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Stress

The stress we put our bodies under impacts the delicately achieved underlying aim of our immune system—to achieve balance. When I think of how delicate this balance is, I sometimes picture an elite gymnast on a balance beam leaping into a flip and landing, again and again, with no margin for error. Stress can act like a midair push, adding a jostle to an already precarious feat.

Credit for revelations of the role of stress is owed to a colorful couple at Ohio State University, Janice Kiecolt-Glaser and her husband, Ronald Glaser, who did seminal research by posing a question that you may well have asked yourself: How come you get sick after final exams?

The Glasers met on October 3 in 1978 at a faculty picnic at Ohio State University. She was junior faculty in psychology and he was then the chair of the Department of Medical Microbiology and Immunology. She was twenty-seven, and he thirty-nine. He’d already been twice married and divorced. On their first date, they went to lunch, and then he took her to his office, presumably to show off what a big shot he was. She noticed his unusual taste in art: A picture of a sperm hung on the wall, and on his desk there was a stand with a dried piranha.

Ronald Glaser and Janice Kiecolt-Glaser. (Courtesy of Kiecolt-Glaser)

“How can you trust a man with a sperm on his wall, who has been married twice?” She laughed, recounting the story.

As they got to know each other, he proposed that they combine their expertise—hers in psychology and his in immunology. “He thought it would be interesting,” Kiecolt-Glaser recalled. “I didn’t even know what a lymphocyte was.”

To this point, little had been done on the subject of stress and the immune system. One early study had found that Swedish volunteers subjected to seventy-seven hours of noise and sleep deprivation suffered ill health effects.

And there was an “odd study,” Kiecolt-Glaser recalled, performed at West Point. It had taken place in the mid-1970s and involved looking at which cadets were more likely to contract infectious mononucleosis, one of the eight types of human herpes viruses. They can be relatively harmless and are among the most common viruses in the world, but this class of virus obviously has a more troublesome side too.

The research took place over four years and involved a class of roughly 1,400 cadets. When a cadet entered West Point, he was tested to see whether he produced antibodies to fight Epstein-Barr virus, the pathogen that causes infectious mononucleosis. In other words, the researchers were testing whether the cadets’ bodies had been exposed to the Epstein-Barr virus and had developed a defense that recognized it.

When the cadets entered, roughly 30 percent lacked the antibody for Epstein-Barr virus. They had essentially not encountered it in any meaningful way. Of that group that had the antibody, 20 percent eventually “became infected,” according to the research paper, written by Yale scholars and published in 1979 in Psychosomatic Medicine. Among the cadets who became infected, 25 percent not only had antibodies but showed clinical signs of being sick. What was surprising was one common thread among cadets likely to develop infectious mono: They were doing poorly in school, had highly accomplished fathers, and were themselves particularly motivated to succeed.

They were “guys who were not doing well and really wanted to,” Jan Kiecolt-Glaser said, “Ambitious guys, struggling in school, with a successful dad.” Stress seemed to be playing a key role in the immune system’s response.

“Ron said, ‘Let’s try a study with medical students.’” Herpes was the perfect test.

Not only is herpes among the world’s most common virus families—nearly all adult Americans have been infected with several of the eight by age forty—it also has a very delicate, even profound, relationship with the immune system. It’s a relationship that tells us something about how our defenses have evolved to make a calculation about when to attack and when to stand back. Sometimes when a pathogen is detected but the pathogen appears not to be spreading and not to be too dangerous, our elegant defenses watch and observe—acting more like peacekeepers than assassins. Herpes is a wonderful example.

It’s worth noting of herpes that the genetics of the virus share key characteristics with human DNA. Notably, both have double-stranded DNA—the famous double helix. That’s one way that herpes can be a bit flummoxing to the immune system, which is always scanning for self and alien. In this case, it can be hard for the immune system to identify the nonself.

Also, once a person is infected, the virus does something else that makes it challenging for the immune system. Herpes essentially lies dormant. For instance, the oral version tends to hang out in cells inside the roots of nerves at the base of the skull (or in other nerve roots near and around the spine). Frankly, I find this to be terrifying—a virus hanging dormant like a pod in the movie Alien.

Meanwhile, the immune system, sensing that something is afoot but not active or not so clearly different from us, shows up and hangs out itself, keeping watch. The presence of immune system cells essentially keeps the herpes in check. “The cops show up and keep the party down,” said William Khoury-Hanold, a Yale immunologist. The herpes is effectively held in check.

Sometimes, though, when the immune system gets preoccupied, stressed, or tamped down, it provides an opening for the virus to emerge. Herpes, sensing this temporary weakness, travels down the nerve roots into the mouth and attacks. Now the Festival of Life is under attack and the immune system must respond in force.

This scenario makes it a terrific test case for stress and the immune system because it allows researchers to see what happens when a person experiences stress: Do our defenses get distracted such that the herpes virus can emerge from its ganglion hideout?

The seminal 1982 study done by the Glasers involved seventy-five medical students. The study measured the level of the subjects’ natural killer cells and their antibodies. The students were tested prior to exams, then on final-exam days, and then, sometime later, when they returned from vacation.

“When Ron saw the results, he didn’t believe it.” After the exam, “the antibody levels were so high he didn’t trust the data.”

The numbers were even higher for the lonelier students. “The stress of exams was bad for everybody, but worse for the lonelier students,” Kiecolt-Glaser explained.

There also was a severe reaction involving the natural killer cells too. Remember that these are among the first-line defenders in the immune system—the heavy artillery. During exams, there was a sharp fall in the number of natural killer cells that circulated outside the bone marrow.

The stress of exams was suppressing a key part of the immune system. Why might this be?

During exams, there is a surge of adrenaline. This precedes the release of steroids.

You already know that steroids dampen the immune system and are used to fight autoimmunity. There is a profound logic behind this relationship—between adrenaline and steroids and the immune system. It is crucial to our survival.

Steroids play a number of pivotal roles in allowing us to survive moments of acute stress. Crucially, for instance, steroids help to maintain the integrity of blood vessels; in times of stress, when the blood vessels might constrict, these steroids keep them intact and, without putting too fine a point on it, maintain your blood circulation and pressure so you don’t faint and die.

These kinds of steroids also have a wavelike impact across our immune system as they circulate through the body. Virtually every cell has a receptor for these types of steroids, and that receptor is called a glucocorticoid receptor. When the steroids become active or elevated, they can reach many, many cells—“every cell in the body,” according to Dr. Jonathan Ashwell, an expert in cell biology at the NIH. It’s a remarkable idea in and of itself. In the giant festival, this hormone courses through the entire confines of the party and has an impact on the behavior of many, many partygoers. At least the ones that are self.

Cell receptors for steroids are outside their nucleus (the innermost part). But when the steroid reaches them, a reaction begins that moves the steroid into the nucleus. There it begins a process by which it interacts with the cell’s DNA to change the proteins made by the cell. Chief among the influences made by these steroids is that “you repress expression of a lot of genes important for an immune response to occur,” Dr. Ashwell explained.

Now why would it benefit us to have our elegant defenses repressed?

The logic comes again from evolution. If your ancestor was under sudden and profound stress—say, fearing a bear or lion attack—it would be problematic for inflammation to create fatigue or fever. For most of human history, stress meant imminent threat, and imminent threat meant the body needed to be alert, fully functional, even a bit superpowered. This is where the hormone cortisol comes in. It is secreted by the adrenal gland.

In times of stress, the release of cortisol comes slightly after the release of one of two other key hormones, norepinephrine and epinephrine. Steroids and these other two hormones are separate but highly related pathways in the stress experience. The first—the release of epinephrine and norepinephrine—is known as the sympathetic response, and it involves the central nervous system. The second—release of cortisol—takes a bit longer to cascade; it goes from the brain to the pituitary and adrenal glands and releases glucocorticoid, a natural immune system dampener.

In times of acute stress, if there’s a virus in your system, the virus fight can wait. The bigger threat has teeth and runs a 3.5-second forty-yard dash.

Immune system responses have “a substantial energetic cost and the potential for collateral damage,” according to Dr. Michael Irwin, the Cousins Professor of Psychiatry and Biobehavioral Sciences at UCLA’s David Geffen School of Medicine and director of the Cousins Center for Psychoneuroimmunology. Dr. Irwin is also one of the foremost experts in the world in the connection between your immune system and your brain and behavior, including stress and sleep. The collateral damage is fever, fatigue, actual swelling, or inflammation—all things that might encourage someone to slow down and rest. Not good when you’re up against the lion.

This relationship between adrenaline and the immune system has another key driver: It is highly regulated by how we sleep.