A Little Stress May Have Big Benefits for Health

Rockefeller University Researchers Show That Acute Stress Sends Early Warning Signal to Immune System

Rockefeller University researchers have shown that brain hormones rally immune cells in response to stress. The findings, reported in the Feb. 2 issue of the Proceedings of the National Academy of Sciences (PNAS), contradict the widely held notion that all stress is bad for health and provides a basis for understanding the role of stress in health and disease.

“We have shown that stress hormones produced by the adrenal gland can enhance immune function in rats,” says McEwen. “These findings further show that hormones released during an acute stress response may help prepare the immune system for a potential challenge, such as wounding or infection, with stress perception by the brain serving as an early warning signal.”

Conventional wisdom dictates that stress harms the immune system, but McEwen and Firdaus Dhabhar, Ph.D., co-author of the PNAS paper and a research associate in McEwen’s lab, reason that stress is an intrinsic part of life for an organism, and survival depends on an organism’s ability to adapt to stress.

Previous work by Dhabhar and McEwen showed that acute stress trafficked, or moved, immune cells called leukocytes from the blood to other areas of the body, including the skin, lymph nodes and bone marrow. They also identified two major stress hormones, epinephrine and corticosterone, as mediators of the stress-induced redistribution of leukocytes.

In the PNAS paper, Dhabhar and McEwen focused on the skin, theorizing that leukocytes dispatched here may increase immune surveillance and enhance immunity. They used a model for immune reactions called delayed-type hypersensitivity (DTH). DTH reactions mediate resistance to viral, bacterial and fungal infections, as well as to certain tumors. They also play an important role in ensuring the effectiveness of vaccines.

To study DTH reactions, researchers typically expose the organism to a novel antigen, much like a vaccination, to establish an immunologic memory. The researchers then challenge the organism later with the same antigen to test its memory.

In the new research, Dhabhar and McEwen manipulated the amount of stress hormones in the rats, varying the concentrations of hormones in the animals to mimic acute and chronic stress. They showed that acute stress or hormonal conditions which mimic acute stress, enhanced skin immunity, while chronic stress or hormonal conditions which mimic chronic stress, suppressed skin immunity. They also showed that in contrast to the natural hormones produced by the body, dexamethasone, a commonly used synthetic version of corticosterone, is a potent suppressor of skin immunity. This finding was in agreement with the well-known use of dexamethasone as an anti-inflammatory steroid.

The scientists also propose a model for the stress response in skin, in which stress hormones and immune cells work in concert to promote enhancement of skin immunity. Stress hormoneS, according to their model, may direct the “soldiers” of the body’s immune system-the leukocytes-to take position at potential “battle stations” in various organs of the body. Calling the stress response a “hormonal alarm,” Dhabhar and McEwen think that acute stress may prepare the immune system for potential challenges such as wounding or infection. In contrast, chronic stress may suppress immune function, decrease leukocyte redistribution and inhibit the function of certain immune cells.

Dhabhar and McEwen’s research may have direct consequences for how doctors treat diseases. Because not all aspects of immunity are beneficial to the body, for example, autoimmunity or an allergic reaction, acute stress hormones can actually make those conditions worse.

One of the paradoxes of stress and immunity is that on the one hand stress is thought to suppress immunity and decrease resisitance to infections and cancer, while on the other it is known to exacerbate autoimmune diseases which should be ameliorated by a suppression of immune function.

“This research begins to provide some common basis for explaining some of these paradoxes,” says McEwen. “If it’s a ‘good’ immune response, like fighting a pathogen or cancer cell, then this acute response protects the body in the short run. If the immune response is dysregulated, for example, during allergy, asthma, or arthritis, acute stress may make it worse.”

McEwen points out that the irony of allergies, autoimmunity and asthma is that very frequently they are treated with stress hormones. If administered properly, for example locally in high doses, or using synthetic steroids like dexamethasone, these hormones mimic the effects of chronic stress and suppress immune function.

“This work provides some basis to understand what kinds of doses and what kinds of steroids to use,” says McEwen.

In addition, stress hormone levels are higher in the morning because they follow a circadian cycle. Earlier work by Dhabhar showed that when the natural clock is at its peak in terms of the cortisol level, the trafficking of immune cells and DTH is enhanced. The recent research further explores the hormonal mechanisms by which acute stress, and by analogy, the circadian rhythm, may affect immune function in vivo.

Dhabhar points out that these studies are important because stress is suspected to play a role in the etiology of many diseases and glucocorticoid and catecholamine hormones are prescribed for numerous clinical conditions. “A determination of the physiologic mechanisms through which stress and stress hormones enhance or suppress immune responses may help our understanding and treatment of some of these diseases. Future studies will aim to facilitate the development of medical treatments designed to harness a patient’s physiology to selectively enhance (during vaccination, wounding, infections, or cancer) or suppress (during autoimmune or inflammatory disorders) the immune response depending on what would be most beneficial for the patient,” says Dhabhar.