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The Wet Surfaces, Immunity And Autism
- 1. 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
- 2. • The aetiologyof 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
- 4. Genetic Determinism • Yourgenome, 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)
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- 8. • Autism mayin 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
- 9. About to bePublished 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
- 10. Traditional View ofImmune 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.
- 11. Changing Models • Immunologyis no longer good Vs bad – • it is the homeostasis of the superorganism! • Complexity is required to apply therapy well
- 12. Immune Concepts Evil- Microbiota Non-Self Evil- Altered Self Pathogens Good – Self Tolerance/ ignorance Good- NormalSelf Mutualists Continuum Model Ancestral Dualistic Model Modern Dualistic Model
- 13. • The continuummodel 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.
- 14. Danger Good – Regulation/Tolerance Mutualists/Normalself Evil- Inflammation Pathogens/A ltered Self Strangers Pathological Inflammation Friends Physiological Inflammation Health of Host Health of Local tissue Timing Genes Nutri- genomics Nutrition Modern Dualism Continuum Model
- 15. Mutualist Pathogen Regulation/Tolerance Inflammation Developmentof Adaptive Immunity (AgS) Control by Innate Immunity (MAMPs) Lymphoid Tissues Lymphocyte Sub Sets Lymphocyte Memory Microbes Immune Responses IL-2 IL-10 TGFB RA IL-23 IL-12 IL-1 TNFα
- 16. • Cytokines • Inflammation •Old Friends • Mucosal Tolerance Hygiene Hypothesis • Kyneurenines • Enzymes • Cytokines • Stressors • IDO Gastro- Neuro- degeneration hypothesis ASD
- 17. Wet Surfaces -MassiveArea 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’
- 18. “the mucosa isdirectly 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.
- 19. Confusion • “People tendto get the immune system the wrong way around; • We’re so focussed on the immune system responding to things, that we forget that 99.99% of the time, its job is NOT to respond to things. • There’s you, your breakfast and your gut, for a start. That’s a lot of stuff not to respond to”. Handley C. Should auld acquaintance be forgot… EMBO Reports Vol 5, No 12, 2004
- 20. Mucosal Immune SystemFor Host Protection The mucosal immune system consists of an integrated network of: Macrophages and dendritic cells, T lymphocytes and their cytokines play a key role in orchestrating a specific mucosal immune response. An uncontrolled mucosal immune system may lead to immunologic diseases such as allergy and hypersensitivity.
- 21. Humans Are Superorganisms Cells 1Trillion 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?
- 22. Our relationship extends Beyondthe 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/nri2515 The gut microbiota shapes intestinal immune responses during health and disease “We respond to our microbiota from birth to death” Swidinki,A
- 23. 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.
- 24. HOW DOES THIS RELATETO AUTISM? www.alexnail.com
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- 26. IMMUNE SYSTEM CLASSIFICATION INNATE IMMUNITY ADAPTIVE IMMUNITY TLR’S –NO MEMORY DEVELOPS MEMORY GUT
- 27. 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.
- 28. Cytokines - Autism2010 • 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 Behav Immun. 2010 Aug 10 View Abstract
- 29. The Innate ImmuneResponse In Autism www.alexnail.com
- 30. • Dysregulated innateimmune 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
- 31. Regulatory Cytokine Transforming GrowthFactor Beta-1 • Decreased serum levels of transforming growth factor-beta1 in patients with autism. K Okada, et al. Prog Neuropsychopharmacol Biol Psychiatry, 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.
- 32. Autism & TheGut www.alexnail.com
- 33. Comparisons of theprevalence of gastrointestinal symptoms between autistic children and their healthy siblings
- 34. • Reasons toconsider 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
- 35. Regulation Inflammation Symbionts CommensalsPathobionts Immunological Equilibrium Regulation Inflammation Immunological Disequilibrium Dysbiosis/Pathogens The gut microbiota shapes intestinal immune responses during health and disease June L. Round & Sarkis K. Mazmanian. Nature Reviews Immunology 9, 313-323 (May 2009)
- 36. N C Occludin Cgn PILT bCtnn ZONAB Epithelial Tight Junctions F-Actin F-Actin Cell Adhesion Cell Adhesion Cell Migration Cytoskeletal Organization Vesicular Trafficking CellCycle Progression Intracellular Membrane Transport and Exocytosis Vesicular Trafficking Cytoskeletal Organization Exocyst Complex Assembly of v-SNARE and t-SNARE Complexes Cell Proliferation Cell Adhesion G1/S Phase Transition mRNA Cleavage and Processing Cell Adhesion and Apoptosis Epithelial Cell Proliferation and Differentiation Non-CiliatedEpithelial Cell CiliatedEpithelial Cell RhoA PathwayActin Based Motility Actin Nucleation and Branching ZONAB CDK4 AP-1 CEBP Paracellular Signaling RhoA SAFB ZO2 Ras Stx4 mLGL Myosin Crb1,3 Afadin SMURF1 PTEN HSF1 CSTF aCtnn Rab GTPases PIP3 PIP2 Cell Adhesion Ga12 Ga12 ARP 2/3 PAR-3 Rac1 TGFbR C C JAMs JAMs TIAM1 PAR-3 CDC42 MAGI 2,3 GSK3ILK JNK Sympk TNFaR TNFa p130 CAS Integrins MAGI1 N C Claudins N C Occludin N C Claudins PKA VAP33 Akt Plasmamembrane 2009 ProteinLounge.com C
- 37. Leaky Gut andAutism • 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, Militerni R, 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
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- 39. • The productionof immunoglobulin A (IgA) in mammals exceeds all other isotypes, and it is mostly exported across mucous membranes. 60mg/kg daily • It is now clear that SIgA can function in high- affinity modes for neutralisation of toxins and pathogenic microbes, and as a low-affinity system to contain the dense commensal microbiota within the intestinal lumen. • A J Macpherson, K D McCoy, F-E Johansen and P Brandtzaeg. The immune geography of IgA induction and function. Mucosal Immunology (2008) 1, 11– 22. doi:10.1038/mi.2007.6 Link
- 40. SIgA • When depletedthe mucosal barrier management of antigen is compromised and microbial translocation (LPS) can occur, a consequence of which: • Increased pro inflammatory cytokines • Increased IL-17
- 41. Conditions That CanChange The Level Of 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
- 42. SIgA Levels InClinic 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 26♂2♀ ave age 7 Ug/ml
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- 44. Serotonin Vs Autism •Studies demonstrating impaired serotonin synthesis in 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, Chugani HT. 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
- 45. Serotonergic Neurons • aregenerated early in brain development and establish extensive cortical and subcortical connections. • 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
- 46. 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
- 47. Serotonin Vs Indolamine2,3 • 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
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- 49. TDO IDO Tryptophan IFN γ TNFα Kyneurenine 3-Hydroxykynurenine Quinolinic acid Nicotinamide NMDAReceptor 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
- 50. Quinolinate/Kyneurenate • An imbalancein 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 kynurenic acids. Pharmacol Rev. 1993 Sep;45(3):309-79. Link
- 51. Quin leads acutelyto 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)
- 52. 5. Quin inducesiNOS (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
- 53. • Proinflammatory cytokinesinduce 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.
- 54. Quinolinate acts asa most potent endogenous excitotoxin to neurons.
- 55. Cytokine regulation oftryptophan 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 IDO expression in cells of hypothalamic and pituitary origin. The ability of IL-10 to suppress IFN-gamma induced IDO expression implies that - • IL-10 has a putative neuroprotective role in the HPA axis. It can act at two levels, systemically by inhibiting sickness behaviour-related Th1 cytokine synthesis and more centrally by inhibiting 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 neuroendocrine regulation.
- 56. Bacteria – Friendand Foe & Autism www.alexnail.com
- 57. Bacterial Species InThe 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.
- 58. Yet … • About200 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
- 59. Treg - Immunommodulation Lowratio of Treg to effector Tcells Normal ratio of Treg to 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
- 60. Probiotics Old friends (innocuous environmental microorganisms, helminths) Treg T Bystander suppression Oldfriends IL-10 TGF-β Retinoic Acid TregT IL-10 TGF-β Retinoic Acid Specific suppression Self/gut contents allergens T cells Immature DC Regulatory DC (DCreg) sIgA sIgA Reduction of peripheral/CNS inflammation 60
- 61. Probiotics May EaseAnxiety: Pilot study • “Two months of supplementation with the bacterial strain from a sachet was associated with a decrease in anxiety symptoms.”
- 62. 62 For instance aspecific part of the microbiota has been shown to cooperate With the development of regulatory instead of the inflammatory IL-17 producing T helper cells in the small intestine. Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR Specific 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
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- 64. Retinoic Acid • Isautism 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, Donna K. Rhoden, and Denece S. Turner JPEN 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
- 65. 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, retinoicacid 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
- 66. HISTORICAL DIETARY CHANGE ↓ INTAKE •PREBIOTICS • MICRONUTRIENTS ↓HARMLESS • HELMINTHS • ‘OLD FRIENDS’ ↓ DEVELOPMENT DCreg AND Treg ↑ SUSCEPTABILTY TO LOCAL & SYSTEMIC PARA-INFLAMMATION ↑ GUT PERMEABILITY ALTERED SIgA PRODUCTION ↑ 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
- 67. HISTORICAL DIETARY CHANGE ↓ INTAKE •PREBIOTICS • MICRONUTRIENTS ↓HARMLESS • HELMINTHS • OLD FRIENDS ↓ DEVELOPMENT DCreg AND Treg ↑ SUSCEPTABILTY TO PARA-INFLAMMATION ↑ GUT PERMEABILITY ALTERED SIgA PRODUCTION ↑ 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 DISEASE THYROIDITIS RA MS IBD’s CANCER + + + ↓Zn,Se + NEUROACTIVE MOLECULES ↑ IDO ↑ TRYCATS ↑ QUINOLINATE ↑ KYNEURENATE ↓ GABA ↓ MELATONIN SEROTONIN P38 MAPK -+ - - - - ASD?
- 68. NEURODEGENERATION ALZHEIMERS SENILITY AUTISM ROS/NS IL-1β, TNFα CORTISOL INDUCEDATROPHY DEPRESSION Imbalanced Cytokine Induction and Binding Is ‘Regressive Autism’ an Immune Mediated Disorder
- 69. What Can YouDo? www.alexnail.com
- 70. 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)
- 71. Clinical Strategies • Assesspatient 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.
- 72. Supermarket dairy shelvesare 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
- 73. Protocol • Saccharomyces Boulardii150-600mg • 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
- 74. Current Understood Usesof PB’s 21 3 4
- 75. • The gutmaintains 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
- 76. Conclusions • Regulatory Tcells 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.
- 77. • 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
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