heart disease to depression and Alzheimer’s disease. “I see
inflammation as one of the chief evils in mammalian biology,”
Of course, the immune system serves a critical function —
and not just for fighting disease. “The immune system is really
important for how the brain develops normally,” says Staci Bilbo,
PhD, an assistant professor of psychology and neuroscience at
Duke University. Cells called microglia are the resident immune
cells in the brain. They’re the central nervous system’s first-line
defense against infections and other invaders. And, Bilbo says,
“they do a lot of important things for building a brain.”
For starters, microglia are involved in synaptic pruning
and programmed cell death. They also express cytokines, the
signaling molecules that serve as messengers between cells and
are a key component of the body’s inflammatory response.
Cytokines are important for the development of basic brain
structures from blood vessels to axons. They are also involved in
regulating cognition and mood, Bilbo says.
She explored the brain’s immune cells by infecting infant rats
with the bacterium E. coli four days after birth, a developmental
period comparable to the third trimester of pregnancy in
humans. The young rats recovered fully from the infection,
and as adults they performed as well as control rats on tests of
memory and cognition. But their early infections had left their
The rats’ microglia had been “primed,” Bilbo says; in essence,
inflammation running wild
the cells had been put on high alert for future infections. When
the rats experienced a second infection — what she calls a
“second hit” — around the time they were learning a new task,
they showed profound memory impairments for that task. The
primed rats, she discovered, were dramatically over-expressing
cytokines in response to the second hit (Journal of Neuroscience,
2011). “Their immune system is changed long-term as a result
of the neonatal infection,” she says. “And because the immune
system impacts brain function, they are altered behaviorally.”
That same pattern appears in many neurodegenerative
diseases in humans, she says. “A peripheral infection will
suddenly make mental functions decline sharply, and you can
measure concentrations of cytokines in the cerebrospinal fluid
that were previously undetectable.”
Other animal studies have further filled in some details. Paul
Patterson, PhD, a neurobiologist at the California Institute
of Technology and author of the book “Infectious Behavior:
Brain-Immune Connections in Autism, Schizophrenia, and
Depression” (2011), explores the origins of mental illness in
mice. He’s infected pregnant mice with influenza virus and also
stimulated their immune systems in the absence of a pathogen.
“When you activate the mother’s immune system, you turn on a
variety of cytokines to fight the infection,” he says.
Patterson found that the offspring of the infected mothers
exhibited a whole list of abnormal behaviors. Among them
were the three “cardinal behavioral symptoms of autism,” he
says: impaired communication, reduced social interaction and
repetitive, stereotyped behaviors ( Trends in Molecular Medicine,
2011). What’s more, the mice showed heightened anxiety and
were more sensitive to hallucinogenic drugs — a sensitivity also
seen in humans with schizophrenia.
These changes can be traced to the presence of a cytokine
called interleukin- 6 (IL- 6). When produced in excess by a
pregnant mouse, the molecule activates subsets of neurons in
the fetus’s brain. IL- 6 also activates cells in the placenta, altering
endocrine function and changing growth hormones. “That’s
bound to have an effect on [fetal] development,” he says.
Cytokines including IL- 6 can also interfere with the
synthesis of serotonin in the brain, Pace adds. An excess of
cytokines leads to a cascade of molecular events that interrupts
the synthesis pathway, preventing serotonin from being
produced. And serotonin, of course, is a necessary ingredient
for healthy mood.
This finding may be particularly relevant for depressed
patients taking selective serotonin reuptake inhibitors (SSRIs).
A study by Charles Nemeroff, MD, PhD, of the University of
Miami, and colleagues suggests that depressed people who
experienced an adverse event in early life may be less likely to
respond to SSRIs than depressed patients who did not endure
an early-life stressor (Proceedings of the National Academy of
Sciences, 2003). That makes sense if an overactive immune
response is working against serotonin in the brain, Pace says.
“If inflammation really is driving that problem, then something
like Zoloft isn’t going to be as effective while inflammation is
For that reason, Pace says, “it’s important to get a sense
of whether or not somebody has had an early-life traumatic
experience.” Such a patient may be more likely to respond to
psychotherapy than to antidepressants alone, for instance.
Pace and other researchers are now exploring alternative
therapies for reducing inflammation and treating depression.
He has found evidence that compassion meditation decreases
the stress hormone cortisol as well as inflammation, at least in
healthy subjects (Psychoneuroendocrinology, 2009). Testing the
technique in depressed patients is the next step.
Scientists are also investigating the use of anti-inflammatory
drugs to treat depression, either alone or in conjunction with
traditional antidepressants. Others have begun to test anti-inflammatories for treating autism and schizophrenia. The
research is still in early stages, but initial results are promising,
He predicts that it won’t be long before anti-inflammatory
medications are prescribed to treat mood and behavioral
disorders. “Watch out for those studies coming along,” he
says. “If you modify the immune status, you should be able to
modify behavior.” n