It’s well established that people who react strongly to stress may be at higher risk for depression and other stress-related disorders. Now, new research points to a surprising source of individual differences in stress response: the peripheral immune system, which controls all immune responses in the body outside the brain.

Led by 2012 NARSAD Young Investigator (YI) Grantee Georgia E. Hodes, Ph.D., of the Icahn School of Medicine at Mount Sinai, a research team studied IL-6 (interleukin-6), a protein that is released when the immune system is active. They found that higher levels of IL-6 are linked with vulnerability to stress and depressive behavior.

The team also included 2010 YI Grantee Kyle A Lapidus, M.D., Ph.D.; 2005 Independent Investigator Grantee Sabine Bahn, M.D., Ph.D.; 2009 YI Grantee James W. Murrough, M.D.; and 2006 and 2008 YI Grantee Scott J. Russo, Ph.D. Their results appeared October 20th in Proceedings of the National Academy of Sciences.

Dr. Hodes and colleagues looked at how much IL-6 was released in the peripheral immune systems of individual mice and people, in response to different kinds of social stress. The main function of the immune system is to protect the body against disease, not to regulate mood. But the researchers found that IL-6 levels play a part in a person’s response to stress––specifically, in a way that predicts social avoidance, an important symptom of depression and stress-related disorders.

The team found that, after a stressful event, mice with higher IL-6 levels were more likely to avoid social interaction later on. That behavior was reduced by blocking IL-6 release in the mice. Stress response and subsequent social avoidance were further tied to high levels of white blood cells––key players in the immune system––and the tendency of such cells to release IL-6. Together, these findings paint a picture of an irregularity in the immune system producing depressive symptoms by affecting stress response.  

The findings appeared to be relevant in the clinic. People with depression for whom commonly prescribed treatments did not work were found to have higher IL-6 levels. Dr. Hodes and her colleagues observed that antidepressant medication did not affect IL-6 levels. This suggests that patients with treatment-resistant depression might be helped by future treatments that block IL-6.

Dr. Hodes says another aspect of the study was exciting to her team. “We were able to make mice more susceptible to stress by replacing their peripheral immune system with that from a stressed mouse via a bone marrow transplant.”  In other words, in these mice the stress response was altered by making changes affecting the immune system, but not by directly intervening in the brain. Dr. Hodes says that her team was also able to block the effects of stress using an antibody treatment that, importantly, did not enter the brain. The brain is protected from large bioactive molecules, including toxins, by a filtration system called the blood-brain barrier.  

The study opens up the possibility of a new way to treat depression with therapies that do not need to enter the brain in order to be effective.

Read the abstract.