In a paper published on Tuesday in the journal PLOS ONE, a team led by Massachusetts General Hospital neurologist Vishal Saxena found that molecular pathways involved in producing key immune system proteins are tied to genes associated with autism. The work hinges on a novel way of combining two sets of genetic evidence: autism-associated variations in DNA sequences and genetic markers that have been identified in studies of autistic individuals and their families.
"Others have talked about immune function contributions to autism, but, in our study, immune involvement has been identified through a completely nonbiased approach," Saxena said in a statement Thursday. "We let the data tell us what was most important, and, most tellingly, viral infection pathways were most important in this immune-related mechanism behind autism."
Previous work has lent weight to the theory that autism can be genetically inherited, but different studies have pointed to different genes as the culprit. Saxena and his colleagues thought that these seemingly disparate autism-related genes are actually linked to some common molecular mechanism, since autism has a typical set of symptoms that affect the same kinds of biological processes.
The researchers first looked at genetic markers linked to autism called copy-number variants, or CNVs, where a large part of DNA is duplicated or deleted. Eventually, they focused on five molecular pathways linked to immune function that were affected by autism-related CNVs.
Using an analysis method called linkage-order gene sets, or LoGS, the team examined how the five immune-related pathways connected to the genetic markers identified by previous family studies of autism.
"The idea behind LoGS is akin to viewing a digital photograph," Saxena says. "When one looks at a digital image from very close up, one only sees a few pixels and is unable to recognize the picture. Zooming out, however, makes the picture understandable. In the same way, looking at single genes may lead to a disorganized view of a disease, but zooming out to the pathway level clarifies and unifies the mechanism."
Four of the five CNV-affected pathways isolated by Saxena and his team turned up in the top spots of their LoGS analysis. The pathways code for either interferons or chemokines, which are proteins made by the immune system, often in response to viral infections.
It may be possible that alterations in the genes that regulate these immune proteins prevent a pregnant woman and her fetus from controlling a viral infection as quickly, and abnormal levels of chemokines could potentially alter the brain of a developing fetus.
But it is still unclear "whether the immune/inflammatory signature we have found ... is part and parcel of the developmental disorder, a consequence of that disorder or its trigger," the authors wrote.
Since the immune system effects that Saxena and colleagues examined likely take place very early on in fetal development, the find does not seem to lend credence to the popular theory linking childhood vaccines and autism, which lacks scientific support.
Changes to immune system function have already been documented in both children and adults with autism spectrum disorder, according to one review by a group of University of California at Davis immunologists published in the journal Brain, Behavior and Immunity this past March.
Brain samples from autistic people show signs of ongoing inflammation, their blood and cerebro-spinal fluid often shows higher levels of molecules that contribute to an inflammatory response, and they have more antibodies that target the brain and altered immune cells, according to the paper.
“Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of [autism spectrum disorder], in particular, deficits in social interactions and communication,” the UC Davis scientists wrote.
SOURCE: Saxena et al. “Structural, Genetic, and Functional Signatures of Disordered Neuro-Immunological Development in Autism Spectrum Disorder.” PLOS ONE 7: e48835, published online 4 December 2012.