The Wet Surfaces, Immunity And Autism

The Wet Surfaces, The

Immune System & The

Brain.

Why And How they

May Affect Behaviour

And Function In

People With Autism

Michael Ash

BSc (Hons) DO ND F.DipION

• The aetiology of ASD is largely unknown, but

genetic, environmental, immunological, and

neurological factors are thought to play a role in

the development of ASD.

• Recently, focused on the connections between

the immune system and the nervous system.

• These neuroimmune interactions begin early

during embryogenesis and persist throughout an

individual’s lifetime, with successful

neurodevelopment contingent upon a normal

balanced immune response

Ashwood P, Wills S, Van de Water JThe immune response in autism: a new frontier for autism research.

. J Leukoc Biol. 2006 Jul;80(1):1-15. Epub 2006 May 12. Review. View Paper

Genetic Determinism

• Your genome, or any part of it, is not you

• The concept that our DNA sequence our

genome- does not equal or predict our

destiny has been extremely difficult for some

geneticists to accept.

• We don’t even have a good idea how many

genes there are, let alone how these genes

work with each other and the environment to

orchestrate human development.

• LL McCabe & ERB McCabe. DNA Promise and Peril. University of California Press; 1 edition (1 Mar 2008)

Oct 2010

• Autism may in fact be a systemic disorder with

connections to abnormal immune responses.• M Careaga, J Van de Water, and P AshwoodImmune dysfunction in autism: a pathway to treatment. Neurotherapeutics,

July 1, 2010; 7(3): 283-92. View Abstract

• Immunological factors have provided more

support for a probable immunological process

or for processes that may play a role in the

acquisition of an autistic condition.• MG Chez and N Guido-Estrada. Immune therapy in autism: historical experience and future directions with

immunomodulatory therapy. Neurotherapeutics, July 1, 2010; 7(3): 293-301. View Abstract

• ....significantly shifted cytokine profiles in ASD.

These findings suggest that ongoing

inflammatory responses may be linked to

disturbances in behaviour.• P Ashwood, P Krakowiak, I Hertz-Picciotto, R Hansen, I Pessah, and J Van de WaterElevated plasma cytokines in autism

spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome.

Brain Behav Immun, August 9, 2010; View Abstract

About to be Published data ---

• ....an altered activation profile for T cells in

ASD. Overall these data indicate

significantly altered adaptive cellular

immune function in children with ASD that

may reflect dysfunctional immune

activation, along with evidence that these

perturbations may be linked to disturbances

in behaviour and developmental functioning

Traditional View of Immune System

• Seen as a system of organs, molecules and

tissues that defend us from disease by

eliminating bad guys.

• This promotes the dichotomy model

good vs bad

• There have been changes to the model of

self/nonself and they are relevant to autism.

Changing Models

• Immunology is no

longer good Vs bad –

• it is the homeostasis

of the superorganism!

• Complexity is

required to apply

therapy well

Immune

Concepts

Evil-

Microbiota

Non-Self

Evil-

Altered Self

Pathogens

Good –

Self

Tolerance/

ignorance

Good-

Normal Self

Mutualists

Continuum

Model

Ancestral

Dualistic Model

Modern

Dualistic Model

• The continuum model states that the perceived duality of mutualistic and pathogenic microbes, normal and altered self, and regulatory or inflammatory immunity, represents extremes of a continuous reality.

• Microbes can express different levels of mutualistic or pathogenic properties and these levels can vary during interaction with the host.

• Similarly, the state of self and of immune responses can navigate between well-described extremes, and the most likely states are combination of these extremes.

Danger

Good – Regulation/Tolerance

Mutualists/Normal self

Evil- Inflammation

Pathogens/Altered Self

Strangers

Pathological Inflammation

Friends

Physiological Inflammation

Health of HostHealth ofLocal tissueTiming

GenesNutri-

genomicsNutrition

Modern Dualism

Continuum Model

Mutualist Pathogen

Regulation/Tolerance Inflammation

Development of Adaptive Immunity

(AgS) Control by Innate Immunity (MAMPs)

Lymphoid TissuesLymphocyte Sub SetsLymphocyte Memory

Microbes

Immune ResponsesIL-2IL-10TGFBRA

IL-23IL-12IL-1TNFα

• Cytokines

• Inflammation

• Old Friends

• Mucosal Tolerance

Hygiene

Hypothesis

• Kyneurenines

• Enzymes

• Cytokines

• Stressors

• IDO

Gastro-Neuro-

degeneration hypothesis

ASD

Wet Surfaces -Massive Area of Contact

– GI. Mucosal surface area 300m2

• Respiratory mucosa 100m2

• Skin 1.5 m2

• Thickness 0.03mm (1/2 width of 60gsm)

‘Tightly regulated mucosal

Immunity is essential to

maintain health’

“the mucosa is directly exposed to the external environment and taxed with

antigenic loads consisting of commensal bacteria, dietary antigens,and viruses at far greater quantities on a daily basis than the systemic immune

system sees in a lifetime”.Mayer L. Mucosal immunity. Pediatrics. 2003 Jun;111(6 Pt 3):1595-600.

Confusion• “People tend to get the immune system the

wrong way around;

• We’re so focussed on the immune systemresponding to things, that we forget that99.99% of the time, its job is NOT to respondto things.

• There’s you, your breakfast and your gut, for astart. That’s a lot of stuff not to respond to”.

Handley C. Should auld acquaintance be forgot… EMBO Reports Vol 5, No 12, 2004

Mucosal Immune System For Host Protection

The mucosal immune system consists of an integrated network of:

Macrophages and dendritic cells, T lymphocytes and their cytokines playa key role in orchestrating a specific mucosal immune response.An uncontrolled mucosal immune system may lead to immunologicdiseases such as allergy and hypersensitivity.

Humans Are Superorganisms

Cells

1 Trillion human cells

10 Trillion bacterial in and on 10 x ratio

DNA

Humans have approx 25,000 genes and bacteria have an estimated 100 times more.

Who has more genes – grape, chicken or human?

Our relationship extends

Beyond the shared

Environmental benefits –

and extends to:

•Nutrient harvesting

•Gene expression

•Mood regulation

•Illness prevention

•Illness resolution

•Weight management

•Immune control

This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.

Nature Reviews Immunology 9, 313-323 (May 2009) | doi:10.1038/nri2515The gut microbiota shapes intestinal immune responses during health and disease

“We respond to our microbiota from birth to death”Swidinki,A

Evidence Is Accumulating

• to suggest that gut microbes (microbiota) may be involved in neural development and function, both peripherally in the enteric nervous system and centrally in the brain.

HOW DOES THIS RELATE TO AUTISM?

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NKc

IMMUNE SYSTEM

CLASSIFICATION

INNATE

IMMUNITY

ADAPTIVE

IMMUNITY

TLR’S – NO

MEMORY

DEVELOPS

MEMORY

GUT

Immune- Cytokines - Autism

• Immunological findings in autism.HH Cohly and A Panja Int Rev Neurobiol, January 1, 2005; 71: 317-Link

• Activation of the inflammatory response system in autism. J Croonenberghs, M Maes et.al Neuropsychobiology, January 1, 2002; 45(1): 1-6. Link

• Elevated cytokine levels in children with autism spectrum disorder.CA Molloy, et al. J Neuroimmunol, March 1, 2006; 172(1-2): 198-205. Link

• It is hypothesised that increased production of proinflammatory cytokines could play a role in the pathophysiology of autism.

Cytokines - Autism 2010

• In conclusion, using larger number of participants than previous studies, we report significantly shifted cytokine profiles in ASD. These findings suggest that ongoing inflammatory responses may be linked to disturbances in behaviour

• Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain BehavImmun. 2010 Aug 10 View Abstract

The Innate Immune Response In Autism

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• Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention.H Jyonouchi, et al. Neuropsychobiology, January 1, 2005; 51(2): 77-85.

• Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study. H Jyonouchi, et al. J Neuroinflammation, January 1, 2008; 5: 52.

• Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. H Jyonouchi, et al J Neuroimmunol, November 1, 2001; 120(1-2): 170-9.

• Intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH* or GI(-) ASD children, suggesting a possible link between GI and behavioural symptoms mediated by innate immune abnormalities.

• TNFα, IL-1, IL-6,

• IL-10, TGF-β• *Non Allergic Food Hypersensitivity

Regulatory Cytokine Transforming Growth Factor Beta-1

• Decreased serum levels of transforming growth factor-beta1 in patients with autism. K Okada, et al. Prog Neuropsychopharmacol BiolPsychiatry, Jan 2007; 31(1): 187-90.

•

Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioural outcomes.P Ashwood, et al. J Neuroimmunol, Nov 2008; 204(1-2): 149-53.

• These findings suggest that decreased levels of TGF-beta1 may be implicated in the pathophysiology of autism.

• Such that lower TGF beta 1 levels were associated with lower adaptive behaviours and worse behavioural symptoms.

Autism & The Gut

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Comparisons of the prevalence of gastrointestinal symptoms between autistic children and

their healthy siblings

• Reasons to consider that microorganisms may be involved in late‐onset autism include

• onset of the disease often follows antimicrobial therapy,

• gastrointestinal symptoms are common at onset and often persist,

• antimicrobials (e.g., oral vancomycin) may lead to a clear‐cut response and relapse may occur when the vancomycin is discontinued, and

• some patients have responded to several courses of vancomycin and relapsed each time it was discontinued.

Clinical Infectious Diseases 2002; 35(Suppl 1):S6–16 Link

Regulation Inflammation

Symbionts Commensals Pathobionts

Immunological Equilibrium

RegulationInflammation

Immunological Disequilibrium Dysbiosis/Pathogens

The gut microbiota shapes intestinal immune responses during health and diseaseJune L. Round & Sarkis K. Mazmanian. Nature Reviews Immunology 9, 313-323 (May 2009)

N

COccludin

Cgn

PILT

bCtnn

ZONAB

Epithelial Tight Junctions

F-Actin

F-Actin

CellAdhesion

CellAdhesion

CellMigration

CytoskeletalOrganization

VesicularTrafficking

Cell Cycle Progression

Intracellular Membrane Transport and Exocytosis

VesicularTrafficking

CytoskeletalOrganization Exocyst

Complex

Assembly of v-SNARE and

t-SNARE Complexes

CellProliferation

CellAdhesion

G1/S PhaseTransition

mRNA Cleavage and Processing

Cell Adhesionand Apoptosis

Epithelial Cell Proliferation and

Differentiation

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PTEN

HSF1

CSTF

aCtnn

RabGTPases

PIP3

PIP2

CellAdhesion

Ga12

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ARP2/3

PAR-3 Rac1

TGFbR

CC JAMs JAMs

TIAM1

PAR-3

CDC42

MAGI2,3

GSK3ILK

JNKSympk

TNFa

R

TNFa

p130CAS

Integrins

MAGI1

N

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Claudins

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COccludin

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PKA

VAP33

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Plasmamembrane

2009

ProteinLounge.com

C

Leaky Gut and Autism

• CONCLUSIONS: The results obtained support the leaky gut hypothesis and indicate that measuring IP could help to identify a subgroup of patients with autism who could benefit from a gluten-free diet. The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism.

• de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, MiliterniR, Bravaccio C.Alterations of the Intestinal Barrier in Patients With Autism Spectrum Disorders and in Their First-degree Relatives. J Pediatr Gastroenterol Nutr. 2010 Jul 28 View Abstract

SIgA Vs Autism

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• The production of immunoglobulin A (IgA) inmammals exceeds all other isotypes, and it ismostly exported across mucous membranes.60mg/kg daily

• It is now clear that SIgA can function in high-affinity modes for neutralisation of toxins andpathogenic microbes, and as a low-affinitysystem to contain the dense commensalmicrobiota within the intestinal lumen.

• A J Macpherson, K D McCoy, F-E Johansen and P Brandtzaeg. The immunegeography of IgA induction and function. Mucosal Immunology (2008) 1, 11–22. doi:10.1038/mi.2007.6 Link

SIgA

• When depleted the mucosal barrier management of antigen is compromised and microbial translocation (LPS) can occur, a consequence of which:

• Increased pro inflammatory cytokines

• Increased IL-17

Conditions That Can Change The LevelOf Secretory IgA In Oral Fluid

• Increased SIgA Level• Acute stress• Some medications• Orophanrygeal carcinoma• Chronic oral infection• Chronic GI infection• Heavy smoking• Alcoholism• Periodontitis• Dental plaque accumulation• Intestinal barrier

dysfunction• Multiple Myeloma

• Decreased SIgA Level• Chronic stress (frustration)• Some medications• Adrenal insufficiencies• Bacterial colonisation on molar

surfaces• Recurrent tonsillitis• Adenoid hyperplasia• Cutaneous candidiasis• Asthmatic with recurrent

respiratory tract infection• Intestinal barrier dysfunction• Nutritional deficiencies• Recurrent herpes infection• Coeliac, Crohn’s, Ulcerative

colitis

SIgA Levels In Clinic Tests M.Ash 2000

SIgA 10

100

200

300

400

500

600

700

1 2 4 6 8 10 12 14 16 18 20 22 24 26 28

SIgA 1

28 Children with Autism 262 ave age 7

Ug/ml

Serotonin & Autism

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Serotonin Vs Autism

• Studies demonstrating impaired serotonin synthesisin the brains of autistic individuals

• Chugani DC, Muzik O, Behen M, Rothermel R, Janisse JJ, Lee J, Chugani HT. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol.1999;45:287-295. FULL TEXT

• Chugani DC, Muzik O, Rothermel R, Behen M, Chakraborty P, Mangner T, da Silva EA, ChuganiHT. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Ann Neurol. 1997;42:666-669. FULL TEXT

• -a worsening of repetitive behaviours after tryptophan depletion…

• McDougle CJ, Naylor ST, Goodman WK, Volkmar FR, Cohen DJ, Price LH. Acute tryptophan depletion in autistic disorder: a controlled case study. Biol Psychiatry. 1993;33:547-550. FULL TEXT

Serotonergic Neurons • are generated early in brain development and

establish extensive cortical and subcorticalconnections.

• Serotonin regulates growth cone motility, synaptogenesis, synaptic plasticity, and the development and activity of multiple neuronal subtypes.

• Sodhi MS, Sanders-Bush E. Serotonin and brain development. Int Rev Neurobiol. 2004;59:111-174. Link

SSRI Study Response

• 129 children – 2-8 yrs of age

• 17% excellent, 52% good, 31% fair to poor• DeLong GR, Ritch CR, Burch SA: Fluoxetine response in children with

autistic spectrum disorders: correlation with familial major affective disorder and intellectual achievement. Devel Med Child Neurol 2002; 44(10):652–659 Link

1/2

Serotonin Vs Indolamine 2,3 • It is concluded that the (TRYCATS) kynurenine,

kynurenic acid, and xanthurenic acid have anti-inflammatory effects trough a reduction of IFNgamma,

• Whereas quinolinic acid has pro-inflammatory effects in particular via significant decreases in IL-10.

• M Maes, I Mihaylova, MD Ruyter, M Kubera, and E Bosmans The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression - and other conditions characterized by tryptophan depletion induced by inflammation. Neuro Endocrinol Lett, December 1, 2007; 28(6): 826-31 LINK

Indolamine (IDO)TRYCATS &

Autism

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TDO

IDO

Tryptophan

IFN γ

TNFαKyneurenine

3-Hydroxykynurenine

Quinolinic acid

Nicotinamide

NMDA Receptor

Kyneurenic acid

5 - Hydroxytryptophan

Serotonin

P38MAPk

+

+

Stressor

Immune Induction Of Neurotoxins

BBB

Liver 95%

Brain 5%>

IDO – Indolamine 2,3 dioxygenase

TDO – Tryptophan 2,3 dioxygenase

N-methyl-D-aspartate

Quinolinate/Kyneurenate

• An imbalance in the production or removal of either of these substances would be expected to have profound implications for brain function, especially if that imbalance were present chronically.

• Identified in Organic Acid test

• Stone TW. Neuropharmacology of quinolinic and kynurenicacids. Pharmacol Rev. 1993 Sep;45(3):309-79. Link

Quin leads acutely to neuronal death or chronically to neuronal function by at least 6 mechanisms.

1. Activation of the NMDA receptor in pathophysiological concentrations

2. Increase glutamate release by neurons, inhibition of glutamate uptake by astrocytes, decrease in glutamine synthetase activity.

3. Lipid peroxidation of the membrane

4. Quin can potentiate its own toxicity and that of other excitotoxins (NMDA and glutamate) in the context of energy depletion (mitochondrial dysfunction)

5. Quin induces iNOS (astrocyte) and nNOS(neuron) leading to over production of NO (= Oxidative stress)

6. Destabilisation of the cellular cytoskeleton Nady Braidy, Ross Grant, Seray Adams, Bruce J. Brew and Gilles J. Guillemin Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons Neurotoxicity Research Volume 16, Number 1, 77-86, DOI: 10.1007/s12640-009-9051-z View Abstract

• Proinflammatory cytokines induce IDO under stress, promote the KYN pathway, deprive the 5-HT pathway of TRP, and reduce 5-HT synthesis. The resultant decrease in 5-HT production may relate to the monoamine hypothesis of major depression.

• The hippocampal atrophy that appears in chronic depression may be associated with imbalances in KP neurotoxic/neuroprotective metabolites.

Quinolinate acts as a most

potent endogenous excitotoxin

to neurons.

Cytokine regulation of tryptophan metabolism in the hypothalamic-pituitary-adrenal (HPA) axis: implications for protective and toxic

consequences in neuroendocrine regulation.

• Our results indicate that cytokines such as IFN-gamma and IL-10 are able to regulate IDOexpression in cells of hypothalamic and pituitaryorigin. The ability of IL-10 to suppress IFN-gammainduced IDO expression implies that -

• IL-10 has a putative neuroprotective role in theHPA axis. It can act at two levels, systemically byinhibiting sickness behaviour-related Th1cytokine synthesis and more centrally byinhibiting the kynurenine pathway.

• Tu H, Rady PL, Juelich T, Smith EM, Tyring SK, Hughes TK.. Cytokine regulation of tryptophan metabolism in the hypothalamic-pituitary-adrenal (HPA) axis: implications for protective and toxic consequences in neuroendocrine regulation. Cell Mol Neurobiol. 2005 Jun;25(3-4):673-80 Link

Cytokine regulation of tryptophan metabolism in the hypothalamic-

pituitary-adrenal (HPA) axis:implications for protective and toxic

consequences in neuroendocrineregulation.

Bacteria – Friend and Foe &Autism

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Bacterial Species In The Genomic Era

• RECENT FINDINGS:

• Upwards of 40,000 bacterial species are estimated to comprise the collective gastrointestinal microbiome, most of which have not been characterised by culture.

• Frank DN, Pace NR. Gastrointestinal microbiology enters the metagenomics era. Curr Opin Gastroenterol. 2008 Jan;24(1):4-10.

Yet …

• About 200 different bacterial species are known to cause human disease.

• Mascie-Taylor, C. G. & Karim, E. The burden of chronic disease. Science 302, 1921−1922 (2003). Article

Treg - Immunommodulation

Low ratio of Treg to effector Tcells

Normal ratio of Tregto effector T cells

Effective levels of sIgA, IL-10 & TGF-β to control adverse inflammation

ASD Anxiety and Allergies

IL-10, TGF-β, sIgA

Th1 Th2

(IFN-γ, IL-1, TNF-α) (IL-4, IL-5, IL-13)

Th17

Retinoic Acid

59

ProbioticsOld friends (innocuous

environmental microorganisms,

helminths)

Treg T

Bystandersuppression

Old friends

IL-10TGF-βRetinoic Acid

TregTIL-10TGF-β Retinoic Acid

Specificsuppression

Self/gut contents allergens

T cells

Immature DC

Regulatory DC(DCreg)

sIgA sIgA

Reduction of peripheral/CNS inflammation 60

Probiotics May Ease Anxiety: Pilot study

• “Two months of supplementation with the bacterial strain from a sachet was associated with a decrease in anxiety symptoms.”

62

For instance a specific part of the microbiota has been shown to cooperateWith the development of regulatory instead of the inflammatory IL-17 producingT helper cells in the small intestine.

Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DRSpecific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine.Cell Host Microbe. 2008 Oct 16;4(4):337-49. View Full Paper

63

ToleranceVit ATH-17TregTGF-β& Autism

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Retinoic Acid

• Is autism a G-alpha protein defect reversible with natural vitamin A?MN Megson Med Hypotheses, June 1, 2000; 54(6): 979-83.

• Symptomatic Vitamin A and D Deficiencies in an Eight-Year-Old With Autism Joseph H. Clark, DonnaK. Rhoden, and Denece S. TurnerJPEN J Parenter Enteral Nutr, May 1993; 17: 284 – 286

• Serum values of cytokines in children with vitamin A deficiency disorders JY Leal, HV Castejon, T Romero, P Ortega, G Gomez, D Amaya, and J Estevez Invest Clin, September 1, 2004; 45(3): 243-56

• Lack of Vitamin A -Reduced IL-10 and reduced Treg and increased TH-17 IL-17 production

TGFβ

• TH17

• IL-17

• IL-6

• IL-21

• Retinoic Acid

• IL-10

The Role of Th17 in Neuroimmune Disorders: A Target for CAM Therapy.

Part III Aristo Vojdani, Jama Lambertand,Gottfried Kellermann eCAM Advance Access published

online on July 21, 2009 eCAM, doi:10.1093/ecam/nep064

•In each case, retinoic acid greatly reduced RORt expression•which resulted in a measurable reduction of Th17 mucosal T cells.

•IL-17-producing CD4(+) T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain

HISTORICAL DIETARY CHANGE

↓ INTAKE• PREBIOTICS• MICRONUTRIENTS

↓HARMLESS• HELMINTHS• ‘OLD FRIENDS’

↓ DEVELOPMENTDCreg AND Treg

↑ SUSCEPTABILTY TO LOCAL & SYSTEMIC PARA-INFLAMMATION

↑ GUT PERMEABILITY

ALTERED SIgAPRODUCTION

↑ LOCAL AND SYSTEMIC PRO-INFLAMMATORY CYTOKINES

↑ MEDICALISATION• ANTIBIOTICS

GUT ORIGINATING CYTOKINE DRIVEN ILNNESS AND DYSFUNCTION

↓ LOCAL AND SYSTEMIC ANTI-INFLAMMATORY CYTOKINES

IL-1, IL-6, TNFα, IFNγ, NFκB. IL-17

IL-10, IL-2, TGFβ

HISTORICAL DIETARY CHANGE

↓ INTAKE• PREBIOTICS• MICRONUTRIENTS

↓HARMLESS• HELMINTHS• OLD FRIENDS

↓ DEVELOPMENTDCreg AND Treg

↑ SUSCEPTABILTY TO PARA-INFLAMMATION

↑ GUT PERMEABILITY

ALTERED SIgAPRODUCTION

↑ LOCAL AND SYSTEMIC PRO-INFLAMMATORY CYTOKINES

↑ MEDICALISATION• ANTIBIOTICS

GUT ORIGINATING CYTOKINE DRIVEN ILLNESS AND DYSFUNCTION

↓ LOCAL AND SYSTEMIC ANTI-INFLAMMATORY CYTOKINES

IL-1, IL-6, TNFα, IFNγ, NFκB

IL-10, IL-2, TGFβ

↓ ANTI-INFLAMMATORY CHOLINERGIC REFLEX• DIETARY FATS• LIFESTYLE• ENZYMES (CCK/BILE)

RISK FACTORS↑ IN UTERO STRESS↓ MUCOSAL MATURITY↑ INTERNAL STRESSES↑ EXTERNAL STRESSES

OXIDATIVE & NITROSITATIVE DAMAGE ↑ H2O2, O2↑ NO2, NO, ONOO↑ DNA DAMAGE↑ ROS/NS

↑ Ω-3, 6, 9 DEMAND ↓ NEUROGENESIS↓ NCAM (neural cell adhesion mols)

↓ BDNF↓ FGF(Fibroblast growth factor)

AUTO-IMMUNE DISEASETHYROIDITISRAMSIBD’s

CANCER

+

+

+

↓Zn,Se

+

NEUROACTIVE MOLECULES↑ IDO↑ TRYCATS↑ QUINOLINATE↑ KYNEURENATE↓ GABA↓ MELATONIN

SEROTONIN

P38 MAPK

-+-

-

-

-ASD?

NEURODEGENERATIONALZHEIMERSSENILITYAUTISMROS/NSIL-1β, TNFαCORTISOL INDUCED ATROPHYDEPRESSION

Imbalanced Cytokine Induction and Binding

Is ‘Regressive Autism’ an Immune Mediated Disorder

What Can You Do?

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Antioxidants Inhibit IDO

• Thomas SR J Immunol. 2001 May 15;166(10):6332-40.

• Antioxidants inhibit indoleamine 2,3-dioxygenase in IFN-gamma-activated human macrophages: post translational regulation by pyrrolidine dithiocarbamate.

• Glutathione (NAC)

Clinical Strategies• Assess patient as potential GIT candidate

• Improve daily nutrition

• Include probiotics (Human Strain)

• Build Beneficial Bio Film

• Remove non beneficial Bio Films

• Include PUFA’s for brain function and improving Bacterial/Immunological cross talk &Treg

• Pro-biotics do not appear to have any contraindications with medications involved in mood disorders.

Supermarket dairy shelves are filled with yogurt products containing live cultures of 'probiotic' bacteria — species that live in the human gut and are proposed to deliver health benefits when eaten at high levels. Three probiotic species seem to alter gene expression in the gut lining of volunteers consuming the cultures. The effect was similar to that of drugs for conditions including inflammation and high blood pressure. Michiel Kleerebezem at NIZO Food Research in Ede, the Netherlands, and his co-workers analysed the gene-expression profiles of tissue taken from the small intestinal inner lining of seven healthy volunteers who had eaten a placebo and three probiotic cultures — Lactobacillus acidophilus, L. casei and L. rhamnosus — in a random order. The altered gene-expression profiles resembled those associated with the regulation of immune responses, cell growth, metabolism and even wound repair

Protocol• Saccharomyces Boulardii 150-600mg

• Lactobacillus GG 30-609 CFU

• Lactobacillus Caseii 20-609 CFU

• Lactobacillus Paracaseii 20-609 CFU

• Lactobacillus, plantarum, rhamnosus, salivarius 20-609 CFU

• Bifido-Bifidus 20-609 CFU

• DHA > EPA (CLO) concentrate 2-4gms (GPR120)

• Vit A 5000 -12000 iu & Vit D 6-12000iu

Current Understood Uses of PB’s

21

3 4

• The gut maintains an extensive and highly active immune system, environmental factors can induce dysregulation of the mucosal immune system and potentially damage tissue locally and systemically.

• In the healthy gut, Th1,Th2,Th17 responses are carefully managed 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.

Conclusions

Conclusions• Regulatory T cells and TGF-β production measured

in the blood of children with autism are inconsistent. T cell subtypes are different TH1> Adversity. TH2 < ASD symptoms

• Immune function abnormalities, in particular, low natural killer cell activity, low glutathione and abnormal cytokine production, is part of the illness in autism.

• Abnormal levels of neurotransmitters such as serotonin, Indolamine (Quin/Kyn), dopamine, epinephrine, and norepinephrine are detected in children with autism.

• A gluten- and casein-free diet or a low antigen diet, with clean omega-3 and omega 6 oils, strain specific probiotics, and moderate to high doses of vitamin-A - can be extremely helpful towards mucosal immune recovery for a ‘subgroup’ of children with autism.

• A low risk to reward strategy, and can be observed to have effect in weeks

vol

The EndThank You

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