Could a molecule that fights infections actually make you more sociable?

It may seem counterintuitive, yet recent research in the Department of Neuroscience at the University’s School of Medicine has shown that an immune system molecule appears to regulate social behavior.

The study, published online this summer in the journal Nature, found that mice that lacked that molecule—interferon gamma—didn’t engage in normal social behavior. It’s a surprising finding, says Dr. Anthony Filiano, lead researcher for the study. “Classically, interferon gamma is thought to fight infection, not to play a role in brain and social behavior.”

Dr. Anthony Filiano, lead researcher for the study, began with the fact that a diverse range of disorders that affect social behavior are accompanied by significant immune system dysfunction. Sanjay Suchak

More fascinating still, the researchers hypothesize from their study that interferon gamma may have evolved to fight infections only after pathogens began to spread themselves by activating the molecule’s sociability function—suggesting that some organisms may have the capacity to affect our behavior without our awareness.

Social deficits and immune dysfunction

For the study, Filiano began with the intriguing fact that a diverse range of disorders that affect social behavior—from autism to schizophrenia to dementia—are accompanied by significant immune system dysfunction. The association sparked his curiosity. Could deficits in the immune system actually be affecting social behavior?

Through experiments, Filiano and his colleagues found social deficits in mice genetically engineered to lack an adaptive immune system—a specialized arm of the immune system, he explains, that responds to the specific type of infection. When presented with inanimate objects and unfamiliar mice, mice behaving normally will spend more time investigating the other mouse than an inanimate object; mice lacking adaptive immunity, however, spent equal time investigating both.

Bethany Bickley

Further examination of the brains of mice lacking adaptive immunity showed a pattern of hyperconnectivity in the prefrontal cortex: as Filiano describes it, “Too many signals, too much traffic.”

That prefrontal cortex is important for social behavior, Filiano says, and there appears to be a link between hyperconnectivity there and impaired social functioning, such as in children with autism. Other mouse studies in which this area has been hyperactivated have shown the same resulting social deficits, he says.

Filiano’s research team ultimately predicted that the immune system molecule interferon gamma appeared to be important for preventing this hyperconnectivity—and their experiments confirmed that mice lacking interferon gamma had the same social deficits as the mice that lacked adaptive immunity, says Filiano.

Filiano cautions this study was performed on mice and that in humans no such definitive link has been established, only “associations between immune system deficits and deficits in social behavior, learning and memory.” Nevertheless, he says, “Our research suggests that deficits in the immune system can cause deficits in learning, memory and behavior.”

Evolutionary battle

Why a deficit in the immune system might affect social behavior remains a matter of speculation. However, Filiano and his fellow researchers hypothesize that the “pro-social” function might actually have been interferon gamma’s original biological role and that pathogens may have evolved the capability to activate that function to drive increased social interactions and thus help spread themselves between individuals. In turn, “the interferon gamma pathways were recycled as an anti-pathogen response to limit the spread of infection as we come together,” Filiano says.

If that hypothesis sounds far-fetched, consider this: A study at Binghamton University, published in 2010 in Annals of Epidemiology, found that participants who had received a flu vaccination engaged in an increased number of social interactions in the 48 hours following the administration of the medication. Researchers called it “the strongest indicator yet discovered of pathogen-mediated behavioral change in otherwise asymptomatic humans.” In other words, the flu virus inside the vaccination could have hijacked some part of the participants’ immune system to make them more sociable—to spread itself.

“We think there are a lot of different types of behavioral responses that happen after you are infected, all controlled by these different immune molecules,” says Filiano.

Bethany Bickley

Studies like these, and the possibility that our immune system might play a role not only in fighting infection but also in regulating behavior, point out how much is yet to be discovered, much less understood, about the complex factors that shape behavior, learning and memory. Jessica Connelly, an assistant professor of psychology at UVA, whose research interests include looking at the role that the hormone oxytocin plays in social behavior, points out that we are far from having even a clear idea of what regulates or constitutes the full range of “normal” human behavior. “The fact that ‘typical’ people are different at an individual level suggests there is some molecular phenomenon that changes at the individual level to fine-tune behavior,” she says.

Will our sense of ourselves as freely acting protagonists in our own stories be changed by what brain research is revealing? “This kind of research points to something that philosophers have been talking about for a long time, which is that ultimately the determinants of our character may lie outside of us,” observes Brie Gertler, a professor in the University’s Department of Philosophy. “We locate moral responsibility in the capacity for reflection,” she says, but the very ability “to step back and reflect and change may be outside of our control. It brings up venerable issues of free will and the shaping of the self and agency.”

As a researcher, however, Filiano says he hopes his work may lead to greater understanding of how immune cells and immune-cell-derived molecules can affect the brain—and ultimately, to benefiting people. “By studying these neuroimmune communications,” he says, “we will open up doors to new therapeutic targets for neurological disorders.”