'Downstream' Inflammation Discovered in Autism

Nancy A. Melville

December 18, 2014

In the largest RNA sequencing of brain tissue from persons with autism that has been conducted to date, researchers with Johns Hopkins University, in Baltimore, Maryland, and the University of Alabama, Birmingham, have discovered that the brains of individuals with autism have an overactive inflammatory process related to microglial cells, relative to persons without autism.

"What's promising about this is the finding of a common feature in autism brains. It suggests the potential for a broad treatment of symptoms without needing to know the underlying cause of each person's autism," coauthor Dan E. Arking, PhD, told Medscape Medical News.

Others have hailed the study as potentially having substantial impact in autism research.

"This is a seminal study which will drive the direction of translational research for many years," commented Patricia Evans, MD, PhD, director of the Neurodevelopmental Disabilities Program in Pediatrics, Neurology and Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. Dr Evans was not involved in the research.

"By using tissue from postmortem brains of autistic individuals, the researchers have been able to directly study the genetic mechanisms at the level of injury, rather than through whole blood or lymphoblastoid tissue," she told Medscape Medical News.

The article was published online December 10 in Nature Communications.

Postmortem Study

For the study, Dr Arking and his colleagues analyzed 104 frozen brain samples from two different tissue banks. Their samples included cortical tissue from 40 brains of persons without autism and 32 brains of patients with autism.

The mean ages of death of the persons with autism and of those without autism were 20 years and 17 years, respectively. There were no significant differences in the cause of death between the autism and the control groups.

In narrowing their focus to the microglial cell in the region-matched autism and control cortical brain samples, the researchers found the M2 microglia to be activated, relative to control samples.

"Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity–dependent genes in autism brains," the authors write.

Exactly what role the inflammation plays in autism ― whether it is benefiting the brain or not ― is not understood. Nor is there an understanding of what is causing the activation.

"There are a number of things that will activate M2 microglia ― type 1 interferon is one of them," explained Dr Arking, who is associate professor in the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine.

"But we don't know if that is specifically driving it in this case."

"All we can say is that the M2 are activated, and this activation seems to be a downstream consequence of the primary cause of autism, which is more likely to be due to mutation of a neuronal gene."

Exploring Inflammation's Role

There are currently FDA-approved drugs that reduce M2 activation, such as the dementia drug nicergoline (Sermion, Pfizer Inc), that have been shown to have a neuroprotective effect, but more research is needed to determine whether reduction of the activation is what is needed in autism.

"It could be that we need to dial the activation down, but it could be that it would need to be dialed up for a short time early on, or something else ― there could be various scenarios, and we don't even know which direction we would need to go yet," Dr Arking said.

"My guess is you would want to dial it down, because chronic inflammation is generally not a good thing, but you would need to do some more testing before going ahead with that. It could also be that this is some type of compensation that is beneficial."

"There is a lot of work that needs to be done to understand the impact of modulating this activation."

Importantly, the findings offer the suggestion of a feature of the autistic brain that is prevalent regardless of the multitude of genes that could be involved in causing the disease.

Seminal Study

In terms of the potential implications, Dr Arking offered the benefits of statins as an example.

"With lipids, it doesn't really matter why you have high cholesterol ― we still know a statin is going to be beneficial."

"This has a similar property, where we can say the vast majority of subjects with autism in our study seem to have this activated M2 signal, and if that is found to be responsible for symptoms, then we may not be quite as concerned as to why each individual has autism as we are in coming up with a single therapy that could be efficacious."

The findings could also be highly relevant to the line of research into viral infection as a potential cause of autism, because activation of M2 is known to be a response to viral infection, Dr Arking noted.

"This could be important in light of emerging data that maternal viral infection during pregnancy, such as the flu during pregnancy, may be a risk factor for autism."

Dr Evans underscored the study’s significance in understanding the underlying aspects of autism.

"Certainly no study to date comes close to the level of sophistication as well as yield of data relative to autistic genetic mapping," she said.

"Further research is needed to better understand how these genes present in the clinical setting, ideally in the first year of life or earlier."

The authors and Dr Evans report no relevant financial relationships.

Nat Commun. Published online December 10, 2014. Full text

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