An Elegant Defense: The Extraordinary New Science of the Immune System: A Tale in Four Lives

by Matt Richtel

Only recently have we begun to understand the pervasive role of our immune system in the brain, where damaged or outdated synapses get pruned by the organ’s own immune cells, allowing ongoing neurological health.

Fully 20 percent of the American population, or 50 million Americans, develops an autoimmune disorder.

Together, autoimmunity is the third most common disease category in the United States (after cardiovascular disorders and cancer).

Smoking tests the immune system like few human habits; the tiny nicks and cuts to the soft lung tissue don’t just create persistent injury but force cells to divide to replace the hurt tissue. Cell division heightens the possibility for malignancy, cancer.

Broadly, it is hard to overstate the toll taken by autoimmunity. Of the five top-selling drugs on the market, three treat autoimmunity, including the world’s bestselling medication, Humira, used to suppress the immune system for treatment in a variety of illnesses. It boasts nearly $20 billion in annual sales.

What we can see clearly now is that arthritis sufferers, people with celiac disease or lupus, even people who suffer seemingly mysterious bouts of fatigue, fever, and pain, all share an often-invisible threat: an elegant defense that is out of balance, an immune system that has overcompensated, been triggered to act without proper constraint.

Then about 500 million years ago, a split occurred, resulting in what would evolve into two major immune system lineages. One lineage belongs to non-jawed vertebrates, such as the lamprey and the hagfish. They developed a defense network that is both fundamentally different from ours and nearly as sophisticated. By comparison to ours, theirs is like an ancient language with different lettering, an alternate scripting of the genetic code that confers many of the same defense advantages. Twenty million years later, around 480 million years ago, the other lineage finds its roots. We know this because creatures that lived that long ago, like the shark, rely on this second lineage. And so do human beings. In the most fundamental sense, we share an immune system with sharks and other jawed vertebrates.

Meanwhile, there’s another twist: About 8 percent of our genetic material was formed from retroviruses. That means we’ve mingled with these viruses and they’ve become part of us, to the point that they can be not only helpful but essential. An example is the placenta, which may have evolved from a retrovirus in such a way that it helped enable the transmission and sharing of material between mother and child.

Survival depends on knowing what is self and what is alien. The immune system must cope with three major challenges: the variability of bad actors, the central circulatory system that sends rivers of blood throughout our body in seconds, and the need to heal.

You’re a full five feet away from the infected person. Not far enough, says the Centers for Disease Control and Prevention (CDC), which puts the flu’s range of travel by sneeze or cough at six feet.

Smallpox was spread through the air, by sneezes, coughs, or close interaction with a victim. It killed 30 percent of those who contracted it. Its lethality has to do with the way it and related viruses pull a stunt on the immune system. The infections can block the transmission of a distress signal that calls killer immune cells into action.

The country scrambled to produce and disseminate the vaccine as quickly as possible. Alas, this happy ending comes with an asterisk. The first big batch of vaccine wasn’t properly made. Cutter Laboratories in California, one of the main producers of the vaccine, inoculated more than 200,000 children in 1955, and within days there were reports of paralysis. Within a month, the program was discontinued, and investigations revealed that the Cutter vaccine had caused 40,000 cases of polio, leaving 200 children with varying degrees of paralysis and killing 10.

MHC is the single most varied or polymorphic of all human genes. Every human being has roughly the same MHC genes, but they are all slightly different. They are the immune system’s fingerprint.

The dendritic cells roam the Festival of Life, brushing up against guests at the packed affair, and presenting their identities to the T cells. If an antigen were perceived as foreign, it would stimulate a heavy response, what is known as a mixed leukocyte reaction, or MLR, a major inflammation of T cells and B cells and other immune cells.

The neutrophil is the cell that Metchnikoff had observed and had himself eventually better understood. The neutrophils represent more than half of our white blood cells—50 to 60 percent.

In much smaller concentration in the body are two other defenders, the eosinophil (less than 5 percent of the white blood cell population) and the basophil (less than 2 percent). Combined, they are known as granulocytes. This name reflects their function. These cells contain tiny enzymatic granules that digest and destroy pathogens.

“When interferon is secreted, you feel sick. It causes aches and pains; you feel terrible,” Zoon explained. Your behavior is being modified—not by the virus directly, but by the response. In very practical terms, a virus invades. The early warning system then sets off a cascade that leads to inflammation, and that also makes you feel rotten. Tired, sore, hot, as I described earlier. You are slowed down, and this can have the very beneficial impact of diverting your body’s resources to fighting the virus and not, say, focusing on your job or going for a jog.

As he looks back at the fateful war in Afghanistan, the hostility of the crumbling Communist regime to anything foreign now looks to him a bit like an autoimmune disease. “You’re trying to destroy what you perceive as nonself, and you destroy a lot of self,” he said. “It’s sort of like autoimmunity,” he added. “It’s exactly what’s happening in the Middle East.”

Among the cells at the scene are macrophages and dendritic cells with Toll-like receptors on the surface. The receptors can instantly determine whether the foreign substance entering the body has the hallmarks of a major pathogen. If a pathogen presents itself—say, a noxious bacteria—not only does the immune system unleash a first-line attack but also the dendritic cells, now aware of the pathogen, begin their journey to find the T cell and B cell necessary to provide a more specific defense.

Many so-called elite controllers, patients like Bob who keep HIV at bay, have a gene that impacts the way the immune system recognizes foreign invaders. Specifically, they share a genetic variant called HLA-B57.

In Bob and other elite controllers, this key gene, B57, seemed different. In the first study of elite controllers, eleven of the thirteen had this gene. By comparison, only 10 percent of the population as a whole have B57.

A pioneering rheumatologist named Dr. Philip Hench, working at the Mayo Clinic, noticed an oddity with one particular rheumatoid arthritis patient. Her joint pain and stiffness seemed to get better when she developed acute jaundice. She got a disease and her joint pain got better, not worse.

For instance, lupus researchers could now see that the condition involved a patient’s own immune cells eating away at free-floating material in the bone marrow. This was a double whammy of sorts. The bone marrow helps gestate and stimulate the immune system, and it was under attack by the very system it had helped spawn.

Linda had taken a test to measure sedimentation rate, which provides a broad-based measure of inflammation. Her score should’ve been under 20. It was 94. Inflammation off the charts.

The Johns Hopkins University School of Medicine divides the materials of the diagnosing of autoimmunity into three categories that collectively sound like types of evidence at a criminal trial. The evidence can be direct, indirect, or circumstantial.

She also noted that many of the genes that are associated with lupus and rheumatoid arthritis are on the X chromosome. (Women have two X chromosomes, whereas men have one X and one Y.) So the math of autoimmunity became greatly weighted toward females. (Another piece of science trivia: When researchers want to create an antibody to study, they use a female animal, not a male. You get more antibodies.)

A woman’s relatively elevated immune system “is associated with living longer. But you have higher antibodies. That might make you sick and cause you to die,” Dr. Hahn said. What an incredible trade-off: longer life thanks to powerful defenses that can turn on themselves!

In November 1998, the U.S. Food and Drug Administration approved one of most anticipated drugs in medical history: Enbrel. It was aimed at treating rheumatoid arthritis.

With Enbrel and other drugs that act on TNF, the idea is to get the cells that are causing problems to commit suicide. Obviously, getting malignant cells to off themselves can be useful in cancer. In the case of rheumatoid arthritis, it’s also advantageous to have overzealous immune cells commit apoptosis. Instead of attacking Linda’s body, the cells would kill themselves.

Enbrel is now one of the bestselling drugs in the entire world. It generated $5.5 billion in sales in the 2017 fiscal year for Amgen, the company marketing it.

The paper was short, less than two pages, in BMJ, titled “Hay Fever, Hygiene, and Household Size.” The author looked at the prevalence of hay fever among 17,414 children born in March of 1958. Of sixteen variables the scientist explored, he described a “most striking” association between the likelihood that a child would get hay fever allergy and the number of his or her siblings. It was an inverse relationship, meaning the more siblings the child had, the less likely it was that he or she would get the allergy. Not just that, but the children least likely to get allergies—also known as atopic diseases—were ones who had older siblings.

At a core level, we have created a mismatch between our immune system—one of the longest surviving and most refined balancing acts in the world—and our environment. Thanks to all the powerful learning we’ve done as a species, our immune system isn’t getting the regular interaction with germs that helped to teach and hone it—that “trained” it. It doesn’t encounter as many bugs when we are babies. This is not just because our homes are cleaner, but also because our families are smaller (fewer older kids to bring home the germs), our foods and water cleaner, our milk sterilized, and on and on. What does an immune system do when it’s not properly trained? It overreacts. It becomes aggrieved by things like dust mites or pollen. It develops what we called allergies, chronic immune system attacks—inflammation—in a way that is counterproductive, irritating, even dangerous. There has been a rise in autoimmunity too.

The Amish in the study “practice traditional farming, live on single-family dairy farms, and use horses for fieldwork and transportation. The Hutterites live on large, highly industrialized, communal farms.” There is another major difference, this having to do with the prevalence of allergy. Only 5 percent of Amish schoolchildren suffered asthma, compared to 21 percent for the Hutterites. On a slightly lesser measure of sensitivity—called allergic sensitization—7 percent of Amish kids qualified, compared to 33 percent for Hutterities.

“As compared with the Hutterites, the Amish, who practice traditional farming and are exposed to an environment rich in microbes, showed exceedingly low rates of asthma and distinct immune profiles that suggest profound effects on innate immunity,” reads the paper in The New England Journal of Medicine.

the United States in 2015 sold 34 million pounds of antibiotics for use in “food-producing animals,” according to the FDA. That was around 80 percent of the antibiotics used in the United States altogether.

The report that came out in 2014 predicted that by 2050, 10 million people will die from resistant bacteria annually, which by that point will be more than the 8.2 million people predicted to die of cancer that year. There is a case to be made that this is among the top three medical crises facing our world, as widespread and shared as climate change but with much more immediate impact.

One review on the subject written by scholars at the University of Colorado at Boulder reported that there are 3.3 million microbial genes in the human gut, “compared to roughly 22,000 genes present in the entire human genome.” Another study estimated there were 1,000 species of bacteria in the gut with 5 million genes. The scope of the microbiome is, in a word, huge.

One of the many variations of T cells, we now know, is called a T regulatory cell, or Treg. It is a powerful subset of our T cells that has been shown, among its other roles, to help suppress the immune system. In the big picture, this makes sense; it is part of a defense network that is primed to destroy party crashers without being so overzealous that they ruin the party. In that respect, Treg cells are not so unusual. What makes them worthy of note here is that there is a decent chance they wouldn’t exist without the presence of the microbiome in the gut. What Mazmanian discovered, using experiments in mice, is that Treg cells don’t get developed when certain gut bacteria are missing. In other words, when the microbiome of the mouse is incomplete, so is the immune system.

“There are entire cell types in the body that don’t exist because the DNA doesn’t have all the information to tell that cell to develop,” he said. It’s not just Treg cells, but natural killer cells and other killer immune cells that appear to be triggered by the bacteria. Broadly, Mazmanian’s work also shows that the microbiome plays a key role in dampening the immune system, in addition to helping it to attack foreign invaders.

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.

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.

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.

“We now have compelling evidence that, in addition to cognitive impairment, sleep loss is associated with a wide range of detrimental consequences, with tremendous public-health ramifications,”

He believes that only part of the immune system gets dampened by this cycle. Stress and lack of sleep, Dr. Irwin believes, make it tougher to fight viruses but easier, or at least less difficult, to fight bacteria.

Often, Dr. Irwin said, the culture adds another layer, pushing us forward, rather than letting the system settle down through withdrawal or sleep. “It’s a badge of honor to see how little sleep you can get by on. If you can sleep less and maintain function at work, you’re a better professional. You’re a better human being. That crazy logic has led to a sleep-deprived society, and that is having huge health consequences.”

Part of the way that Hodgkin’s and other cancers disguise themselves is by tricking the T cells that would ordinarily help kill off the mutation. What the cancer does is send a signal to the T cell to self-destruct. Why would the T cell do that? Why would it even have such a receptor on its surface capable of receiving a self-destruct signal? It’s because the immune system has many mechanisms that are aimed at slowing it down, shutting it off, keeping it from overheating. Cancers take advantage of these fail-safe mechanisms to survive. The self-destruct receptor on the T cell is called programmed death. For short, PD. On the cancer is a molecule called PDL-1, a programmed death ligand that binds to or connects to the PD receptor on the T cell. Inside Jason’s body, malignant B cells had grown and were using PDL-1 to put the brakes on the killing part of his immune system. At the same time, now that the immune system had received a message that the cancer was “self” and not alien, the immune system actually set out to protect and support the cancer.

cancer is a product of the same evolutionary processes that lead to our own survival, or that of any other species or organisms. When a mutation occurs inside us, it thrives if it has developed the ability to evade our body’s defenses. Over the course of our lifetimes, we’re being thrown tons of twists by malignant cells, and it takes only a handful to turn on the immune system’s brake and start a cascade of malignancy. “It’s basically evolution at work in real time, a Darwinian survival system,” Dr. Lesokhin said.

“What happens today is that many people are living with imaginary bears at every step of their lives—something in the news or around the bend is going to get them.” What followed was what he called a “norepinephrine high.” It was a survival mechanism, in the short term. But in the long term, it was dangerous, even deadly.

he said that norepinephrine and epinephrine can start to feel, perversely, exciting. “You get addicted to it. You need it. Suddenly it’s going on all the time. The brain is driving it. Now you get all the disruptions of excess. You get dis-regulation of the immune system.”

mention these people not for the sake of merely giving thanks, but because the science bears out that the ability to find connection during times of sickness, including anxiety and depression, is instrumental in healing. It helps the immune system find balance, and this makes sense from an evolutionary perspective; the idea that you are part of a community is powerful incentive and motivation for your body’s machinery to seek harmony. Left alone, you might recede further.