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Kindle Notes & Highlights
by
Matt Richtel
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December 2 - December 6, 2020
The Toll-like receptor is as elemental a concept as in all of our survival and in the science of immunology, and it had taken years to uncover.
The innate system shows up, discovers a pathogen, and mounts an initial but generic attack, meaning the attack is not specific to the pathogen. It can hold off the evildoers but often cannot kill them completely. That requires specific attacks from a particular T cell or B cell armed with the receptor or antibody that matches the antigen on the surface or inside the bacteria or virus or parasite.
The innate immune system scans organisms for the presence of one of a handful of key identifying markers that are shared by viruses and bacteria. For instance, most bacteria have wiggly tails. Toll-like receptors scan for these. Or they look for a particular variety of large molecules—called lipopolysaccharides—that characterize a class of bacteria called gram-negative bacteria (such as E. coli); or they look for nucleic acids associated with viruses.
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.
We are born with primitive detection mechanisms that can discern not only what is alien but what is pathogen. As a first-line defense, the molecules of the innate immune system recognize a large class of pathogens and signal the T cells: That thing you just identified as alien is bad—go kill it.
AIDS led to a turning point in the story of immunology. The study had been so much about the lab and the mice, about inscrutable language and piecemeal science. Then came this crucible.
While basic immunology continued, there was an exciting new emphasis on applying the decades of hard-earned knowledge to more practical things, like the interaction of the immune system with sleep, stress, allergy, cancer, or nutrition, and like poorly understood symptoms that were actually autoimmunity.
It was a parasite called pneumocystis carinii. Under the microscope, this looks like round clumps. The lungs of McCune’s patient were swarming with these things. The thing is, ordinarily they’re not that dangerous. “You probably have them growing in you right now,” McCune told me. “But your immune system is keeping them down.”
There is a telling sentence in the CDC note: “The CDC defines a case of AIDS as a disease, at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease.”
The 1918 flu pandemic killed up to 50 million people worldwide, according to the Centers for Disease Control, nearly 700,000 in the United States. The CDC says that it is still not totally clear what made this flu so deadly.
There is a key aspect to that flu that is consistent with other deadly viruses. The people who died weren’t overcome by the flu itself but by their immune system’s response to the flu.
“It was a cytokine storm,” Dr. Fukuda said. “People were dying from having an overwhelming response.”
In 1984, 3,454 people died of AIDS. It was going to get much worse. More than four times that amount would die four years later, and then the disease exploded globally.
Bob knew all the operatives, who in turn knew Reagan and Nancy, the first lady, and the operatives knew that Reagan liked them; some speculated his son was gay. “We couldn’t believe he flipped on us,” Bob said.
At the highest level, there are two ways to understand and stop the spread of a pathogen like a flu virus or HIV. One path is to examine the chemistry, the biology, and the response of the immune system—the antibodies, the hard science. The other is to look at the circumstances surrounding a disease or outbreak, the epidemiology.
One woman got up in front of the packed lecture hall, with perhaps a thousand people in attendance, and offered head-twisting epidemiology. She put up a graph with two axes. On the y-axis was the severity of the disease, and on the x-axis was “the number of fisting [anal fist-fucking] events per week.” The intimation was, there was something involving the ripping of tissue.
The two main kinds of T cells that had been discovered were known with characteristic blandness as CD4 and CD8. CD4 T cells are called helper cells, and they induce action by other immune system cells; CD8 cells are killers.
In the course of studying leukemia, Dr. Gallo started looking at retroviruses in animals. These viruses were known to cause leukemia in some animals. That’s why he was studying them. It wasn’t known if there was such a thing as a human retrovirus.
In a retrovirus, the RNA turns viral; it has contracted a virus. The viral RNA is equipped with a special enzyme that causes a process called reverse transcriptase, which turns the RNA into DNA. In other words, the virus causes the process to go in the opposite, or reverse, direction from the typical genetic process by which DNA instructs RNA.
This was generally understood when Dr. Gallo entered the picture. He was the first to discover a retrovirus in human beings. It was called human T-lymphotropic virus type I. HTLV. This is a retrovirus that infects T cells. We understand much more about it now than was grasped then.
There were 16,908 deaths related to AIDS in 1987, according to the New York Times, 20,786 in 1988, 27,409 in 1989, and 31,120 in 1990.
Protease is the enzyme in HIV that helps the virus mature once it leaves the nucleus of the cell it has infected. If the enzyme gets inhibited, the virus doesn’t mature. The virus doesn’t spread. The immune system remains intact. The patient doesn’t die.
For instance, the first major drug had been azidothymidine, or AZT, which was approved in 1987. AZT interferes with the enzyme that causes the retrovirus to transform from RNA to DNA.
Together, AZT and a protease inhibitor led to a significant increase in CD4 cell counts. (If you want to geek out, values of CD4 cells rose by 30 or 40 cells per milliliter of blood, a significant figure when the amount in a healthy person is 800 cells per milliliter of blood. Better yet, the CD4 count didn’t drop.)
By 1997, the death rate due to AIDS had dropped 47 percent. AIDS fell out of the top ten causes of death in the United States, plummeting from eighth to fourteenth.
The hemophiliac was in his twenties, and he had HIV but no viral load, the term for how much of the virus coursed around inside a person. With HIV, the viral load typically took a fascinating path. Initially, it would spike so that there were a million copies of the virus in each milliliter of plasma. (One patient was studied whose load spiked to 5 million copies.) Huge numbers. Then, however, the viral load would typically fall sharply during a chronic phase of the illness and then spike again as death neared.
This was, is, a CD8-dictated mechanism. Bingo. HIV would win, unless the body’s T cell foot soldiers unleashed an immediate effective response.
Still, every minute of 1998, an estimated 11 men, women, and children got HIV. Overall, 5.8 million people worldwide were newly diagnosed with AIDS, bringing the total of people living with the disease to 33.4 million, according to UNAIDS, a United Nations organization cooperating with the World Health Organization.
The drugs increased patients’ vulnerability to diabetes, for instance. Perhaps this was not surprising, given the delicate balance of the immune system; strengthening it to fight HIV meant triggering echoes that, in this case, seemed to cause the body to attack itself and its ability to process sugars.
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. HLA stands for human leukocyte antigen.
There was a third key discovery. It now appeared that Bob and the other elite controllers had survived likely due to a very specific moment in the interaction between their immune systems and HIV: the first point of contact. “The evidence is pointing us to what we call the prime—the priming event. It’s when the immune system first sees virus,” Dr. Migueles said. “We suspect people like Bob start down the road to being an elite controller right at the beginning.”
The initial response, whether to flu or HIV or a cold, might well echo through the immune system. The right first response could save your life, not that you have particular control over such a thing. However, knowing this can inform the way we build medicines, or study individuals to see their susceptibility to various viruses, say, through genetic testing.
Dr. Migueles said that intensive study of HIV has helped develop “a flow chart of the multiplicity of relationships” in how the immune system cascade works. “That’s where the treasure chest is.”
The thing about autoimmunity is that the questions and answers sometimes don’t get any further than focusing on the symptoms. My joints ache, I have fever, I’ve got this rash, I have diarrhea, constipation, mind-numbing fatigue.
In 1926, according to a Mayo history, 574 patients were admitted to the rheumatology service with joint swelling and pain. The presumption was that the cause was chronic infection—something foreign was sparking it. This was, of course, wrong. Vaccines were tried. They led to serious side effects, even death.
Dr. Hench had a hunch. When patients experience stress and are under duress, it typically means that they are secreting adrenaline. Dr. Hench theorized that joint pain and inflammation were being dulled by a secretion from the adrenal gland, a small, triangular-shaped nub located atop each kidney that produces essential hormones.
Then in 1948 at the Mayo Clinic, the very scientists who had begun working there in 1929 gave Compound E to a twenty-nine-year-old woman immobilized with severe rheumatoid arthritis. “Two days and two more injections later, the patient could walk and left the hospital to enjoy a three-hour shopping spree,” reads a recounting of the story published in the same 2010 scientific article.
You might know Compound E by a different name, cortisol. Cortisol is a steroid that suppresses the immune system. Steroids are the first line of defense against many autoimmune disorders. They are a mixed blessing, as you’ll see later on. For the moment, though, the discovery of steroids in the field of immunology and medicine was analogous to the discovery of a vaccine or antibiotic; they were a tremendous revelation, a response to a vexing problem, but a response that came without an understanding of the underlying mechanism of the disease they were meant to treat—autoimmunity.
In 1948, a related test was developed to probe for the presence of antinuclear antibodies. These antibodies can bind to the nucleus of a normal cell and had been shown to be present in virtually everyone with systemic lupus.
Direct evidence involves being able to transmit and reproduce the condition from one human to another—to, in effect, replicate the autoimmune process. There aren’t very many examples of this. The best involves a doctor in the 1950s who pursued a time-honored tradition in science: experimenting on himself.
scientists pursued a second course, indirect evidence. This entails replicating a human condition in mice. This is doable with multiple sclerosis, where the immune system interferes with the central nervous system. It can be induced in mice by vaccinating the mice with an antigen that is much like the one that humans attack in themselves.
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.
In day-to-day terms, the downside of a strong immune system, then, is that it can become more susceptible to being inflamed or set off by lack of sleep or stress or—this will likely go without saying—genetics.
These are the same kinds of mechanics, incidentally, that make smoking such a risk for rheumatoid arthritis. Smoking introduces all sorts of foreign particles into the body, sucked down the throat and into the lungs, turning the immune system into a busybody surveying the particles and damage.
What was so widely anticipated about Enbrel, made by a Seattle company called the Immunex Corporation, was that it was designed specifically to limit the effects of an overreactive immune system without undermining the entirety of the system.
The monoclonal antibody used in Enbrel is produced in hamster ovaries.)
This nationalism proved to function as a kind of autoimmune disorder: Hitler was attacking productive, healthy, essential parts of the whole of Germany and Austria. On Kristallnacht, in November 1938, Merredith’s mother saw her father and mother taken into the street, put on their hands and knees, and made to lick shards of glass from broken windows.
It wasn’t until the early 1990s that it was confirmed that her mother was suffering from ulcerative colitis and Guillain-Barré syndrome, a rare and nasty disorder. Here, our elegant defense, the immune system, turns against the lining that coats the ends of long nerve cells that extend along the periphery of the body. The linings of the nerves, known as myelin sheaths, are crucial because they help the body to quickly and efficiently transmit information by insulating these cells and, in effect, keeping out other information. In Merredith’s mother, though, T cells and B cells had begun to
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She had developed a very rare, dangerous autoimmune condition known as pyoderma gangrenosum. It appears to involve massive stores of tumor necrosis factor going on the attack against self.
This nineteenth-century essay, incidentally, says it can be difficult to distinguish between hay fever and asthma or rheumatism. This is worth noting because these turn out to be autoimmune disorders, and allergies wind up as a close cousin. The immune system is overreacting.
