An Immune Element In Autism? Gene Screen Finds More Evidence

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DNA double helix (National Human Genome Research Institute)
DNA double helix (National Human Genome Research Institute)

A better early blood test for autism.” That’s how the headlines tended to read in last week’s coverage of new findings by Harvard-led researchers published in the journal PLOS ONE.

But there was another aspect of the new research worthy of at least a grabby sub-headline: the analysis of gene activity in children with autism found a strikingly strong role played by genes connected to immune function.

[module align="right" width="half" type="pull-quote"]'The main point is: This is not a monolithic disease.'[/module]

That robust immune element surprised the work’s senior investigator, Dr. Isaac Kohane of Harvard Medical School and Boston Children's Hospital. And it may have practical implications, says Dr. Martha Herbert, a Harvard neurologist and author of “The Autism Revolution.” The study looked at genes getting switched off and on, and “diet and environment could contribute to at least some of these genetic changes,” she said.

So “anti-inflammatory approaches to diet modification — such as a high nutrient plant- based diet, solidly adequate Vitamin D levels and plenty of antioxidants and essential fatty acids — could help to downregulate the more troublesome of the gene expression changes. Since these are low-risk interventions, they could be pursued even while we wait for this kind of blood test for autism to become more accurate.”

Dr. Kohane, a bio-informatics specialist, was a relative newcomer to autism research when he began the gene expression work, and any preconceptions stemmed from the dominant thinking in the field: that autism was all about synapses, the connections between neurons. He went into the gene analysis unbiased, he says, open to whatever signals the genes themselves would produce. As he tells it:

Remember, gene expression is not DNA, it’s genes getting switched on and off — it’s RNA. You’re looking at real-time physiology: genetic potential plus environmental influences. What I was expecting to see was either nothing, or a lot of synaptic genes. So I was really pleased when I looked at the gene expression signature — the sets of genes switched on and off in these children we studied — and sure enough, there was a good group of 55 genes that predicted with some accuracy who had autism and who did not.

We saw a group of genes that were characteristic of the synapse, so that was very reassuring, that in the blood you could see something developing in the brain. But then I saw there were a number of other genes that were involved in inflammation.

I wondered whether I was seeing this because I was looking at white blood cells. But why would it be that I saw it in one group of kids, the ones with autism, and not in the control group? And so then I started looking through the literature and there was this whole other parallel set of literature about the immune gene signatures in autism.

It included very dramatic findings from autopsies of children who had various accidents, both cases with autism and children who did not have autism. They saw in the pathology of children with autism these very activated microglia, which are immune cells in the brain, really going on a rampage and displacing neurons.

I also saw there had been previous studies of brains of kids with autism, and they showed that one gene expression signature in the brain had a high inflammatory profile. Also, spinal taps on children with autism — and the fluid in the spine goes back and forth between the brain and spinal cord — that, too, had all these inflammatory markers.

Then I looked further into the literature and sure enough, if you have an infection during a pregnancy, your child is at increased risk for autism — but not all women, only those genetically at risk. And then I looked at a large study done in Denmark, where they have all their citizens in registries, and if your mother has rheumatoid arthriits, an autoimmune disease, or your father had type 1 diabetes, an autoimmune disease, you are at greater risk of having autism.

[module align="right" width="half" type="pull-quote"] 'This is giving us better insight into the fact that there is not one autism. There are autisms.'[/module]


So I said first of all, as a newcomer to this field, using computational tools in an unbiased way, I thought it was curious that in a review of the literature, not a single gene from any of these lists had appeared in most popular reviews.  Maybe in part, that’s because there’s been such a controversy around immunizations that perhaps the community wanted to stay away from anything that looks immunological. Or it is that only in the last decade did we really began to understand that there is really a very active immune system in the brain, led by the scientist Carla Shatz. She was a pioneer in showing us that there was an active immune system in the brain. It was previously thought it was an immunologically silent organ.

An important note: What are ‘immune genes?’ It may be a totally relativistic or contextual term. In the sense that the same cytokines in your blood that cause immune cells to move around, specifically to move toward infection, have been shown in the brain to be important in development, to make neurons move around. So from the perspective of the cell sending this signal, it says, “Oh, I’m seeing this signal, I should move toward the signal. So what we may consider an inflammatory signal in the blood is a development signal in the brain. It’s the same signaling system, but it has different meaning because its context is different. (We’re seeing this again and again in genomics: The same system reused in different tissues.)

What does all this mean? What we saw was that the gene signature sometimes very definitely expressed both in the immunological pathway and in the synaptic pathway for one given individual. But in some individuals it was just one or the other. So this is giving us better insight into the fact that there is not one autism. There are autisms.

There have been a number of mutations found in the synaptic pathway but I’m confident we’re going to find mutations in a variety of pathways. It’s like heart disease: You can have heart disease due to immunological reasons, due to mechanistic reasons, due to inflammation and environment. Autism will be the same mixed bag.

Ultimately, I think what the research is going to tell us is that there are a set of individuals who are at risk from immunological circumstances. So for example, we know many mothers get infections during pregnancy but the vast majority don’t have kids with autism. So what are the genetic characteristics of these children that set them up for autism? I think that this study adds to a growing body of evidence that there are a number of genetic factors that we should look for.

And then what can be done? We could protect the mothers. There are some things that you could do that would be ridiculous for an average mother, but you could imagine instituting Draconian infectious disease precautions to protect genetically vulnerable mothers.

Also, as Martha Herbert says, whatever the causes, if there is an immunological component you can imagine that there are going to be some therapies that are more immunologically based. For example, just as we're now treating Irritable Bowel Disorder and Rheumatoid Arthritis for the first time very successfully using antibodies targeting specific proteins, maybe, if we get a confirmation of which proteins go awry in autism, we could actually treat it similarly.

But the main point is: This is not a monolithic disease.

Further reading: Harvard Medical School posted on the study here.

This program aired on December 11, 2012. The audio for this program is not available.

Carey Goldberg Twitter Editor, CommonHealth
Carey Goldberg is the editor of WBUR's CommonHealth section.