It had long been thought that the brain is a special place in the body, largely sealed off from the immune system. We talk about the blood-brain barrier and the “immune privileged” status of the brain, as though it exists in another dimension, totally out of reach. Neurons, we were told, were too precious to risk being lost in a street fight with a virus or bacteria, so the brain must be in some sort of protective bubble, isolated from both infections and immune activity.
As so often happens in science, the reality has proven far more complex. Increasingly, we are discovering new connections between the nervous and immune systems that are challenging this notion.
We should have known better. One of the most fundamental aspects of immune defense, fever, is well known to affect both our mood and behavior, things that are seated squarely in the brain. When you are running a fever, you just feel different. You lose appetite, energy, and even enthusiasm for things that you normally enjoy. You feel like crap. This is no accident and it is not due to the elevated body temperature itself. Strenuous exercise on a hot day can raise body temperature even more than fever usually does, yet it does not cause lethargy.
We don’t often think of it this way, but the feelings associated with fever are psychological symptoms. It changes our mood and our subjective inner feelings, but it also alters our behavior. We are less likely to leave the house, do any work, or even socialize. We just want to lay in bed and rest. The evolutionary value of this is obvious. By nudging us toward rest, we conserve valuable energy for the immune fight. The psychological symptoms of fever have probably saved many human and animal lives.
There may also be a social aspect to fever. By knocking us off our feet, fever may act to reduce our interactions with others. This would be clever indeed because, if the infection is contagious, this could help reduce its spread to other members of our group. In most cases, among the people we interact most with are our close biological relatives. (This is important because it allows for kin selection to favor a behavior that has benefits for offspring and close relatives, not just ourselves.)
The idea that immune activity can alter our social behavior just got a big boost. Researchers at the University of Virginia have discovered how a very important immune molecule, interferon gamma, has direct and profound affects on social behavior in mice.
Interferon gamma (IFN-γ) is one of the most famous of all immune system molecules. It is a powerful anti-viral protein that can have pronounced effects on almost every cell in the body. It is both a warning beacon, telling cells that an infection is brewing, and a master regulator of the immune response itself. IFN-γ is released by various kinds of white blood cells whenever an infection is detected. When it touches other cells, it forces them to put up their defenses and engage in a whole host of defensive activities designed to stop, fight, and destroy an invading pathogen. Powerful stuff.
What the researchers found was that perturbing the interferon gamma signaling network makes mice less social. Importantly, the reduced sociality appears to be a direct effect, not a consequence of motor defects or increased anxiety. IFN-γ seems to operate specifically on the desire to spend time with others. The scientists went on to place IFN-γ within a signaling network in the brain that specifically links immune activity with social behavior, demolishing any notion of a barrier between the brain and the immune system.
The implications are far reaching. It is compelling that IFN-γ could operate to reduce the sociality of mammals when they are fighting infection. This would go above and beyond the connection to fever. A common feature of immunology is overlapping mechanisms to accomplish similar goals. This is because our immunity has evolved over millions of years of struggle against also-evolving viruses and bacteria. In fact, if this finding is confirmed, I suspect that virologists will soon discover ways that viruses try to deactivate this action of IFN-γ in order to boost social interactions in their hosts, facilitating contagion.
There is also an implication for the study of social personality types and neurodiversity. Thoughtful study of those on the autism spectrum has led to a shift in thinking away from the “disorder” model of autism and toward the “neurodiversity” model. Briefly, many now believe that the autism spectrum is actually just one end of a continuum of personality types that includes nuerotypical personalities as well. Through random mutation, evolution is a diversity-creating machine. It seems possible, likely even, that personality and nuero-functioning would be part of that diversity. After all, the genius of human biology is that we’re not evolved to be any one specific kind of thing. Our greatness is our adaptability. With our powerful brains to guide us, we are the planet’s ultimate generalists. For that, diversity is essential.
Besides its role during infection, interferon gamma also seems to operate at a different baseline in each of us. There has been speculation that the different levels of baseline IFN-γ activity may explain why some are prone to exaggerated allergic and immune responses and might predict who survives an episode of sepsis and who doesn’t. IFN-γ levels may even correlate with general sickliness, though a genetic basis for this has not yet been discovered.
However, with the knowledge that IFN-γ also has a direct effect on social behavior comes the implication that it may have a role in personality and nuerodiversity. If the diversity in IFN-γ levels correlate with the diversity of social behavior, a key mechanistic connection will have been made. However, this begins to sound a little too neat, in my view, keeping in mind the lesson that began this story: life is rarely as simple as our ideas are.
Nevertheless, the emerging picture of a common biology to immunity and social behavior is a compelling story of the creative genius of evolution. The next time an infection has got you down, bear in mind the good that IFN-γ is doing for your loved ones by acting on your brain and keeping your sick body away from them.
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