Autism and 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

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

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. Acquired (specific) Innate (non-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. Immunoglobulins • 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

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

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

29. Immunopathology in ASD • Dysregulationof immunityin 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 studyJournal 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. Low IgM Low IgG M.I.N.D. Institute Huge variation in IgE Low Normal IgA

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 • Abnormal (dysregulated) immune system, normal gut microbes • 2.Normal immune system, abnormal microbes +/- abnormal barrier • We conclude that IBD is characterizedby an abnormal mucosal immune response but that microbial factorsand 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) overgrowthalso 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