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

[Guest guest]

[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@...;. 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.