Re: ExtraDAN: Jane El-Dahr, talk 1 of 2 (long)

[Guest guest]

,

You are awesome! Thank you so much for all this info...

In GFCFKids@y..., kjorn@t... wrote:

> [Dr. El-Dahr had one presentation for the parent session (this one)

> and one for the general session. My laptop was recharging and so my

> notes by hand were slow…and I got a bit lost halfway through. But

her

> slides contained a lot of the information and it is included here.

> The numbers are the slide numbers so you will know when a new slide

> was up. There is some good stuff on allergies vs intolerances and

how

> to handle them. Kd.]

>

> 1. DAN Practicum 2001: Immunologic Issues in Autism

> Jane El-Dahr, MD

> Head, Section of Pediatric Allergy/Immunology/Rheumatology

> Tulane Medical Center, New Orleans, LA

>

> 2. Immune mechanisms – She showed a diagram illustrating the

> relationship of antibodies and antigens and interferons. [sorry but

I

> couldn't follow it and she was going fast – it looked like a

football

> play with all the arrows going everywhere]

>

> 3. The interactions involve the following systems:

> -Immune

> -Endocrine

> -Neurologic

> -Gut

>

> 4. Neuroendocrine Interactions – another diagrams and more arrows

>

> 5. The Immune System

> This is the body's defense system, guarding against foreign

invaders.

> She said she will use the military model as an analogy.

>

> 6. Innate and Acquired Immunity

> [another diagram – I think I can re-create this one]

>

> Innate immunity

> _________________|_____________

> | | |

> Physical barriers Cells Chemical barriers

> | | |

> Skin, mucous [ PMN's ] pH, lipids, enzymes,

etc.

> membranes [ monocytes ]

> |------------ [ Macrophages, ] -------------|

> | [ eosinophilis, NK cells ] |

> Cytokines| / \ |

Cytokines

> | Antibodies Cytokines |

> | / \ |

> |----------B cells T Cells--------|

> |__________________|

> |

> Acquired Immunity

>

> 7. Innate (no memory required)

> - nonspecific and primitive: weapons (swords, guns, grenades).

> - Reacts the same way every time – does not get smarter with each

> skirmish.

> - Wite blood cells of many types. Act the same against a splinter

or

> bacteria to destroy the " invader "

> - Inflammation in autism may originate

>

> 8. Innate (no memory required)

> - Physical and chemical barriers: like armor or shield

> --skin

> --mucous membranes

> --high pH

> --cough reflex

>

> 9 Complement (innate)

> - Proteins which complement the other parts of the immune system.

> - Complicated interactive mechanism needed to efficiently clear

> infections or immune complexes

> - Problems would predispose to recurrent infections or autoimmune

> disease

> - Found to be defective in some children with autism by Warren

>

> 10. Antigen Presenting Cells

> -Scout for invaders; capture and hold foreigners until the

commanders

> or troups arrive; jailors of POW camps

> - Sometimes kills germ without waiting

> - Types: macrophage, microglia – brain, follicular dendritic cells –

> lymph nodes (cells in small intestine where Dr. Wakefiled has found

> measles)

>

> 11. Adaptive – Acquired (memory)

> - Highly specific for individual pathogens.

> - Has memory of previous encounters and initiates a stronger attack

> if another skirmish occurs

> - Discriminates between " self " and " non-self " so does not engage in

> friendly fire

> - Lymphocytes are the commanders; their products are crucial to

this

> process

>

> 12. B Lymphocytes

> - B cells: in charge of making different types of immunoglobulins

or

> antibodies – small specific proteins that bind to invaders, marking

> them for death.

> - Immunoglobulins/Antibodies (also known as humoral immunity) are

the

> troops and come in 4 types:

>

> 13. Immunoglobulin types

> - IgA: Admiral; the navy, cruising mucosal (wet) surfaces as first

> line of defese. In tears, saliva, respiratory secretions, GI tract.

> (Low in a large subset of children with autism)

> - Low IgA predisposes someone to autoimmune diseases and GI

> infections (rotavirus, giardia, etc.)

>

> 14. Immunoglobulin – IgA

> - IgA deficiency: <10; low: 10-normal range

> - By age 5, about half of low values normalize in typical children.

> - IgA1 in bloodstream, fairly constant.

> - IgA2 in GI secretions, variable, not easy to measure accurately.

> High fecal levels probably consistent with abnormal GI flora.

>

> 15. Immunoglobulin – IgM

> - IgM: Marines; small but rapidly deployed force who will hold

things

> at bay until the main troops arrive.

> - Generally normal to high in children with autism.

>

> 16. Immunoglobulin – IgG

> - IgG: General; the army – large force, takes longer to muster but

> once there, remains a long time to ensure control; if called for a

> second encounter, much bigger response. Composed of 4 subclasses.

> (IgG and IgG subclasses may be high or low in autism.)

>

> 17. Treatment: Low IgG

> - IVIG 400 mg/kg q 4 weeks as replacement dose.

> - Dr. Sudhir Gupta found improvement in autistic symptoms in some

> children. (Gupta Set all, Dysregulated immune system in children

with

> autism: beneficial effects of intravenous immune globulin on

autistic

> characteristics. J Autism Dev Disor 1996; 26:439-452) Continue for

6-

> 18 months.

> - DBPC study by Dr. Gupta, results not yet published

>

> 18. Immunoglobulin – IgE

> - IgE: too Eager; designed to kill parasites but causes allergy or

> hypersensitivity; over-reacts to innocuous agents – rogue warriors.

> (Often high in autistic children)

> - Children with autism seem to have TH2 predominance with tendency

to

> have elevated levels of IgE.

>

> 19. Allergy – IgE

> - IgE allergy usually manifests as eczema, hives, rhinitis,

> conjunctivitis, or asthma; sometimes as vomiting and diarrhea.

> - Total IgE <20, unlikely to find specific allergies; >100, very

> likely to find; 20-100, search if symptomatic.

>

> 20. IgE – Indoor Allergens

> - If IgE is elevated or if having symptoms, send RAST IgE for

> avoidable things: dust mites, cat, dog

> - Dust mite avoidance: zip-up covers for pillows, mattress, and box

> spring on bed(s). Pillow covers at Kmart, Wal-Mart; vinyl zip

covers

> with washable mattress pad OK for bed.

> - Animal allergies: Pet out of house > out of bedroom, HEPA filter

> for bedroom, use denaturant on carpets. [she said it is best to

keep

> the pet out of the house, but if that is not always possible,

please

> at least keep the pet out of the person's bedroom]

>

> 21. IgE – Outdoor allergens

> - If IgE is high or if the child has significant seasonal symptoms,

> send " local " IgE inhalant panel – available from all major labs

> - If not local panel not available, ask for 2-3 trees, 2-3 grasses,

> ragweed mix, alternaria, cladosporium, and aspergillus in addition

to

> the indoor allergens (mites, cat, dog)

>

> 22. IgE- Antihistamines

> - Antihistamines are worth trying and may have efficacy in

decreasing

> core autistic symptoms. (Niaprazine in the treatment of autistic

> disorder. Rossi PG, Posar A, Parmeggiani A, Pipitone E, D'Agata M,

J

> Child Neurol 1999;14:8 547-50). Try less-sedating/non-sedating ones

> first:

> - Claritin (loratidine) syrup: Does not cross Blood/Brain Barrier,

> does not cause sedation

> - Zyrtec (cetirizine) syrup: Is somewhat sedating (does cross BBB)

so

> give at bedtime.

>

> 23. IgE – Food

> - If child has atopic dermatitis/eczema, primary foods to measure

IgE

> RAST against are milk, wheat, egg white, soy, peanut, shrimp, fish

> (trout and codfish).

> - Peanut/nut and shellfish/fish IgE allergies are rarely outgrown,

> egg/soy are if avoided for more than one year

> - Gluten/casein intolerance (lack of normal digestion causing

opioids

> to accumulate or autoimmune reaction) is NOT IgE mediated.

>

> 24. IgE – Food

> -Positive IgE to foods indicates that the child is allergic but

does

> not always mean that there will be symptoms when the food is

> consumed – eliminate for at least 10-14 days, then challenge for 3

> consecutive days.

> - Parents are to watch for worsening of symptoms when the food is

> reintroduced, not improvements when the foods in avoided

>

> 25. Gluten and Casein tests

> - No problem-free test is currently available for gluten/casein

> opioids. IgE of IgG Abs do not address this aspect of food

intolerance

> - If possible, check for celiac disease – predisposes to GI

cancers –

> BEFORE avoiding gluten: Celiac disease is diagnosed with IgA Abs.

> Must know if child is IgA deficient to interpret; IgA deficiency

> increases risk. Very small chance of this being present.

>

> 26. Allergy/Intolerance – IgG

> -If gut is permeable so food leaks into the bloodstream, IgG to

foods

> will be made since they are foreign proteins.

> - Everyone has IgG Abs to a few foods; autistic children have them

to

> lots of foods, indicative of increased intestinal permeability and

a

> TH2 shift in the immune system.

> - If the food is avoided, the levels will drop or disappear. Half-

> life of IgG is about 24 days.

>

> 27. IgG Food RAST

> - Pinpoint suspect foods for elimination and challenge – if gut

> heals, likely food will be tolerated later. Don't assume food must

be

> avoided forever.

> - Probably best to wait until on gf/cf diet to get clearer picture.

> Once the inflammation from those foods has calmed down, gut may be

> less leaky and other foods less of a problem.

>

> 28. IgG Food RAST

> - Remember foods can cause problems without antibodies being

> produced. Consider elimination/challenge with corn and soy.

> - Individual food IgG tests available from all major laboratories;

> children who only eat a few things don't need to be tested against

> 100 foods.

>

> 29. T Lymphocytes

> - T cells: CD4 (helpers) commanders

> --TH1 – viral infections, fungal infections

> --TH2 – Immunoglobulins, allergy

>

> 30. T Lymphocytes

> - T cells: CD8 - Cytotoxic T cells, kill viruses and fungi with

other

> cells: CIA

> CD16/56 – Natural killer cells, kill cells infected

with

> virus: RAMBO (often low in activity/numbers in autism)

>

> 31. Cytokines: cellular messager

> - Th1 (viral, fungal, infection): IFN-gamma, IL-2, TNF. Helps T

> cells. Activates cytotoxic T cells, NK cells, macrophages –

CELLULAR

> IMMUNITY

> - Th2 (immunoglobuin, allergy): IL-4, IL-5, IL-10, IL-13. Helps B

> cells. Directs antibody production – HUMORAL.

>

> 32. Th1 and Th2 Balance

> - Need both to work in balance; there should be feedback between

them

> to maintain this. Autistic children are often shifted towards Th2

> (allergy) and away from Th1 (viral/fungal killing). This leaves

them

> predisposed to viral and candidal infections and autoimmunity.

>

> 33. Th1 and Th2 – diagram on these two

>

> 34. Inflammation

> - Repair mechanism in response to tissue damage (protective) or

> damage from allergy (destructive); acute or chronic.

> - Chemical weapons – kill the target, but the surrounding area gets

> hit also.

> - Phagocytes (jailors) release prostaglandins, kinins,

leukotrienes;

> cause leakage from blood vessels, coagulation; neutrophils brought

in

> to clean up.

>

> 35. Inflammatory Cytokines

> - Dr. H. Jyonouchi, Univer. Of Minnesota, studied children with

> regressive autism and found extrememly increased levels of the

> inflammatory cytokine TNF-alpha.

> - Other cytokines were highly variable but many differences from

> control children were demonstrated.

> - Research tools only at this point.

>

> 36. Treatment – Inflammation

> - Nonsteroidal anti-inflammatories: Ibuprofen, Naproxen, COX-2

> inhibitors (Vioxx, Celebrex)

> - Leukotriene blockers: Montelukast (Singulair), Zafirlukast

> (Accolate).

> - Steroids: Prednisone.

> - Specific cytokine blockers: anti-TNF, others being developed

>

> 37. MHC or HLA (self-recognition)

> - Inherited markers of self; on outside of many cells so

> recognize " self " as OK.

> - Military insignia – branch of armed service, division, battalion,

> company; mane tags at a reunion.

> - Certain MHC types over represented in autism – related to

> autoimmunity?

>

> 38. Apoptosis

> - Programmed cell death; cellular suicide – kamakazis

> - Cells die without inflammation.

> - Cell surface market called Fas or CD95. needed for cell to

undergo

> this process.

> - TNF-alpha or cytotoxic T cells give " suicide signal " to the

> targeted cells.

>

> 39. Immunopathology

> - Immune deficiency/dysfunction: defective or ineffective response.

> - Hypersensitivity: overactive response, out of proportion to

> potential damage.

> - Autoimmunity: Inappropriate reaction towards self.

> - Dysregulation in autistic children leads to all three problems.

>

> 40. Vaccine Titers

> - Check IgG antibodies to rubeola (measles), mumps, and rubella so

> that a vaccine waiver can be written certifying adequate protection

> which is life-long once present.

> - DO NOT BOOST THESE CHILDREN WITH MMR!!!

>

> 41. Vaccine Titers – High

> - Vaccine titers are standardized for " protection " ONLY; how high

is

> too high is essentially unknown. Normal post-vaccination titers are

> usually many many times above the protective level listed.

> - Check IgG to tetanus, diptheria, hepatitis B surface antibody, H.

> flu, polio if evaluation immune function. Pertussis IgG antibodies

> not standardized; protective levels unknown.

>

> 42. Autoimmunity

> - Loss of ability to tell self from non-self.

> -Thought to be genetically susceptible individual plus

environmental

> trigger.

> - Molecular mimicry – foreign antigen so similar to " self " that

body

> gets confused.

> - Cell breaks open, spilling contents OR substance bind to

something

> in or on the cell; in either case, body doesn't think it has seen

> this before and reacts as though it is completely foreign and must

be

> destroyed.

>

> 43. Molecular mimicry

> [slide showing sequence similarities between microbial proteins and

> human host proteins – very technical, I didn't follow it, but shows

> there are similarities]

>

> 44. Autoimmunity

> - Genetic predisposition/MHC marker important.

> - Can be caused by T cells losing tolerance with cytokine

> dysregulation or by B cells making auto-antibodies.

> - Can be localized to a single organ (anti-brain Abs, anti-thyroid

> Abs) or systemic with multiple different types of auto-antibodies.

>

> 45. Autoimmunity and Autism

> - Family histories of autoimmune disease, expecially in mother

> (rheumatoid arthritis, lupus, IDDM)

> - ANAs, IDDM, anti-thyroid antibodies sometimes present in children

> with autism – rarely looked for.

>

> 46. Autoimmunity and Autism

> - Many kinds of anti-brain antibodies found: against MBP and

against

> NAFP and GFAP

> [some journal references here]

>

> 47. Autoimmunity and Autism

> - Many kinds of anti-brain antibodies found: against temporal lobe

> (IgG and IgM) and against serotonin receptors

> [two journal references here]

>

> 48. Autoantibodies

> - Available through Specialty Labs

> , www.specialtylabs.com:

> Anti-Myelin Basic Protein (MBP)

> Antuoantibodies (#1056),

> Anti-neurolfilament autoantibodies (#1052).

>

> -V.K. Singh at Utah State does anti-MBP and anti-NAFP antibodies:

> singhvk@c...;. Also will measure anti-serotonin Abs

> and anti-measles Abs. Research only so not covered by insurance.

>

> 49. Autoimmunity and Autism

> - Simon Murch MD: IgG antoantibodies in the small intestine with

> crypt cell proliferation; colon with CD8 T cell infiltration

> [reference here]

> -MHC types predisposing to autoimmunity over represented but

genetics

> complicated [reference here]

>

> 50. Immunity/Autoimmunity: ASD

> Tendency towards:

> - Increased Th2

> - High IgE

> - Low IgA

> - IgE and IgG to foods

> - Leaky, permeable gut

>

> 51. Immunity/Autoimmunity: ASD

> -Th1 low with impaired ability to control viruses and yeast

> -Decreased NK (natural killer) cell activity

> -Autoantibodies with production of multiple kinds of anti-brain

> antibodies (and others?)

> -Altered CD95-mediated apoptosis?

>

> 52. Immunity/Autoimmunity: ASD

> - Inactivated DPP IV, causing opioids (?)

> -Zinc deficiency

> -Genetic predisposition

> -Responds to IVIG

> -Immune Dysregulation and Autoimmunity are hallmarks

>

> 53. Immunity/Autoimmunity: Hg

> Mercury – Immune dysregulation and Autoimmunity are hallmarks;

> - Th2 predominance with high IgE

> - Alters immune response to foods; IgE and IgG Abs made

> - Increases gut permeability, damages intestinal mucosa

>

> 54. Immunity/Autoimmunity: Hg

> - Th1 low with impaired ability to control viruses and yeast

> - Decreases NK cell activity

> -Induces autoantibodies with production of multiple kinds of anti-

> brain antibodies and others [reference here]

> -alters CD95-mediated apoptosis

>

> 55. Immunity/Autoimmunity: Hg

> -May inactivate DPP IV, causing opioids

> - causes zinc deficiency

> -depends on complex genetics

> -Responds to IVIG [reference here]

>

> 56. Mercury effects on CNS

> - Impairs motor planning

> -Decreases facial recognition

> -Blurred vision, constricted visual fields

> -Causes insomnia, irritability, tantrums, excitability, social

> withdrawal, anxiety, difficulty verbalizing, altered taste, sensory

> disturbances or mouth

>

> 57. Mercury effects on CNS

> - Slows reaction time (physical and mental)

> -Impairs short-tem memory

> -Causes difficulty with concentration

> -Alters EEG, especially temporal lobes

> -depletes intracellular glutathione

> -modifies muscarinic cholinergic receptors

>

> 58. Mercury effects on CNS

> -Disrupts neuronal migration

> -Interferes with microtubule formation, mimicking a mitochondrial

> disorder

> -Affects hippocampus, cerebellum, other

> -symptoms of neurotoxicity delayed –Most toxic to infants and males

> (doesn't this all sound familiar???)

>

> 59. Treatment – Autoimmunity

> -Oral tolerance for anti-MBP: Sphingolin one capsule in the am on

> empty stomach Correct dosage not established. Mad cow risk:

> Ecological Formulas (1-).

> -Oral steroids – daily or pulse dose weekly. Many side effects,

> although pulse dosing decreases them.

>

> 60. Treatment – Autoimmunity

> -High (Immunomodulatory/autoimmune) dose IVIG: Bradstreeet/El-Dahr,

> presented at the International Symposium on Autism, Arnhem,

> Netherlands, 12/99 and Irvine, CA 6/00: 1-1.5 gm/kg (max 2) every 4-

6

> wks effective in the majority of children with anti-MBP Abs in

> improving at least one DSMIV category. Used for severe children

> otherwise unresponsive with (+) brain Abs, immune dysfunction,

> seizures. Stop if no significant improvement after 3 treatments.

> - Dr. Gupta currently using 800 mg/kg.

>

> 61. Treatment – GI issues

> -For low IgA, chronic diarrhea or constipation, consider

probiotics.

> Make sure casein free.

> Kirkman's acidophilus/mixed probiotics certified casein free (1-800-

> 245-8282, www.kirkmanlabs.com)

> Culturelle aka Lactobacillus GG best studied in infectious or post-

> antibiotic diarrhea and food allergy (1- for local

> availability, or 1- Vitamin Research) [www.vrp.com]

>

> 62. Treatment – GI issues

> Colustrum – Kirkman's is the only one known to be as casein free as

> possible – others contain casein despite claims. [none are

completely

> casein free – companies can " claim " anything] Use more than

directed

> at first if tolerated.

> Oral human Immunoglobulin (Baygam) being studied. Survives in GI

> tract, contains antibodies to all common human pathogens.

> Transfer Factor

>

> 63. Treatment – Viral

> - Consider trial of Valtrex for herpes virus. HHV-6 response to

this

> not clear. Would not continue long term unless child responding.

> - Oral IFN-alpha proposed as anti-measles agent. Studied in the

> ines during measles outbreak, shortened course of symptoms.

> [reference here]

>

> 64. Future Directions

> - If heavy metal toxicity/mercury is the root of the immunologic

> disturbances, this will need to be addressed before

immunomodulatory

> therapies are efficacious in the long term.

> - Controlled trials to pinpoint which subgroups will respond to

> various therapies are critical.

>

> 65. Immune mechanisms – diagram here – same slide as Slide 2.

>

> 66. Disclaimers

> - These guidelines are my personal opinions and do not represent

> official recommendations or beliefs or Tulane University.

> - I have no financial relationship with any companies or products

> discussed.