SOURCE LIST FOR NYT OP-ED

People, lots of interest in my recent NYT op-ed.

I’m posting a source list below. I’ll add more later, so check back. The literature on autism and inflammation is extensive, as is the literature linking autism to autoimmunity. But this should provide a solid entry-point for those curious to know more. I’m including reviews when possible. Easier to read for lay people, and they also contain extensive citations for those who want to dig deeper.

I’m listing them more-or-less in the same order they appear in the op-ed. I’m doing this in a hurry, so I apologize for messiness. I’ll clean up later. But seems important to get the sources up now.

Anyone has questions, shoot. Any scientists interested in investigating this angle, I’m happy to talk and / or recommend other scientists for collaboration.

And I’ll counter would-be rebuttals of my piece soon.

9/1/12 note: I’m adding more sources. Most are cited in the reviews already given, but here they are nonetheless. I’m marking additions with *

SOURCE LIST

Inflammation in “autistic” brain tissue.

*Another measurement of inflammation in brain tissue by different group

Great review on ongoing inflammation in autism. Note that severity of symptoms often correlates with markers of inflammation.

Here’s a review on severity of symptoms correlating with markers of inflammation.

* Another recent study showing that elevated levels of the pro-inflammatory IL-17 (which is implicated in many an autoimmune disease) correlates with symptom severity in autism.

* And another, this one focused on a different measure of immune activation

* One showing less of an anti-inflammatory factor called proganulin in autism

*And another free paper showing less TGF-beta, an important anti-inflammatory signalling molecule, correlates with symptom severity in autism.

* Activation of both th1 and th2 arms of the immune system in autism.

NEUROGLIAL ACTIVATION

Here’s the seminal paper noting neuroglial activation in “autistic” brain tissue

More recent replication of the above—glial activation in autistic brain tissue

* And again from a slightly different angle

*Evidence of disturbed neuronal migration in autistic brain tissue (also replication of glial activation).

GENETIC EXPRESSION IN AUTISTIC BRAIN TISSUE

Evidence of immune dysregulation at the transcriptome level in “autistic” brain tissue.

*And again, with a focus on over-expression of inflammation-related pathways

More on gene expression changes in the brain in animal models after prenatal inflammation.

CYTOKINE PROFILES IN AUTISM

*On cytokines skewed toward a pro-inflammatory profile in the “autistic” brain

*More on pro-inflammatory markers in autistic spinal fluid (the central nervous system)

Discussion of possibly treating the immune dysfunction in autism

MATERNAL INFECTION IN AUTISM

Large Danish study linking maternal infections to autism

Two good reviews by Paul Patterson on, among other things, maternal infection and autism. Includes refs to his and others’ experimental work on this. The first one’s free.

One

Two

Recent article in NEJM that covers changes in burden of disease in the US – i.e. the transition from infectious to degenerative disease.

MATERNAL AUTOIMMUNITY IN AUTISM

Large Danish study on autoimmunity in the family and especially in the mother, and the risk of ASD in offspring. More refs to come on this. Numerous smaller studies find the same, although sometimes with different autoimmune diseases. But this is largest to date.

GENES ASSOCIATED WITH AUTOIMMUNE DISEASE AND IMMUNOREGULATION IN AUTISM

Alleles associated with autoimmune disorders also associated with autism.

And for HLA*DR4 in the mother especially

And alleles associated with less production of regulatory (anti-inflammatory) cytokine IL10 in mothers who tend to produce those antibodies that bind to fetal brain proteins.

*Also, interesting study on a link between a gene variant that makes macrophages, critical cells of the innate immune system, more aggressive, and autism. Note that the more circulating macrophage inhibitory factor a subject had (the more activated this aspect of innate immunity, essentially), the worse the symptoms.

FETAL BRAIN-DIRECTED ANTIBODIES

On those antibodies directed at fetal brain proteins showing up in mothers of autistic children

On the macaques exposed to those antibodies during pregnancy

OTHER MATERNAL RISK FACTORS

On maternal allergy and asthma diagnosed during pregnancy associated with autism in offspring. Psoriasis, an autoimmune disease, is also a risk factor in this study.

On maternal metabolic disorders and risk of autism in offspring

On markers of inflammation in amniotic fluid and risk of autism

ON GENERAL PROBLEMS OF IMMUNOREGULATION IN MODERNITY

Classic NEJM paper on the decline of infections and the rise of allergic and autoimmune disease in the developed world.

Free paper by Graham Rook on what he calls the “old friends” hypothesis – that we require contact with certain organisms from our evolutionary past for proper immunoregulation.

Paper on autism in developing world. Note the review section. Nice to have those refs all in one place.

** The observation that in a Cambodian population with poor sanitary amenities, autism was nearly absent. It’s just an anecdote, but interesting given that the author is a specialist in autism.

Kevin Becker’s paper linking autism, asthma, and the hygiene hypothesis

Good paper that sums up the evolution of the “hygiene hypothesis,” recasting it as “microbial deprivation,” not absence of early-life infection (the original formulation by David Strachan in 1989.)

Review on sexual dimorphism in prenatal immune programming. Important stuff that doesn’t get the attention it deserves.

William Parker and neuroimmunologist Staci Bilbo positing that autism may be member of “mismatch” diseases – that is, the result of an immune system that “expects” a certain environment, and finds one very different.

Here’s Parker’s call for development of “domesticated” helminths

And again

Parker’s comparison of wild and lab rats. Anyone interested in his evolutionary minded approach should look into his work on the appendix.

Good review by Joel Weinstock and David Elliott on how helminths modulate the host immune system.

PREVENTING DAMAGE FROM PRENATAL INFLAMMATION

Article in which scientists genetically fortified IL10 (anti-inflammatory) production, inflamed pregnant mice, and saw no problems in offspring. Lesson: control inflammation, and you prevent interference in fetal brain development.

Here’s another by Columbia scientists showing that prenatal anti-inflammatory treatment (with an NSAID) also prevents problems in offspring. Same idea, different intervention.

More discussion from the Swiss scientists on autism and schizophrenia resulting from prenatal inflammation

Discussion of probiotics to help autistic children with gut troubles

Parallel work on the prenatal origins of asthma. Great stuff. Pay close attention to Prescott’s studies on low FOXP3 (regulatory t-cells) expression in placenta of children who go on to develop allergies. Allergy begins in the womb. More links TK on this. But the gist is, much research suggests uncanny similarities between prenatal inflammation in both autism and asthma.

Studying positing that asthma prevention will have to begin before birth

The trial on TSO (porcine whipworms) in autism. It’s no longer at Mt. Sinai. It has moved to Albert Einstein.

Eric Hollander is leading the TSO-autism trial.

Here’s one study showing whipworms benefit Crohn’s

A company called Coronado Biosciences is working on getting FDA approval for TSO as treatment for IBD.

TREATING INFLAMMATION IN AUTISM

There’s also some evidence that anti-inflammatory treatment may ameliorate symptoms in autistic children. It’s thin at this point – I didn’t include it in the op-ed– but worth noting here. Three small studies:

This one is randomized and placebo-controlled.

Another.

And another.

For more refs on other anti-inflammatory treatments that have shown some benefit in autism, see Ashwood’s reviews.

Here’s a list of ongoing research into the immune-brain-autism connection at Autism Speaks.

I would also suggest people read Paul Patterson’s book Infectious Behavior. He’s the scientist who pioneered much of the prenatal immune / infection research. My entire op-ed more-or-less appears in his book, although he doesn’t emphasize the hygiene hypothesis to the degree I did.

And of course, read my book when it comes out Sept. 4. My focus is on autoimmune and allergic disease, but I do have one chapter on autism.

For those interested in the bigger picture question of what the human immune system “expects” in evolutionary terms, check out The Hygiene Hypothesis and Darwinian Medicine, edited by an expert in the field, Graham Rook. It’s a compilation of sourced articles by leading researchers. Anyone who has journal access should be able to download it, chapter by chapter, from Springer.