As social animals, humans rely on a delicate balance—the benefits of getting together versus the harms. And because the harms include a higher risk of swapping pathogens and spreading disease, it may come as no surprise that the balance depends, in part, on the immune system. The immune system, a new study has found, affects—and even controls—social behavior.

This connection between the brain and the immune system remained unrecognized until now because the brain, scientists believed, was “immune privileged.” Yet a team of scientists based at the University of Virginia Health System established just a year ago that meningeal vessels directly link the brain with the lymphatic system.

Following up on this discovery, which opened the door for entirely new ways of thinking about how the brain and the immune system interact, the University of Virginia researchers investigated how meningeal immunity could influence behavior. Previous studies by other investigators suggested that behaviors such as spatial learning and memory could be affected. The University of Virginia researchers focused on social behavior.

According to these scientists, immune system problems could contribute to an inability to have ordinary social interactions. This finding, they add, could have great implications for neurological conditions such as autism-spectrum disorders and schizophrenia.

The scientists presented their work July 13 in the journal Nature, in an article entitled, “Unexpected Role of Interferon-γ in Regulating Neuronal Connectivity and Social Behaviour.” The article describes how mice deficient in adaptive immunity exhibit social deficits and hyperconnectivity of fronto-cortical brain regions.

“Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses,” wrote the article’s authors. “Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour.”

The researchers also discovered, through a meta-analysis of transcriptomes, that organisms such as flies, zebrafish, mice, and rats activate interferon-γ responses when they are social. Normally, this molecule is produced by the immune system in response to bacteria, viruses, or parasites. Blocking the molecule in mice using genetic modification made regions of the brain hyperactive, causing the mice to become less social. Restoring the molecule restored the brain connectivity and behavior to normal. In a paper outlining their findings, the researchers note the immune molecule plays a “profound role in maintaining proper social function.”

“The brain and the adaptive immune system were thought to be isolated from each other, and any immune activity in the brain was perceived as sign of a pathology. And now, not only are we showing that they are closely interacting, but some of our behavior traits might have evolved because of our immune response to pathogens,” explained the study’s senior author and chairman of UVA's Department of Neuroscience, Jonathan Kipnis, Ph.D. “It's crazy, but maybe we are just multicellular battlefields for two ancient forces: pathogens and the immune system. Part of our personality may actually be dictated by the immune system.”

The researchers note that a malfunctioning immune system may be responsible for “social deficits in numerous neurological and psychiatric disorders.” But exactly what this might mean for autism and other specific conditions requires further investigation. It is unlikely that any one molecule will be responsible for disease or the key to a cure, the researchers believe. Instead, the causes are likely to be much more complex. But the discovery that the immune system—and possibly germs, by extension—can control our interactions raises many exciting avenues for scientists to explore, both in terms of battling neurological disorders and understanding human behavior.

The relationship between people and pathogens, the researchers suggest, could have directly affected the development of our social behavior, allowing us to engage in the social interactions necessary for the survival of the species while developing ways for our immune systems to protect us from the diseases that accompany those interactions.

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