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Stress and immunity

Robert Sapolsky: Stress and immunity

It turns out that during the first few minutes (say, up to about thirty) after the onset of a stressor, you don't uniformly suppress immunity—you enhance many aspects of it (phase A on the accompanying graph). This is shown with all realms of immunity, but in particular for innate immunity. This makes sense—it may be helpful to activate parts of your immune system that are going to make some swell antibodies for you over the next few weeks, but it makes even more sense to immediately activate parts of the immune system that are going to help you out right now. More immune cells are rushed into the circulation and, in the injured nervous system, more inflammatory cells infiltrate the site of injury. Moreover, circulating lymphocytes are better at releasing and responding to those immune messengers. And more of those generic antibodies of the innate immune system are released into your saliva. This boosting of immunity doesn't occur only after some infectious challenge. Physical stressors, psychological stressors, all appear to cause an early stage of immune activation. Even more surprisingly, those immunosuppressive villains, glucocorticoids, appear to play a major role in this (along with the sympathetic nervous system). So, with the onset of all sorts of stressors, your immune defenses are enhanced. And now we are ready for our usual other side of the two-edged sword, when the stress goes on longer. By the one-hour mark, more sustained glucocorticoid and sympathetic activation begins to have the opposite effect, namely, suppressing immunity. If the stressor ends around then, what have you accomplished with that immunosuppression? Bringing immune function back to where it started, back to baseline (phase B). It is only with major stressors of longer duration, or with really major exposure to glucocorticoids, that the immune system does not just return to baseline, but plummets into a range that really does qualify as immunosuppressing (phase C). For most things that you can measure in the immune system, sustained major stressors drive the numbers down to 40 to 70 percent below baseline. The idea of temporarily perking up your immune system with the onset of a stressor makes a fair amount of sense (certainly at least as much as some of the convoluted theories as to why suppressing it makes sense). As does the notion that what goes up must come down. And as does the frequent theme of this book, namely, that if you have a stressor that goes on for too long, an adaptive decline back to baseline can overshoot and you get into trouble. Why did it take people so long to figure this out? Probably for two reasons. First, because many of the techniques for measuring what's happening in the immune system have only recently become sensitive enough to pick up small, rapid differences, the thing needed to catch phase A, that fast immunostimulatory blip at the beginning of a stressor. Thus, for decades, people thought they were studying the immune response to stress, whereas they were actually studying the recovery of the immune response to stress. As a second reason, most scientists in this field study major, prolonged stressors, or administer major amounts of glucocorticoids for prolonged periods. This represents a reasonable bias in how experiments are done—start with a sledgehammer of an experimental manipulation. If nothing happens, pick a new field to study. If something does happen and it's been replicated enough times that you're confident about it, only then begin to think about more subtle elaborations. So in the early years, people were only studying the sorts of stressors or patterns of glucocorticoid exposure that pushed into phase C, and only later got around to the subtler circumstances that would reveal phase B. This reorientation of the field represents a triumph for Allan Munck of Dartmouth University, one of the godfathers of the field, who predicted most of these new findings in the mid-1980s. He also predicted what turns out to be the answer to a question that pops up after a while. Why would you want to bring immune function back down to the prestress level (phase B in the diagram)? Why not just let it remain at the enhanced, improved level achieved in the first thirty minutes and get the benefits of an activated immune system all the time? Metaphorically, why not have your military that defends you always on maximal alert? For one thing, it costs too much. And, even more important, a system that's always on maximal, hair-trigger alert is more likely to get carried away at some point and shoot one of your own guys in a friendly fire accident. And that's what can happen with immune systems that are chronically activated—they begin to mistake part of you for being something invasive, and you've got yourself an autoimmune disease. Such reasoning led Munck to predict that if you fail to have phase B, if you don't coast that activated immune system back down to baseline, you're more at risk for an autoimmune disease. This idea has been verified in at least three realms. First, artificially lock glucocorticoid levels in the low basal range in rats and then stress them. This produces animals that have phase A (mostly mediated by epinephrine), but there isn't the rise in glucocorticoids to fully pull off phase B. The rats are now more at risk for autoimmune disease. Second, doctors have to occasionally remove one of the two adrenal glands (the source of glucocorticoids) from a patient, typically because of a tumor. Immediately afterward, circulating glucocorticoid levels are halved for a period, until the remaining adrenal bulks up enough to take on the job of two. During that period of low glucocorticoid levels, people are more likely than normal to flare up with some autoimmune or inflammatory disease—there's not enough glucocorticoids around to pull off phase B when something stressful occurs. Finally, if you look at strains of rats or, weirdly, chickens, that spontaneously develop autoimmune diseases, they all turn out to have something wrong with the glucocorticoid system so that they have lower than normal levels of the hormone, or have immune and inflammatory cells that are less responsive than normal to glucocorticoids. Same for humans with autoimmune diseases like rheumatoid arthritis. Thus, early on in the stress-response, the immune system is being activated, rather than inhibited, and a big thing that the stress-response does is make sure that immune activation doesn't spiral into autoimmunity. So that has forced some revisionism in this field. But just to add to this, once stress has gone on long enough to begin to suppress immunity, some of what have classically been taken to be aspects of immune suppression are actually more subtle versions of immune enhancement. This is seen in two ways. Give someone massive amounts of glucocorticoids, or a huge stressor that has gone on for many hours, and the hormones will be killing lymphocytes indiscriminately, just mowing them down. Have a subtle rise in glucocorticoid levels for a short time (like what is going on at the start of phase B), and the hormones kill only a particular subset of lymphocytes—older ones, ones that don't work as well. Glucocorticoids, at that stage, are helping to sculpt the immune response, getting rid of lymphocytes that aren't ideal for the immediate emergency. So that indirectly counts as a version of immune enhancement. A second subtlety reflects reinterpretation of something people have known since the dawn of humans (or at least during Selye's prime). As noted, glucocorticoids not only kill lymphocytes, but also yank some remaining lymphocytes out of the circulation. Firdhaus Dhabhar of Ohio State University asked, Where do those immune cells go when they are pulled out of the circulation? The assumption in the field had always been that they all go into immune storage tissues (like the thymus gland)—they're taken out of action, so that they aren't much use to you. But Dhabhar's work shows that they don't all get mothballed. Instead, glucocorticoids and epinephrine are diverting many of those lymphocytes to the specific site of infection, such as the skin. The immune cells aren't being deactivated—they're being transferred to the front lines. And a consequence of this is that wounds heal faster. Thus, early on during exposure to a stressor, glucocorticoids and other stress-responsive hormones transiently activate the immune system, enhancing immune defenses, sharpening them, redistributing immune cells to the scenes of infectious battle. Because of the dangers of the systems overshooting into autoimmunity, more prolonged glucocorticoid exposure begins to reverse these effects, bringing the system back to baseline. And during the pathological scenario of truly major, sustained stressors, immunity is suppressed below baseline. (transcript lecture "Why Zebras Don't Get Ulcers", Robert Sapolsky)

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