The Immune System's Link With Stress and Depression: What Attorneys Should Know

If you practice law in Washington, DC, you already know the job comes with pressure. What you may not know is that the connection between heavy, sustained stress and the arrival of depression has been documented for a long time. A study from the Icahn School of Medicine at Mount Sinai, published October 20 in the Proceedings of the National Academy of Sciences, points to something more specific: some people appear to carry a higher built-in risk for stress-driven depression or anxiety, and the reason may sit inside their immune system. Any lawyer dealing with depression has reason to pay attention to this.

The immune system kicks off an inflammatory response whenever the body runs into infection or disease. How stress feeds into that response is also well studied. During a stretch of depression or anxiety, the body ramps up its inflammatory molecules and its white blood cell count. For years the open question was one of order: was extra inflammation already sitting in the body before anyone got diagnosed, or did the depression itself set off the inflammatory reaction?

The Mount Sinai team went looking in the peripheral immune system. They zeroed in on a particular group of structures and processes, in the lymph nodes and other tissues, whose job is to fight off disease. Under too much stress, the body answers with a tangled chain of inflammation. A trigger such as a virus prompts white blood cells to release inflammatory proteins called interleukins, which are meant to beat back infection and limit further harm. That machinery can misfire, though. It can turn over-reactive and hypersensitive, and given enough time the inflammatory system can quit working properly and start causing disease on its own. Working with a social stress model in mice, the researchers found differences in how sensitive the peripheral immune system was before any stress took place, differences they say can forecast and drive vulnerability to social stress.

To build the stress, they put non-aggressive mice next to an aggressive mouse for ten minutes a day across ten days. Over that stretch they watched repeated social defeat play out consistently. This is a strictly emotional stressor, closer to bullying and what bullying does to a person than to any physical injury. In later social tests, some of the non-aggressive mice kept choosing to settle near an empty cage rather than approach an unfamiliar mouse. Those animals got the label susceptible. The ones the team called resilient behaved the opposite way. The susceptible mice showed obvious social avoidance after being repeatedly forced into a subordinate position, and that kind of avoidance is a path into depression.

Twenty minutes after the very first exposure to stress, investigators read the cytokine profiles of the mice. Interleukin-6, or IL-6, is one of the cytokines that stress regulates, and it ran highest in the susceptible mice compared with the resilient ones. The susceptible mice also carried higher levels of leukocytes, the white blood cells that put out IL-6, before any stress happened at all. The team then saw a matching rise in serum IL-6 across two separate groups of human patients with treatment-resistant Major Depressive Disorder, which ties the animal findings to people. This is the first evidence suggesting that an IL-6 reading taken before social stress can predict who will be more vulnerable to a later stressor.

"Interleukin-6 could be a risk factor for the development of depression in vulnerable individuals," said Dr. Scott Russo, PhD, Associate Professor of Neuroscience and the trial's leader. "We believe our studies could have significant impact on the development of new antidepressant therapeutics that inhibit IL-6, which may reduce stress-induced relapse in patients with major depressive disorder."

Lead author Georgia Hodes, PhD, a Postdoctoral Researcher in Neuroscience, described where the data pointed. "Our data suggests that pre-existing individual differences in the peripheral immune system predict and promote stress susceptibility," she said. The team also found that when mice received bone marrow transplants of stem cells engineered to make leukocytes without IL-6, or when they were given antibodies that block IL-6 before stress, the animals developed less social avoidance than their control groups. In her words, that showed the emotional reaction to stress can be produced or shut down out in the periphery.

Some of the follow-up work is striking. Swap a non-stressed mouse's peripheral immune system for that of a stressed one, and the recipient became more susceptible to social stress and started acting defeated. Strip IL-6 out of the whole body, or just out of the leukocytes, or trap it outside the brain, and resilience went up.

There is real promise here for treating depression, and Repeated Social Defeat Stress in particular. If the stress response can be switched on or off in the peripheral nervous system, that opens room for new approaches to stress disorders. Further out, scientists might be able to lower a person's vulnerability to stress and head off the depression that can follow by reworking that person's own immune system.

The takeaway from the mouse work: nudging IL-6 levels upward in the peripheral nervous system of self-isolating, depressive mice appears to make them more resilient and more willing to engage socially.

Sources: Bruce, M. (Ed.). (2014, September 25). Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Retrieved November 19, 2014, from the Proceedings of the National Academy of Sciences (pnas.org, 111/45/16136). Mount Sinai Medical Center. (2014, October 20). Stress-related inflammation may increase risk for depression. ScienceDaily. Retrieved November 19, 2014.