Human Errors
Page 14
Not surprisingly, depression often accompanies autoimmune disease. When your symptoms are debilitating, when you have few treatment options, when you face difficult side effects of treatment, such as acne and weight gain, as well as the looming specter of a life marked by chronic illness, you can become depressed. This is exacerbated when people around you are less than understanding. The lack of support plus the depression often leads patients to withdraw socially, which makes both the physical symptoms and the depression even worse, sending them into a downward spiral of declining health. As my friend puts it, “It feels like I’m drowning, and when I reach out for help, people put weights in my hands and tell me to swim harder.”
Autoimmunity is as scientifically baffling as it is heartbreaking. Symptoms can be localized, as in rheumatoid arthritis, which causes painful inflammation in certain joints, or they can be systemic, as in lupus, in which B cells attack other cells everywhere in the body. In both cases, the immune system simply attacks parts of its own body. There’s no conceivable reason. This is not some unfortunate evolutionary tradeoff that brings some other benefit. There is no upside to autoimmune diseases. They are simply mistakes. The immune system sometimes misfires.
Autoimmune diseases appear to be on the rise, but, as with other chronic illnesses, it is unclear how much of the increase is due to better diagnostics and extended longevity. The National Institutes of Health estimate that 23.5 million Americans, or more than 7 percent of the population, suffer from one of the twenty-four most common autoimmune diseases. This number is surely an underestimate given that additional autoimmune diseases have already been identified and many more await official scientific classification.
The strangest autoimmune diseases also shine the most penetrating light on this evolutionary flaw. For starters, consider myasthenia gravis (MG), a neuromuscular condition that begins as droopy eyelids and muscle weakness and can progress to complete paralysis—and, if untreated, can ultimately lead to death.
Nothing is actually wrong with the muscles of MG patients. Their immune systems simply begin making antibodies that interrupt normal muscle activity. To get a muscle to flex, a motor neuron releases tiny packets of neurotransmitters onto receptors located in the muscle tissue. The neurotransmitter causes the muscle to contract. It all happens very fast. But if your immune system interferes with the neurotransmitter’s receptors, as happens in people with MG, your muscles slowly start to weaken.
The immune systems of patients with MG produce antibodies that attack the neurotransmitter receptors on muscles. Why? No one knows. Fortunately, what follows is not a huge systemic response. If it were, MG would be quickly fatal. What happens is that the antibodies literally get in the way of the neurotransmitters’ receptors. As MG progresses, the immune system releases more and more of these antibodies, and patients gradually lose the ability to flex any of their muscles.
Not too long ago, if you had MG, you would die within ten years due to the eventual inability to expand your chest and breathe. Fortunately, myasthenia gravis has become one of the many success stories of modern medicine. In the early part of the twentieth century, the mortality rate of MG was around 70 percent. Today, it is well below 5 percent in the developed West. A series of treatments have been developed over the past six decades, culminating in the current regimen of immunosuppressants combined with special drugs that counteract the effects of the bad antibodies.
This treatment is no picnic. In addition to causing side effects, the inhibitors must be taken at precise intervals, often meaning patients must wake in the middle of the night to take a pill. Many of them must do it every night for the rest of their lives. If they sleep through their alarms because they are sick, had a little too much to drink, or are just exhausted, they will likely have flare-ups of MG symptoms the next day. Even the most careful patients must contend with the occasional crisis, which often requires hospitalization.
Around sixty thousand people suffer from MG in the United States, and it is slightly more common in Europe for some reason. Like most other autoimmune diseases, there aren’t even any real hints as to the cause. The immune system simply screws up, and once it starts making the antibodies, it can’t stop. Although a genetic form of the disease has been found, it is very rare. The vast majority of cases have no explanation other than some sort of design flaw in our species’ immune system. Thankfully, science now saves the lives of most MG sufferers, but for thousands of generations before the previous one, it was a terminal illness.
Like MG, Graves’ disease is an autoimmune disease caused by the immune system developing antibodies to a perfectly normal, abundant, and important molecule in the body. In Graves’ disease, for no apparent reason, the patient begins making antibodies that act on the receptor for a hormone called thyroid-stimulating hormone (TSH). As its name implies, TSH is the master hormone of the thyroid gland; it induces the gland to release thyroid hormones (THs). These hormones travel throughout the body and have myriad effects, mostly related to energy metabolism. Nearly every tissue has TH receptors, which explains why these hormones have such varied effects in such disparate parts of the body.
In Graves’ disease, the antibodies to the TSH receptor do something quite strange. Instead of blocking the receptor and turning it off, they actually stimulate the receptor, probably by mimicking TSH itself. In so doing, they prompt the thyroid to release its eponymous hormones.
Normally, the body closely monitors the amount of THs being released by the thyroid. But in the bodies of people with Graves’ disease, the thyroid is pounded with the TSH-mimicking antibodies. It responds by releasing ever-increasing amounts of THs, leading to a condition called hyperthyroidism.
Graves’ disease is the most common cause of hyperthyroidism. Its symptoms include rapid heartbeat, high blood pressure, muscle weakness, trembling, heart palpitations, diarrhea, vomiting, and weight loss. Most patients develop visible goiters, and their eyes become excessively watery and may even bulge; babies born to women with hyperthyroidism suffer a higher rate of birth defects. The patient may also have psychiatric symptoms such as insomnia, anxiety, mania, and paranoia, and severe cases can result in psychotic episodes. A relatively common condition, hyperthyroidism usually begins after age forty and affects around 0.5 percent of men and 3 percent of women in the United States.
Face of a person with Graves’ disease, with the bulging eyes and enlarged thyroid gland (goiter) characteristic of this mysterious autoimmune disorder. Before modern science identified treatments for this condition, many of its victims ended up in sanitariums, suspected of demonic possession.
Prior to this disorder being described in 1835, it seems likely that undiagnosed Graves’ disease was frequently fatal. It is easy to imagine that the psychiatric symptoms, along with bulging eyes and goiter, might have led our extremely superstitious forebears to suspect demonic possession. Indeed, many histories of sanitariums in Europe in the Middle Ages include tales of paranoid patients with growths on their necks and bulging eyes. Many of these were likely Graves’ patients, previously healthy and productive, abandoned by their family and peers to live their last years in agony.
Mercifully, modern medicine has brought a host of effective treatments for Graves’ disease that usually do not require immunosuppressants. There are several drugs that can be used to inhibit the thyroid gland. There are also drugs to counteract the most threatening symptoms, such as beta-blockers to slow the heart and reduce blood pressure. These treatments do not have many difficult side effects. In addition, radioactive iodine can destroy part of the thyroid gland; this treatment can be repeated if needed. Finally, surgery to partially or completely resect the thyroid can reverse the condition. This must then be followed by thyroid hormone supplementation, easily absorbed with a once-daily pill. Thus, Graves’ disease can now be viewed as an example of science triumphantly solving a problem that our own bodies cause—although for countless generations of humans, the story wasn’t so rosy.
If modern m
edicine has all but triumphed over some autoimmune diseases, like Graves’ and MG, another condition in this category—lupus—remains incurable and almost completely shrouded in mystery. Officially called systemic lupus erythematosus, lupus can affect a nearly endless list of tissues in the body, causing a whole assortment of symptoms that can vary widely among patients, from muscle and joint pain to rashes and chronic fatigue. In fact, many scientists consider lupus a collection of related diseases rather than a single disorder. Estimates vary, but in the United States, at least three hundred thousand and as many as one million people suffer from lupus. Autoimmune diseases discriminate by sex, and lupus is no exception; women are four times more likely than men to suffer from lupus.
While the actual cause of lupus is poorly understood, the initial trigger is believed to be a viral infection. What kind of virus it is—and why the infection screws up the immune system permanently—is anyone’s guess. What we do know is that B cells, the antibody factories of our immune system, begin to create antibodies that target and attack proteins inside the nucleus of its own body’s cells. The immune system, in short, begins to wage war against itself.
When the B cells begin attacking themselves, they undergo a reaction called apoptosis, or programmed cell death. Apoptosis is a controlled form of cellular suicide in which cells dismantle themselves slowly and carefully so as to not trigger panic in surrounding cells and neatly package all of their recyclable materials for their neighbors to absorb. Apoptosis is crucial for embryonic development, cancer defense, and the general health and maintenance of tissues, but it is also a key way that the body’s cells protect other cells from viruses. When a cell senses that it is infected, it kills itself by apoptosis in the hope that it will take the virus down with it, thus sparing the rest of the organism. In most contexts, apoptosis is a rather beautiful example of the poetry of life: cells selflessly sacrificing themselves for the good of the being.
It’s not so poetic in lupus. When the B cells start killing themselves in large numbers, they overwhelm the body’s ability to clear the debris effectively and safely, and they begin to pile up. Compounding this mounting problem, B cells in this activated state are “sticky” due to some receptors on their surface that are designed to seek out infected cells and cling to them. The dying B cells tend to form clumps of cells and cell fragments. This recruits other kinds of immune cells that try to engulf and clear the debris. These immune cells, while attempting to help, sometimes get pulled into the mess. The result is a chain reaction of inflammatory responses that occur throughout the body, focused mostly in the lymph nodes and other lymphatic tissues such as the spleen.
That’s the clinical version of what happens. The simplified version goes more like this: Lupus patients feel like crap pretty much all the time.
Because these microscopic clumps can get caught just about anywhere in the body, lupus patients suffer a long list of symptoms that can change over time. The clinical symptoms of lupus are pain, which can be in specific muscles or joints but also more broadly in the torso or head; fatigue, which can be episodic or chronic; swelling, which can be restricted to extremities or present as generalized water retention; fever; skin rashes; oral ulcers; and depression. Most symptoms are caused by the sticky clumps of cellular debris that get lodged in unfortunate places, such as the microscopic filter system of the kidney, the gas-exchange sacs of the lungs, and even the pericardium, the fibrous sac around the heart. These clumps do more than just gum up the gears of the particular tissue. When they get stuck, they are still engaged in an active inflammatory reaction, which can then spread to the nearby tissue. Once again, it’s just an absolute mess of autoimmunity.
Lupus is especially frustrating in its prediagnosis stages because the patients’ symptoms change, which makes it difficult for their doctors to identify the illness, and the patients often lose confidence in their ability to accurately identify and report their problems. Lupus patients are frequently labeled with a whole host of misdiagnoses, including and especially psychiatric ones. You were complaining of chest pain, but now it’s joint pain? Now it’s something else again? Maybe what you need is a psychiatrist.
Well, maybe yes. As with other autoimmune diseases, lupus is often accompanied by a range of psychiatric symptoms, including anxiety, insomnia, and mood disorders. These stem mostly from the headaches, fatigue, chronic pain, confusion, cognitive impairment, and even psychosis that can accompany lupus. One study found that 60 percent of women with lupus were also clinically depressed. Given all the challenges they face, I’m surprised it’s not 100 percent.
Just as the symptoms of lupus vary widely, so do the treatments for it. While nearly all lupus patients take one immunosuppressant or another, this must be coupled with medicines specific to the unique manifestation of lupus that each patient has. Lupus patients can expect years-long experimentation with different medical regimens in search of the combination that works best—which can then suddenly stop working for no reason.
Fortunately, the prognosis for patients with lupus has improved steadily over time—and when it comes to lupus, the time frame is long indeed. The disease has been called lupus since the twelfth century, but descriptions of the disorder date back to the classical period. It has been recognized as an autoimmune disease since the 1850s, but definitive laboratory tests eluded scientists for a hundred years. Today, lupus patients have a life expectancy that is nearly the same as the general public’s. But this comes at great cost. There is no such thing as a symptom-free day with lupus, and flare-ups can render patients bedridden for weeks at a time.
It’s hard to see lupus as anything other than poor design. Our species’ immune system has checks and balances to ensure that the body mounts a vigorous response against foreign cells and proteins while leaving its own cells and proteins alone. During a viral infection, some of the restrictions are temporarily loosened so that the body can more aggressively fight the virus that has hijacked its cells. With lupus, the switch never gets reset, and patients live the rest of their lives in a fight against a phantom virus. The response itself is preprogrammed and useful in its proper context. It is the switch that fails. While all autoimmune diseases are rough, lupus is arguably the most baffling. When the immune system fights itself, it loses either way.
Myasthenia gravis, Graves’ disease, and lupus are just three of the many autoimmune diseases that humans can develop. While the National Institutes of Health tracks only the twenty-four most common ones, such as rheumatoid arthritis, inflammatory bowel disease, myasthenia gravis, lupus, and Graves’ disease, the American Autoimmune-Related Diseases Association estimates that more than one hundred autoimmune conditions exist, and they affect fifty million Americans, or about one-sixth of the population. Some of the other diseases that are confirmed or strongly believed to be autoimmune in nature are multiple sclerosis, psoriasis, vitiligo, and celiac disease. Many also suspect that autoimmunity underpins at least some cases of type 1 diabetes, Addison’s disease, endometriosis, Crohn’s disease, sarcoidosis, and many others. There are hundreds of ways that our immune systems can go wrong and end up making us very, very sick.
To be fair, humans do share a few of these autoimmune diseases with other species. For example, dogs are known to get both Addison’s disease and myasthenia gravis. Both dogs and cats can also get diabetes. Interestingly, these diseases are much more common in domesticated animals than in wild animals. We have no clue why the wild cousins of domesticated species and our own close relatives the apes are not heavily burdened with the scourge of autoimmune diseases.
To date, no syndrome similar to lupus has been described in any species other than humans, not even domesticated animals. The same goes for Crohn’s disease and many other disorders. While biomedical research has managed to create animal models for some autoimmune diseases, they don’t appear to be common in other animals. When it comes to autoimmune diseases, humans and our companions seem to be sicker than wild animals, and we don’t know why.
But to call our immune system perfectly designed would be equally inaccurate. There are millions of people who once happily walked this planet only to meet their demise because their bodies simply self-sabotaged. When bodies fight themselves, there can be no winner.
Overreact Much?
It seems that almost everyone is allergic to something these days. And as anyone with a severe peanut sensitivity can tell you, not all of these allergies are created equal. There are rather innocuous allergies that cause mild flulike symptoms—or an itchy tongue in the case of some food allergies—but allergies can also be lethal. In 2015 in the United States, at least two hundred people died from food allergies; over half of those deaths were caused by peanuts. Tens of thousands more were hospitalized.
While allergies are not quite as baffling as autoimmune diseases, the two conditions share a common thread: In both, the human body’s immune system simply gets it wrong. But unlike an autoimmune disease, in which the body overreacts to itself, an allergy is the result of the immune system overreacting to a foreign substance—one that is totally harmless.
Any molecule that triggers an immune response is called an antigen, and antigens are usually proteins. Antigens can be found anywhere and everywhere. Everything we eat, touch, and inhale contains potential antigens, but nearly all foreign substances that we encounter are completely benign.