hyperplasia of isolated lymphoid follicles (ILF) associated with a 100-fold expansion of anaerobic flora in the small intestine. Reduction of bacterial flora by antibiotic treatment of AID-/- mice abolished ILF hyperplasia as well as the germinal center enlargement seen in secondary lymphoid tissues.
48
49
50
Abnormal somatic hypermutation and class switch recombination is responsible for production of pathogenic multi-reactive antibodies.
% elevation of antibodied at 2 SD above the mean
70 60 50 40 30 20 10 0
Gliadin Peptide DPPIV HSP-60 SK VIP MBP NFP Tubulin STM6P Milk BTN
54 42 36 45 32
58 48 50 51
56
12
16 10 8 3
20 15 7 10 10
Detection of Antibodies in Patients with Autism
51
52
MUCOSAL IMMUNE ABNORMALITIES
IMBALANCED GUT FLORA
INTESTINAL BARRIER DYSFUNCTION
SYSTEMIC INFLAMMATION
NEUROINFLAMMATION
NEUROINVASION
NEURODEGENERATION
From mucosal immune abnormalities to neuroinflammation and neurodegeneration.
53 53
54
Aristo Vojdani, Ph.D., M.T. Immunosciences Lab., Inc. 822 S. Robertson Blvd., Ste. 312 Los Angeles, California 90035 Phone (310) 657-1077 Fax (310) 657-1053 E-mail: drari@msn.com Autism One May 20-24, 2009 Chicago, Illinois
Immunology of Autism
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
A model for the multifactorial nature of autoimmune disease. Sex hormones represent an important modulatory factor in the immune and autoimmune response. Sex hormones include the gonadal sex steroids as well as other hormones that indicate differences between men and women. Whitacre CC, Nature Immunol , 2:777-780, 2001
3
4
Infections, Toxic Chemicals and Dietary Peptides Binding to Lymphocyte Receptors and Tissue Enzymes are Major Instigators of Autoimmunity in Autism
Aristo Vojdani, Jon B. Pangborn, Elroy Vojdani, Edwin L. Cooper; International Journal of Immunopathology and Pharmacology, Vol. 16, 189-199 (2003)
“This study is the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with Autism.”
5
Fig. 2. Scattergram of serum titer of IgG, IgM and IgA antobodies against Gliadin peptides in healthy control subjects and autistic patients and CD69 in healthy control subjects and autistic patients expressed as optical density in ELISA test.
6
Fig. 3. Scattergram of serum titer of IgG, IgM and IgA antobodies against Streptokinase in healthy control subjects and autistic patients and CD69 in healthy control subjects and autistic patients expressed as optical density in ELISA test.
7
Aristo Vojdani, Ph.D., M.T. (310) 657-1077
8
“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.”
9
120
Gliadin
Percent Positive Gliadin or HSP 60 Peptide Antibodies
HSP 60
Gliadin
HSP 60
Gliadin
HSP 60
100
80
60
40
20
0
Elevated DPP IV Antibodies
Elevated DPPI Antibodies
Elevated CD 13 Antibodies
Percent Positive Sera From Patients with Autoimmune Disease for IgA , IgG , and IgM Antibodies against Gliadin and HSP 60 Peptides who are positive for DPP IV, DPPI, or CD 13 Antibodies.
10
100
Gliadin HSP 60 Gliadin HSP 60 Gliadin HSP 60
90
Percent Positive Gliadin or HSP 60 Peptide Antibodies
80 70 60 50 40 30 20 10 0
DPP IV Antibodies
DPPI Antibodies
CD 13 Antibodies
Percent Positive Sera From Patients with Autism for IgA , IgG , and IgM Antibodies against Gliadin and HSP 60 Peptides who are positive for DPP IV, DPPI, or CD 13 Antibodies. 11
12
13
Stem Cell
Primitive cell produced in the bone marrow and transformed into T cells in the thymus and B cells in the bone marrow. All blood cells (the entire WBC family, RBC’s, and platelets) are produced from stem cell transformation.
14
Macrophage
Housekeeper and frontline defender, this cell engulfs and digests debris that washes into the bloodstream. Encountering a foreign organism, it summons helper T cells to the scene.
15
16
17
18
19
20
T-Cell Newly formed in the thymus and ready for further specific instruction and development in the spleen and lymph nodes.
21
Mature T-Cell
Programmed with exquisite specificity, the mature T cell enters systemic circulation to “read” a specific antigen and orchestrate the body’s defenses against it.
22
Memory Cell
Generated from an initial infection, this defense cell may circulate in the blood or lymph for years, enabling the body to respond more quickly to subsequent infections.
23
24
Antibody
Engineered to target a specific invader, this Y-shaped protein molecule is rushed to the infection site, where it either neutralizes the enemy or tags it far attack by other cells or chemicals.
25
Interactions of cellular and humoral immunity as defense against invaders
26
27
60
% ABNORMAL NK, T AND B CELL FUNCTION
50
40
38 34 31
30
20 15 10
8
6 3
*
2
0 NK T-CELL FUNCTION B-CELL FUNCTION CYTOKINES AND CHILDREN % ABNORMAL LYMPHOCYTE FUNCTION AND CYTOKINE LEVELS IN CONTROLS WITH AUTISM
28
NK Cell Cytotoxic Activity
29
Neuroimmunolog y
Journal of Neuroimmunology 205 (2008) 148-154
journal of
Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15
A. Vojdani, et al.
Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (p < 0.001). Low NK cell activity in both groups did not correlate with percentage and absolute number of CD16+/CD56+ cells. When the NK “The induction of NK cell activity by IL-2, IL-15 and glutathione was more cytotoxic activity was expressed based on activity/100 CD16+/CD56+ cells, several patients who had displayed NK cell activity below a LU exhibited normal NK cell activity. Overall, after this correction that 45% of pronounced in 15 subgroup with very low NK cell activity. We concludefactor, 45%of the children with autism still exhibited low NK cell activity, correlating with the intracellular level of glutathione. a subgroup of children with autism suffers from low NK cell activity, and that low Finally, we cultured lymphocytes of patients with low or high NK cell activity/cell with or without glutathione, IL-2 intracellular levels of glutathione, IL-2 and IL-15 may be responsible.” and IL-15. The induction of NK cell activity by IL-2, IL-15 and glutathione was more pronounced in a subgroup with very low NK cell activity. We conclude that 45% of a subgroup of children with autism suffers from low NK cell activity, and that low intracellular levels of glutathione, IL-2 and IL-15 may be responsible. 30
120
n = 113
n = 289 n = 189 n = 226 n = 129 n = 49 n = 21 n = 37 n = 36 n = 25
NK Cell Activity in Lytic Units
100 80 60 40
32.5
n = 26
20 0
0
18.8 13.8
22.2
23.3
22.4
24.4 16.8 20 16.8 9.6
C
0.5 1
2
1 3
4
1.5 5
6
2 7
8
2.5 9
10
Figure 1 Distribution of NK cell activity activity measured with autism from 10 with Figure 1 -– Distribution of NK cellmeasured in 1027 patientsin 1027 patientsdifferent clinics (1-10) in comparison to Controls (C). n = number of subjects in each group; box point autism from 10 different clinics (1-10) in comparison to Controls (C). shows mean value. n = number of subjects in each group; box point shows mean value.
31
100 90 80 70 60 50 40 30 20 10 0 Controls 1 2 3 4 5 6 7 8 9 10 Figure 2 - % NK cell activity below 15 lytic units in controls and patients with autism obtained from 10 different clinics
81% 70% 56% 50% 53% 46% 41% 56% 71% 64%
8%
Figure 2 – Percentage of NK cell activity below 15 lytic units in controls and patients with autism obtained from 10 different clinics.
32
33
70% 60%
6-12
% regulatory T cells
50% 40% 30% 20% 10% 0%
0-5 13-25
Classification of controls and children with autism based on % regulatory T cells (CD4+CD25+) in blood.
34
% with different levels of TGF-β
60%
50%
40%
30%
20%
10%
0% 10-30 ng/mL 31-60 ng/mL 61-100 ng/mL
Classification of controls and children with autism based on TGF-β production by PMBC.
35
Levels of cytokine production in controls and in children with autism.
36
37
38
80
50% Individuals w/ IL-17 greater than RR of 57 µg/mL 45% 40% 35% 30% 25% 20%
47.50%
70
60 Interleukin-17 Level (Pg/mL)
51+29
50
40
36+21
30
15%
15% 10% 5% 0%
20
10
0 Healthy Controls Children w/ Autism
Healthy Controls
Children w/ Autism
PBMCs from healthy controls and children with autism were stimulated with 10 µg/mL PHA and incubated for 48 hours at 37C. Aliquots of cell culture supernatant were removed and assayed for level of IL-17. The percentage of IL-17 elevation above the reference range is calculated.
39
40
Neuroimmunolog y
♦ We measured autoantibodies against nine different neuron-specific antigens and three crossreactive peptides in the sera of autistic subjects and healthy controls by means of enzymelinked immunosorbent assay (ELISA) testing. ♦ The antigens were myelin basic protein (MBP), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), α-B-crystallin (α-B-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), Streptococcal M protein (STM6P) and milk butyrophilin (BTN). ♦ Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. ♦ These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. ♦ These results suggest a mechanism by which bacterial infection and milk antigens may modulate autoimmune responses in autism.
journal of
“These results suggest a mechanism by which bacterial infection and milk antigens may modulate autoimmune responses in autism.”
41
42
43
Chapter 19, Neuropsychiatric Disorders and Infection, pp 171-186, S.H. Fatemi (ed.) Taylor & Francis Ltd., London, 2005
44
Immune Response to Dietary Proteins, Gliadin and Cerebellar Peptides in Children with Autism
Vojdani et al. Nutritional Neuroscience, 2004; vol. 7: 151-161 ♦ A significant percentage of autism patients showed elevations in antibodies agaisnt gliadin and cerebellar peptides simultaneously. ♦ The reaction of anti-cerebellar peptide to gliadin peptide was 22%. ♦ Binding of anti-myelin basic protein, anti-milk, anti-egg and anti-soy to gliadin was less than 10%.
♦ We conclude that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.
45
46
O.D. FOR ANTIBODY BINDING TO GLIADI CEREBELLAR PEPTIDE
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Rabbit Anti-Gliadin 8 A.A. Peptide Rabbit Anti-Cerebellar 8 A.A. Peptide
(EQVPLVQQ)
(EDVPLLED)
Reaction of rabbit anti-gliadin or anti-cerebellar 8 amino acid (A.A.) peptides with non-specific protein (HSA) non-specific peptide and specific peptides gliadin 18 A. A. and cerebellar 22 A.A. peptides measured by O.D. in 47 ELISA.
Science, 2002, 298:1424-1427
Activation-induced cytidine deaminase (AID) plays an essential role in class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes. Deficiency in AID results in the development of hyperplasia of isolated lymphoid follicles (ILF) associated with a 100-fold expansion of anaerobic flora in the small intestine. Reduction of bacterial flora by antibiotic treatment of AID-/- mice abolished ILF hyperplasia as well as the germinal center enlargement seen in secondary lymphoid tissues.
48
49
50
Abnormal somatic hypermutation and class switch recombination is responsible for production of pathogenic multi-reactive antibodies.
% elevation of antibodied at 2 SD above the mean
70 60 50 40 30 20 10 0
Gliadin Peptide DPPIV HSP-60 SK VIP MBP NFP Tubulin STM6P Milk BTN
54 42 36 45 32
58 48 50 51
56
12
16 10 8 3
20 15 7 10 10
Detection of Antibodies in Patients with Autism
51
52
MUCOSAL IMMUNE ABNORMALITIES
IMBALANCED GUT FLORA
INTESTINAL BARRIER DYSFUNCTION
SYSTEMIC INFLAMMATION
NEUROINFLAMMATION
NEUROINVASION
NEURODEGENERATION
From mucosal immune abnormalities to neuroinflammation and neurodegeneration.
53 53
54
