by Matt Richtel
The T cells first determine if you specifically have come under attack. The concept is called the major histocompatibility complex, or MHC—another immunological term that goes down like cold lemonade on a freezing day.
The net consequence of MHC is that it allows T cells roaming the Festival of Life to avoid killing what Doherty calls the “normal guys” that happen to be nearby. “The assassination is precise, local, and very specifically targeted!
“The MHC is a central component of our immune surveillance system,” Doherty said. “It’s the key to self-recognition.”
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.
This is one of the key markers that differentiate an individual from everyone else in the world.
This extraordinary notion led to one of the most fascinating pieces of scientific theory I ran into while researching this book. The theory has to do with mate preference, incest, and the MHC.
Studies have shown the MHC gene gives off a scent. The scent is used as a factor in how people choose their mates. If one person’s MHC is too similar to another’s, the MHC will act as a repellent. The scent of MHC that is sufficiently different will act as a magnet.
This is significant from several perspectives. For one, it shows the unconscious drive for a certain level of diversity, given that diverse couplings provide to offspring a broader set of abilities. Relatedly, it also creates the possibility that the immune system originated not just to keep us away from pathogens but also to help us choose mates that are sufficiently self but not too much. In fact, the MHC could be part of the reason that incest has evolved to be so abhorrent.
Finally and more broadly, the role of MHC also raises a possibility that the immune system is so primitive and fundamental that it evolved in concert with a seemingly unrelated survival function: the need to reproduce. This question hasn’t been answered. It is a viable theory explained to me by Dr. Thomas Boehm, a pediatrician and researcher at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany.
As humans developed, he told me, “We had to make sure we did not kill ourselves by homogenizing. The one system that is ideally suited is the MHC.”
In a 2006 paper, Dr. Boehm wrote: “I have proposed that this mechanism to assess genetic individuality was initially used for sexual selection and only later became incorporated into immune-defense systems. Whether this primordial system provided only transient coverage against the emerging possibility of self-reactivity and was later replaced by the MHC, or whether it directly evolved into the MHC, is unclear.”
This is partially speculation. It also speaks to the likelihood that the immune system is so fundamental to human existence as to be part of the essence of the species.
I mentioned earlier that the T cell and B cell, and other core aspects of the immune system, have been in place for around 500 million years and that the foundations of our elegant defense go back so far in our evolutionary history that we share it with the world’s other jawed vertebrates—a massive category that includes sharks, skates, and rays. “They have an immune system like ours, a thymus like ours, that makes T cells,” explained Dr. Cooper, who has become one of the leading authorities on the evolution of the immune system.
Even as evolution led creatures to walk onto land, turned them (or us) bipedal, saw the transformation of our communications, and enabled the development of modern tools, the immune system remained largely the same. And recall that to find a different immune system (at least on this planet) you need to go back to a point in biological divergence where the jawed vertebrates split off from the non-jawed vertebrates.
This tells us that, while the immune systems are different, certain defense functions seem essential for survival. One such function is redundancy. There are multiple molecules and cells in both systems, including some proteins that seem to do virtually the same thing—whether it be attacking, inducing attack, or slowing it.
Why so much redundancy? For instance, Dr. Cooper has asked why do we need both T cells and B cells? Wouldn’t one such set of specialized cells be enough? Couldn’t one of the systems have evolved to take care of that? The answer to these questions remains elusive except for one basic point of proof, Dr. Cooper notes: If they weren’t both necessary, they wouldn’t both exist—“we don’t maintain things that are not useful.”
Overall, though, the scientists were getting closer, and deeper, pressing even beyond the microscopic. And with each advance came the chance to explore questions that had, previously, seemed almost pointless to ask. I’ll give you one: what is a fever?
You think you know, right? I did too. The body heats up. But it’s a much more profound question than I had realized, one that would illuminate a new level of understanding of the immune system, namely, that it has a vast, virtually unmatched telecommunications system. This helps explain how, when your body gets invaded, the defense signals can be sent so quickly and effectively, when necessary, calling all hands on deck.
Fever also helps explain inflammation, a concept I also figured was fairly self-evident. Not so much.
What is inflammation?
What is fever?
A stubborn scientist obsessed with rabbit fevers discovered truths previously thought unattainable.
15
Inflammation
In the late 1960s, a woman showed up at Yale University Hospital with a sky-high fever, peaking more than once at 104 degrees. In her mid-twenties, originally from the Caribbean, the woman was shaking with chills, miserable. It didn’t make any sense. That’s because the woman suffered no infection.
It was true that she suffered from an autoimmune disorder called lupus. But that condition wasn’t known to cause this level of fever, and she otherwise had no alien infection, no pathogenic bacteria, no viruses. She harbored none of the things that are understood to cause such a fever.
This case was interesting to the doctors in general, but it was of special interest to one medical student. He became no less than obsessed. Charles Dinarello was in his third year of med school, on his way to becoming a pediatrician, and he had already developed a general interest in fever. Then he saw this young woman in the bed. The patient focused Dr. Dinarello’s curiosity on fever, a subject that had long vexed researchers. It wasn’t clear where fever came from or what its purpose was—to kill the infection, or was something else going on?
This is not at all a simple question. The body, for instance, doesn’t have a central furnace. It doesn’t have a thermostat or an organ that produces heat. But somehow, when provoked, the body—the immune system—sends its internal temperature soaring. Think for a moment about the power and strangeness of this response; the temperature rises intensely throughout the festival. Why and how?
When Dr. Dinarello started his investigation—one that would bear fruit in the mid-1970s—a few things were clear about our body’s temperature, and they will sound self-evident.
Most people have a body temperature within a relatively restricted range, roughly 97 to 99 degrees Fahrenheit for adults and slightly elevated for children, 98 to 100.4, give or take. In later writings, Dr. Dinarello would note that body temperature throughout the day tended to fluctuate more “in some young women than in men.” Interestingly, body temperature was at its peak at around six P.M. each day. These temperatures Dr. Dinarello referred to as low-grade fevers that are likely not representative of disease.
When we experience a fever, we become tired and develop chills. We feel it all over, a very powerful neurological response. It was one of the very earliest of medical observations—the relationship of illness and fever—with early scientists making the connection in 450 BC.
In 25 AD, one of the little-known forefathers of medicine, Aulus Cornelius Celsus, wrote of fever as one of a handful of major signs of inflammation, along with pain, redness, and swelling.
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nbsp; Celsus, by the way, while he was far ahead of his time, had some curious theories as to the causes of various fever-related ailments. A translation of his work produced in the mid-1930s quotes him as having written:
Of the various sorts of weather, the north wind excites cough, irritates the throat, constipates the bowels, suppresses the urine, excites shiverings, as also pain of the lungs and chest. Nevertheless, it is bracing to a healthy body, rendering it more mobile and brisk. The south wind dulls hearing, blunts the senses, produces headache, loosens the bowels; the body as a whole is rendered sluggish, humid, languid. The other winds, as they approximate to the north or south wind, produce affections corresponding to the one or other. Moreover, any hot weather inflates the liver and spleen, and dulls the mind; the result is that there are faintings, that there is an outburst of blood. Cold on the other hand brings about: at times tenseness of sinews which the Greeks call spasmos, at times the rigor which they call tetanos, the blackening of ulcerations, shiverings in fevers.
Pain, headache, fatigue, shivering, fever. Inflammation.
The I-word.
Yes, because of its great importance, the previous line deserves its own paragraph. A definition of inflammation written by the Institute for Quality and Efficiency in Health Care, a group funded by the German government, sums up the sheer breadth of the concept: “Inflammation is—very generally speaking—the body’s immune system’s response to stimulus.”
In the context of health—of the lives of Jason, Linda, and Merredith, of Bob, and of you and me—inflammation is the reaction of the body to an event that challenges our well-being. This can be the inhalation of a virus, the poke of a splinter, the ingestion of noxious bacteria, the claw of a bear or a cat, or even a noise loud enough to cause injury to our hearing. At the moment of insult or stimulus, the defenses react.
Outwardly, leading signs of inflammation include pain, redness, swelling, loss of function, and heat, including fever. Each of these flows from activity going on inside the body aimed at limiting damage from the insult, and also repairing the damaged area. Before I turn to fever and its discovery, I want to put fever into context by illustrating the broader inflammatory picture.
Say you step on a splinter. Virtually instantly, your body recognizes the need for a response. As a preparatory step, the blood vessels in the area open, or dilate. This allows more defenders to reach the action, and it leads to redness and heat in the region. More blood, more cells, more oxygen. The blood vessels go through a second change, becoming more permeable. Now other defenders can move into the tissue, along with clotting agents. These are different kinds of proteins, and as their numbers grow, the region experiences swelling. All this activity can lead to pain. In that way, the inflammation can be seen as having an important impact on behavior by, say, limiting use of the foot that stepped on the splinter so that your elegant defenses have time to shore up the skin.
The inflammatory response, aimed at making sure the area of invasion is fully secure, can well exceed the pinprick of impact. In fact, there can be more tissue damage twenty-four hours after the insult takes place than there was at the moment it happened. During that period, the elegant defenses are examining, cleaning, and rebuilding enough of a physical space to make sure that no danger is left behind and that they can rebuild healthy new tissue seamlessly in the region around it.
Another example of an everyday inflammatory response is the one set off by the common cold. It often is caused by a rhinovirus, which makes a battleground of your nose. The virus replicates there. The blood cells in the area open up to allow for easier access by immune cells. They flood in. Swelling! The vessels become permeable, allowing more flow of fluid. Leaking! Your stuffy nose explained.
So what does this inflammatory response look like up close, on the molecular level?
It resembles the aftermath of a disaster—an armed attack, a multicar crash, a hurricane. I distinguish such events from, say, a fender bender, where one cop might show up and send everyone home. When an insult, like the splinter, happens, it might seem like a fender bender from the outside, but our elegant defenses need a lot of information to make that call and to repair the area of the insult, however small it may be, and this brings multiple cells into the fray. Let’s meet them.
I’ve already introduced you to one of the key cells. It is called a macrophage. It is the cell type observed a hundred years ago by Élie Metchnikoff, the Russian scientist who, as I described earlier, stabbed a starfish larva with a splinter and, looking through the microscope, saw wandering cells swarm to the site of the insult. Metchnikoff observed macrophages devouring other cells in the region of the splinter.
The technical term for one cell eating another is phagocytosis. That word derives from the Greek word phageîn, which means to eat. So the macrophages are big (macro) eaters. These cells are like the love child of a janitor and a cop who eats first and asks questions later. They attack cells in the region that might be damaged or infected by consuming them and then chemically blitzing the devoured particles.
These macrophages derive from and are a subset of a broad group of immune cells known as monocytes. Some monocytes turn into macrophages. But others take on a very different function.
Until now, I’ve described largely T cells and B cells. If you’re surprised to hear there are any more cells in the immune system, you’re in good company. In fact, the more that immunologists over the previous century explored inflammation, the more they realized that our defenses are broken down into many different cells and receptors with widely varied functions. This reckoning ultimately forced them to redefine the very nature of our immune system, though not until the late 1980s.
In the meantime, piecemeal discoveries were made that were crucial in determining the different types of cells and their functions essential to the body’s defense.
For instance, I mentioned that macrophages are a kind of cell called a monocyte. Then in the mid-1970s, Ralph Steinman threw a wrench into science by discovering a sibling monocyte.
“In science, it is a rare event for one individual to make a discovery that opens a new scientific field, work at the forefront of its research for forty years, and live to see his endeavors transformed into novel medical interventions. [Steinman’s] discovery of dendritic cells changed immunology.”
Thus began the Nobel citation about the work of Dr. Ralph Steinman, a physician and researcher who in 1973, trying to fill out the details of an immune system that looked increasingly complex, used an electron microscope to discover an unusual-looking cell. The cell had long tentacles resembling branches, hence the name derived from dendron, which is the Greek word for tree.
Dr. Steinman and a collaborator surmised that these cells played a key role in the immune system, and then proved it. Through a series of experiments, they showed that these cells, when presented with a foreign cell or organism, could stimulate or induce a powerful response from T cells and B cells.
Artist’s modeling of a dendritic cell. (NCI/NIH)
Steinman’s research began to get at how these dendritic cells worked. He showed that the treelike cells played a key role in presenting antigens to the immune system cells. This allowed the T cells, for example, to see whether their receptors fit the antigens being presented.
In practical terms, when your body is invaded by an alien organism, the dendritic cells take a piece of the organism and display it to soldiers and generals to determine if attack is warranted. 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.
Some scientists initially dismissed this discovery. It seemed to differ from or even contradict the commonly held belief that macrophages were a kind of front-line immune cell, largely distinctive from the all-powerful T cell and B c
ell. Bit by bit, though, evidence mounted that the T cell and B cell are being tremendously aided by, and are reliant upon, other cells. In fact, T cells and B cells, together known as lymphocytes, make up only as much as 40 percent of the white blood cells.
The monocytes comprise 5 percent, give or take.
The biggest chunk is made up of cells known as neutrophils. They are both spies and assassins.
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. Their work in the body, we now know, is a bit like that of a cold war spy—a deadly agent but one who is often quietly looking and listening for trouble and then occasionally getting drawn into violence. The journey of the neutrophils begins in the bone marrow, where the defenders are born and from which they make their way into the bloodstream and circulate. The neutrophils might dip into tissue or an organ for a bit, look for pathogens and, finding none, then return to the bloodstream, to continue monitoring and smelling. They can pick up scents, or chemical releases, of pathogens.
When they “smell” such a thing, the neutrophils squeeze from a blood vessel into the tissue where the infection has taken root. The neutrophils, drawn magnetically to the infection, begin to eat it, devouring the invaders. Then the neutrophils release a chemical called an enzyme, which destroys the pathogen. It is a violent affair, one that leaves the neutrophil itself spent, almost like a bee that has inflicted its one sting. The neutrophil begins to dissolve, creating of itself digestible chunks that can be cleaned up by cells with a more janitorial function.
