"In an earthquake," says Dr. Esther Sternberg, "some people fall apart, but others are fine." The differences, she suspects, indicate where the "set points" are for their stress hormones, those powerful brain chemicals that alert other parts of the body to trouble or excitement.
It is common knowledge that stress affects behavior (the reaction to the earthquake) and moods (depression, anxiety, happiness). Those are its easy-to-observe effects. But, stressful situations, by triggering the release of hormones and various other chemicals that can't be seen, also power a range of activities by cells and inside them.
"The role of stress in diseases like heart disease or ulcers has not been questioned," says Sternberg. But, she adds, for a long time there was tremendous resistance in the scientific community to the notion that stress could alter immunity.
Now, it is becoming crystal clear that stress hormones exert potent effects on the immune system. They alter the body's ability to combat disease and, perhaps more significantly, can cause a number of diseases related to immune function.
Sternberg began her search for brain-immune connections in 1979. She was examining an old man with epilepsy (a brain problem) who was in the hospital with inflamed skin (an immune problem). The man had a terrifying form of epilepsy -- idiopathic intention myoclonus. Whenever he "intended" to do something, he'd have a seizure, which made normal functioning virtually impossible.
The patient was crying and moaning and saying that he wanted to die. His skin was so raw and sensitive that the nurses had had to construct a tent of sheets over him so that he could stay warm but wouldn't have to endure the excruciating pain of the bedsheet rubbing against his body.
Sternberg
diagnosed the patient's skin condition as the scarring disease called "scleroderma" -- from
the Greek words skleros, meaning hard and derma, meaning skin -- but she was
unclear what had caused it. The man had been taking two drugs to control
his seizures, and Sternberg was suspicious that one of the two drugs -- 5-hydroxytryptophan
(5-HTP) -- might somehow have triggered the inflammation.
When 5-HTP enters the brain, it is converted to another brain chemical called serotonin. Patients with "intentional" seizures have low levels of serotonin; they are given 5-HTP to boost the brain serotonin and (it is hoped) control the seizures. Sternberg searched the medical literature for reports that 5-HTP could cause scleroderma but found none. Thus, it fell to her to prove that an association of the drug with the skin rash was possible.
"This inflammatory disease was," says Sternberg, "a powerful, graphic example of how the brain and the immune system might affect each other." It develops, like other related "autoimmune" diseases, when the immune system fails to recognize that the person's own tissue is a normal part of the body and so reacts against "self."
"I was determined," says Sternberg,"to find the cause of my patient's horrible scarring." She hoped that eventually she would also be able to develop a treatment for it.
Sternberg began
sprinkling serotonin on isolated cells of the immune system to see what
would happen to them. She quickly realized that this approach would not
shed light on either the origin or the course of scleroderma. She needed
to find animals that, like her patient, developed the scarring disease.
Two related strains of rats fit the requirements. Lewis rats were susceptible to scarring and other inflammatory diseases; their genetic cousins -- Fischer rats -- were not. But when Sternberg injected the Fischer rats with a drug that blocked brain serotonin, they too became so susceptible to inflammations that they actually died within 12 hours of exposure to inflammatory stimulants.
Sternberg's explanation for the differences between the rat cousins and for the conversion of the Fischer rats from inflammation-resistant to inflammation-susceptible was that there must exist regulatory links between the immune system and the brain. Normally, the brain of a Fischer rat produces a hormone called CRH that, through a chain of biochemical reactions, turns off inflammatory responses after they have accomplished the good they were intended to do, such as responding to a wound or halting an infection. Sternberg showed that the Lewis rat has a profound defect in the part of its brain -- the hypothalamus -- where CRH is made. The Lewis rat was simply incapable of making enough CRH to turn off its inflammation in a timely fashion (4). Thus, its inflammatory responses could make it sick and even kill it.
Sternberg's analyses of links in the chain of brain-immune interactions took
her, a decade later, full circle back to scleroderma. In the spring of 1989,
Dr. Richard Silver, a rheumatologist -- a doctor specializing in diseases of
joints, muscles, and connective tissues -- called Sternberg to discuss two of
his patients. They seemed to have the exact syndrome that the man with
idiopathic intention myoclonus had, which Sternberg had described in her
1980 publication (1).
The main difference was that Silver's patients were
taking tryptophan (T) instead of 5-HTP. Might the conditions be related?
Sternberg and Silver immediately embarked on a collaborative study of how
Silver's patients handled T, which is a precursor of 5-HTP.
Silver's patients were not the only people who, upon taking T, were getting sick. About six months later, Sternberg heard a radio report of a puzzling epidemic that was wreaking havoc in Los Alamos, New Mexico. There, people taking large doses of T were developing "the flu" and other serious medical problems. Some had died. One of the signs of their disease was that they had way too many eosinophils -- a type of white blood cell -- in their blood streams. Sternberg remembered that her scarred epileptic patient had also had eosinophilia.
The Los Alamos epidemic was spotted by the town librarian. Three local doctors called her within a couple weeks, all making similar requests: Could she please search the medical literature to see if there were reports of diseases of eosinophilia associated with the ingestion of T. The librarian, struck by the unusual identical requests, asked the doctors if they were all seeing the same patient or if several patients were involved. The literature search yielded one reference -- Sternberg's 1980 paper describing the scleroderma patient who had taken 5-HTP. The Los Alamos doctors concluded that, indeed, the culprit might be the related substance T that their patients were taking.
Sternberg realized, when she heard the radio report, that the Los Alamos patients and the patients she and Silver were studying probably all had the same disease. The Los Alamos doctors were seeing the disease in the early phase when patients seemed to have the flu; she and Silver were studying patients in whom the disease had advanced to scarring.
T was the latest nutritional fad. People bought T, an amino acid, in the local health food store. Most were "self medicating" with it, spurred on by claims that it would help them sleep better, or ease their depressions, or solve a variety of other problems.
As soon as the Los Alamos epidemic was recognized as an epidemic, a network of doctors, researchers, chemists, toxicologists, epidemiologists, and rheumatologists from the NIH, FDA, CDC, and university labs as well as general practitioners across the country got involved. "We were driven," says Sternberg, "by a need to figure out the cause of the disease before more patients died."
Eventually, the epidemic was named EMS -- eosinophilia myalgia syndrome. EMS seemed to strike people who had taken certain batches of T, all of which had been produced by one manufacturer in Japan, Showa Denka KK.
In the early stages of the disease, the patients had aching muscles (myalgia) and their bloodstreams were overflowing with eosinophils. Later, when they developed the scarring disease, the skin and nerves and many organs -- the heart, the lungs, and others -- were affected. "So many organs are involved with scarring," said Sternberg in Congressional testimony, (because) "this is a disease of the connective tissue, the glue that holds organs and, effectively, the whole body together (3)."
The tainted batches of T included some 60 impurities. Sternberg and her colleagues showed that, in the inflammation-susceptible Lewis rats, the impure T as well as one of the impurities caused a disease much like EMS. This impurity was a chemical doublet consisting of two T molecules linked together. Pure T itself, in high doses, also could cause scarring of the pancreases of the rats. It didn't cause EMS, but it could be harmful in high doses.
Many of the people who swallowed the bad batches of T are still sick today. Their problems range from minor rashes to badly scarred skin and organs, feelings of anxiety, sleep disorders, and fatigue. Many patients, says Sternberg, were left crippled "in a body cast of their own skin."
In the end, some 5000 to 6000 people may have had the disease, and more than 40 people died. By 1992, some 1800 lawsuits had been filed against Showa Denka KK (2).
The U.S. Congress held hearings to look into the epidemic and assess the possibility of regulating the sale of T. "At the 1991 hearings," said Sternberg in Congressional testimony, "I was asked what do we do to prevent this (type of tragedy) from happening again. It is striking to me now that I am once again before this subcommittee, not to answer that question but to answer the opposite question. That is, should we make food supplements, of which L-tryptophan was classed as a member, more available in order to provide the public with greater freedom of choice." Congress ultimately voted not to regulate the sale of T. "Uninformed choice," Sternberg had said, "is not freedom, particularly if that choice carries with it the risk of death."
The T epidemic has mostly settled down, and Sternberg has returned to her clinical and laboratory studies of stress and the immune system. She and others have shown that the immune system and the brain and the rest of the nervous system "talk" to each other through a number of chemical "mediators" -- cytokines from the immune system and neurotransmitters (like serotonin) and hormones from the nervous system.
The chatter among the mediators is elaborate and complicated, but the goal of all their signalling is a common one -- to keep the body's brain and immune systems in balance (6). When balance is lost and the host encounters an inflammatory trigger or psychological stress, diseases as different as EMS, arthritis, seasonal affective disorder, multiple sclerosis, and chronic fatigue syndrome can develop. It is often difficult to identify which mediator has signalled too much or too little in a sick patient, notes Sternberg, because, by the time the patient seeks medical help, the whole signalling system may already have been thrown out of whack.
Signals between the immune and nervous systems travel between the
hypothalamus (H), the pituitary gland (P), and the adrenal glands (A),
collectively called the HPA axis. When inflammation strikes the body,
cells of the immune system respond by releasing cytokines, which travel to
the brain. The cytokines induce cells in the hypothalamus to make and
release CRH. CRH travels to the pituitary and instructs it to release the
hormone ACTH. ACTH induces the adrenal glands that sit on top of the kidneys
to make and release other hormones. The pituitary and adrenal hormones then
find the immune cells and suppress their activities. When the immune cells
stop producing cytokines, the cycle shuts down, and the inflammation subsides.
Any disturbances to the loop can cause a once-helpful inflammation to explode
into an uncontrolled inflammatory disease.
Sternberg has shown that perturbations in the HPA axis can cause normally resistant animals, like the Fischer rats, to become susceptible to inflammatory diseases. In addition, she recently showed that, when hypothalamic tissue from resistant rats is transplanted into susceptible rats, the rats resist inflammations.
Would it be possible to similarly alter the immune responses to stress signals and immune-disease susceptibility in people? Sternberg says that every person is born with a unique set of genetic predispositions that affect disease susceptibility. Some of these predispositions may be so strong that, even with the tiniest exposure to a disease-causing or inflammation-causing agent, the person will get sick. Others may be much weaker, and, in those cases, whether the individual will get sick or not will depend on other factors. One such factor is the stress response. Another is gender: women have a 4- to 10-fold higher chance of getting an inflammatory disease than do men. Timing is another: hormone production fluctuates daily and monthly in individuals and also over longer periods in their lifetimes.
So many variables figure into the equations of health and disease that it is often difficult for a doctor to settle on the best solution for treating a sick patient. But Sternberg is optimistic, despite the uncertainties: "For any disease there will be a balance of components. In some patients, one or other factor may be so powerful that the others count very little. In other individuals, though, all the factors contribute -- all come into play. It will depend in each situation which is more powerful. "The bottom line, though," says Sternberg, "in dealing with these complex but interesting stress-related diseases of the immune system is that it is better to know the question and not know the answer than not to know the question."
