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IMMUNE SYSTEM
I AM BECAUSE YOU ARE
Biology is about recognition and misrecognition.
—DONNA HARAWAY1
The role of the physician is to translate “medically unknown symptoms” into social problems.
—NANNA MIK-MEYER2
What do you call second-class citizenship? Why, that’s colonization.… They try and make you think they set you free by calling you a second-class citizen. No, you’re nothing but a 20th century slave.
—MALCOLM X3
The body has an ancient and powerful mechanism to heal itself: the inflammatory response. Inflammation occurs when the body’s innate immune system responds to damage or a threat. Inflammation can be acute or chronic, localized or systemic, but it involves a whole host of cells and molecular messengers participating in a complex, choreographed set of interactions. The goal is repair and recovery—restoration of the body’s optimal working conditions, a state called homeostasis.4
The acute inflammatory response is a time-limited event. Activity increases sharply in the face of a threat or injury and then resolves when the threat has passed and the damage is repaired. Once healing is complete, specific regulating molecules turn off the response.5 Sometimes, though, the response doesn’t switch off, and the result is a chronic systemic inflammatory state. When that happens, the body’s healing mechanism is transformed into a smoldering fire that creates ongoing harm. The result is a crucial breakdown in the immune system’s ability to repair damage and restore homeostasis.
Acute inflammation can begin with an infection, when innate immune cells recognize molecular signatures found on the surface of bacteria, fungi, or viruses called pathogen-associated molecular patterns. These signatures haven’t changed much over millions of years of evolution, and because humans have evolved in tandem with these organisms, our innate immune cells have developed ways to recognize them. Acute inflammation can also be triggered by cellular injury. In this situation, damage-associated molecular patterns, which consist of cellular debris, are released in response to physical or chemical injury.6
Following activation by these molecular patterns, tissues and immune cells release a host of signaling proteins called cytokines. Some of these messengers amplify inflammation—they’re called pro-inflammatory—and other, anti-inflammatory ones abate it. Pro-inflammatory cytokines—interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-a), for example—keep the inflammatory response cooking. They stimulate the release of other inflammatory mediators, such as C-reactive protein (CRP) from the liver. These are some of the key biomarkers currently used to track acute inflammation.7
The acute and chronic inflammatory responses share some important characteristics and molecular mechanisms, but they also differ in essential ways. While acute inflammation is triggered by molecular patterns both from pathogens and from damages, chronic inflammation is prompted in the absence of infection. It is set off by damage-associated molecular patterns and other SOS signals from living cells that are under duress.8 As such it is often referred to as “sterile” inflammation. Hormones and nerve signals that respond to psychological stress can set off these SOS signals.9 So can air pollution and other characteristics of modern life. When the inflammatory response is sustained from repeated triggers, molecules generated by innate immune cells in response to these SOS signals create collateral damage. Add to that damage from an entire lifetime of exposures that generate more inflammation, and the body never has a chance to repair.
Acute inflammation can occur at any age, as we know from the toddler with an ear infection or the teenager with a skateboarding injury. But chronic inflammation happens only with advanced age. The older you get, the more likely you are to suffer from it; not only that, it ages you disproportionately. Your birth certificate might claim you’re middle-aged, but you could clock decades older on the inside. This close relationship between aging and inflammation has led to the clever neologism “inflamm-aging.”10
Central to this relationship is cellular senescence, the process by which aging cells permanently stop dividing but remain metabolically active. Under certain conditions, some senescent cells go on to express the senescence-associated secretory phenotype.11 This functional change transforms them into vigorous producers of the pro-inflammatory cytokines and other molecules that drive systemic inflammation. Mounting evidence indicates that senescent cells with this phenotype are involved in the onset and progression of the age-related diseases of chronic inflammation, such as cardiovascular disease, diabetes, chronic kidney disease, chronic obstructive pulmonary disease (COPD), osteoarthritis, and Alzheimer’s.12 These cells may be driving the runaway inflammation of severe Covid in the elderly13 and the pathology in autoimmune diseases, such as rheumatoid arthritis.14
But not all aging cells develop this phenotype as they become senescent. Ones that do have accumulated a lifetime of cellular damage due to a variety of exposures.15 While both endogenous and external factors can drive the development of chronic inflammation, a study documenting 210 healthy twins found that external factors—environmental and social—had the biggest influence.16 Damaging exposures are the game changer, converting our aging cells into ones that do us harm.
The sum of lifetime exposures to nongenetic drivers of health and illness, from conception to death, is called the exposome.17 The exposome encompasses chemical, social, psychological, ecological, historical, political, and biological elements that determine whether aging cells will become drivers of chronic systemic inflammation.18 The exposome of modern industrial societies is rife with triggers for inflammation-related diseases. Modern diets contain more processed foods and less fiber, both of which can alter the gut microbiota population and function, leading to changes in the immune system that can create inflammation.19 When we are physically active, skeletal muscle releases anti-inflammatory cytokines called myokines,20 but modern lifestyles increasingly limit the occasions for strenuous activity. Some cities are entirely unwalkable, necessitating travel by car. There’s a reason that doctors are forever telling you to eat more fiber and get more exercise.
The exposome of modern life differs radically from that of Indigenous and traditional people who maintain critical relationships with the living systems upon which their lives and health depend.21 While systemic inflammation and its accompanying diseases have increased dramatically across industrialized societies,22 they remain rare in traditional ones, such as the Shuar hunter-gatherers of the Amazon,23 the Hadza of Tanzania,24 the Tsimané foragers who tend the forests of Bolivia,25 the horticulturalists of Kitava, Papua New Guinea,26 the subsistence farmers of rural Ghana, and even the Irish Travellers before they were recently forced into settled modern housing.27 Members of these groups are exposed to a variety of microbes and infections, but they do not show the same chronic systemic inflammation that drives modern noncommunicable disease.28
The immune system is toned by the exposome, much the way a muscle is toned by exercise or a guitar string is made taut by turning a tuning peg. Immune systems toned by damaging exposomes seem to respond to an insult like Covid with overwhelming inflammation, like a string being pulled too tight. Severe Covid is overexpressed in socially oppressed groups.29 Early in the pandemic, in the Zhejiang Province of China, severe cases were more often seen in agricultural workers and less frequently in people who were self-employed.30 This trend repeated around the world.31 An exposome that counteracted damage, making room for more care—like giving workers a guaranteed income so they could stay home with their families during the pandemic—would allow for a more measured immune reaction in the face of a real or perceived threat.32 The interaction of the exposome with the genome gives rise to the disparities we see in health and illness across different demographics. While genetics play a part, the exposome’s impact, we argue, is more immediate and, importantly, more alterable.
Were we writing a simple how-to book, we might point to ways you as an individual could address the pro-inflammatory exposome of the industrial world. For example, disruptions in circadian rhythms caused by the blue light from a phone at night lead to an increase in inflammation-driven diseases such as diabetes, depression, high blood pressure, and obesity.33 So you could simply download an app that turns blue light to yellow at night. Or you could take melatonin, which has potent anti-inflammatory properties.34 But many exposures aren’t optional. They are systemic. Those who are working the night shift,35 experiencing job stress, debt, and economic precarity,36 enduring trauma from surviving genocide or police killings,37 living with industrial waste,38 noise,39 and wildfire pollution40 are people for whom exposure is rarely a matter of choice. The combined impact of the modern exposome is a shift in the inflammatory response, from one that heals to one that harms.
This damage is a consequence not of individual choices but of the mandates of a certain social, economic, political, and environmental ecology. To see these connections, and then repair them, is not to pine for a preindustrial lifestyle. It is instead to reject the logic of personal responsibility when so much of what shapes our health is beyond individual control. Once you see it, it’s impossible to make peace with a world that causes this systemic harm—not without wanting to change it. This activation is what the philosopher Alain Badiou calls “exile without return,” a practice we must apply to our medical approach. One must banish oneself from an empire of institutionalized medicine built on injustice and build a better way of healing, along with others committed to the same vision.41
Ideas of expulsion and belonging are ones that medicine deals with rather centrally. When you say you’re shrugging off a cold, or fighting an infection, you’re invoking a language of self-defense, together with an understanding of what should remain within the bounds in your body and what should not. No branch of medicine deals more directly with those issues of territory and belonging than immunology.
THE IMMUNES STRIKE BACK
The word immunity derives from a legal quirk of the Roman Empire. Munus in Latin kicked off the English word municipality. Munera (the plural of munus) were the duties that Roman citizens were obliged to perform.42 As the Roman Empire expanded, it extended a kind of second-class citizenship to nonmunicipal cities within the boundaries of its empire. Foreign residents of these civitates liberae et immunes were not properly Roman in the same way as Rome’s nonslave male inhabitants. They were thereby exempt—immune—from the duties that made them fully Roman.
It is unclear whether Rudolf Virchow, one of the founders of modern medical immunology, knew of this history, but he certainly understood what it felt like to be immune, to be within a world yet estranged from it. During the Revolutions of 1848, Virchow was both a citizen of Berlin and not properly of the Berlin in which he found himself. He was armed and ready to fight the old world so that the new world might be born. The Prussian forces “shot at us from a great distance, out of range for a pistol,” he reported from atop the barricade.43
Virchow wasn’t alone. The Revolutions of 1848 reverberated throughout Europe and the world. From Finland and France to Chile and Brazil, restive urban workers recognized their second-class citizenship and rose up to demand justice—equality, better working conditions, a political and social voice. Within the literature that informed the uprisings, The Communist Manifesto, which first appeared in German in February 1848, is perhaps the most widely known. It is no coincidence that just a few years earlier, in 1845, one of its authors—Friedrich Engels—had written an epidemiological work, The Condition of the Working Class in England.44
In order to write it, the twenty-four-year-old Engels had excused himself from “the dinner-parties, the port-wine and champagne of the middle classes,” to spend time in conversation with Manchester’s working class.45 He used ethnography, epidemiology, geography, and class analysis to account for why he found “the rate of mortality four times as high in some streets as in others, and twice as high in whole classes of streets as in other classes.”46
Clearly, Virchow had read Engels.47 In 1848 he and his colleague Rudolf Leubuscher editorialized in their new journal Medical Reform that “medicine is a social science, and politics nothing but medicine on a grand scale.”48
Virchow was born into a farming family, but one well-connected enough to secure his admission to the best medical college in Berlin, where he proved an exceptional student.49 In 1848, at the age of twenty-six, he was appointed to a governmental commission to investigate an outbreak of typhus in Upper Silesia—what is now modern Poland and Czechia—a region that had been annexed by the Kingdom of Prussia and was under the domination of its German-speaking aristocrats.50 While he was there, he saw how disease and hunger ran together, in “a devastating epidemic and a terrible famine.”51 His diagnosis was a social critique:
The worker has been permitted to demand the means of his subsistence, he has been guaranteed work to enable him to acquire the means, there were those highly praised Prussian schools to provide him with an education appropriate to his class and, finally, the sanitary police were entrusted with the task of supervising his living conditions. And what an army of well trained civil servants were available to enforce the laws. They intruded into private affairs, watched over the most intimate social relations, and assiduously patronised any attempt on the part of “the subjects” to improve themselves. The law was there, the civil servants were there, and yet thousands of people died of famine and epidemics. The laws were useless, for they were nothing but words on paper. Similarly the actions of the civil servants merely resulted in words on paper.… The civil servants had not been appointed by the people to serve their interests. Rather they were appointed by the police state and to serve the interests of the state. Thus, the civil servants were either the oppressors of the people or mere typewriters.52
A radical new political vision was needed to address the impact of Prussian imperial rule on public health. Lack of education in the native language, “the Catholic hierarchy,” and “the great landed proprietors” were the silent vectors of the typhus epidemic.53 And the doctor’s prescription: “education in the Polish language; self-government, separation of church and state; shifting of taxes from the poor to the rich; improvement of agriculture; development of cooperatives; and the building of roads.”54
Like epidemics, famine is neither natural nor inevitable. The widespread hunger that Virchow witnessed in Upper Silesia was a policy failure driven by external events, ones that swept across Europe. The market economy was being brutally enforced throughout the continent. In England’s first colony, Ireland, a lack of genetic diversity had left the potato crop vulnerable to infection by a fungus. From 1845 to 1849, a million Irish citizens died from famine. And yet in 1846 Ireland exported 500,000 pigs and 30,000 tons of grain to England, where prices were higher. The Irish died for want not of food but of money to buy it.
When local government officials in Cork proposed paying Irish laborers higher wages for a public works program that would allow them to buy food for their families, The Economist scolded them for the error of suggesting
to pay them not what their labour is worth, not what their labour can be purchased for, but what is sufficient for a comfortable subsistence for themselves and their family. Do they not see that, on this principle, they must pay a man not in proportion to the value of his labour but in proportion to the size of his family—that they must pay the decrepit and imbecile married man with ten children at least 2 [shillings] per day, while the able, diligent, frugal, and fore-looking bachelor may be put off 4 [pence] or 6 [pence]? Do they not see that to do this would be to stimulate every man to marry and to populate as fast as he could, like a rabbit in a warren—in other words that to apply this to Ireland would be to give brandy to a man lying dead drunk in a ditch?55
To put it bluntly, as The Economist did in 1846, “they have been kept at home and taught to rely more than ever on others and less than ever on themselves.” Rather than be tempted by such policy, Ireland’s colonists should adhere “to the principles which have been deduced from many facts by scientific men and confirmed by experience.”56 Suffering was the stimulus the poor needed to enter the labor market. Any attempt by the government to interfere with the laws of laissez-faire would merely prolong the economic injury, rather than allowing it to heal.
The same liberal economics that plagued the Irish also harmed the Silesian colonial subjects. The Silesian textile industry was in steep decline and got no support from the Prussian Empire, despite a workers’ uprising in 1845.57 The convergence of an El Niño cycle, which disrupted weather patterns,58 incubated crop diseases and drove up food prices across the continent, combined to expose deeply entrenched inequities between the German-speaking elite and the Polish periphery of Prussian society—a political, social, and economic system that made the famine possible.59 When Virchow returned to Berlin that spring, he found a world on fire. The city was one of several across Europe where the urban poor had reached a breaking point. Decades of political organizing had raised workers’ hopes and expectations, so when the combination of climate shock and disease precipitated a global food price spike, they were ready to take to the streets.60
Throughout Europe, states crushed the Revolutions of 1848. Virchow himself was exiled from his post at the Charité Hospital for his participation in the uprising.61 And while in his later years he might have resigned himself to the counterrevolution,62 his biological research would continue to be animated by ideas of action and reaction, justice and exploitation, belonging and betrayal. He hypothesized that infectious diseases like tuberculosis and typhus were caused not by the bacterium itself but by the body’s reaction to the bacterium. He also speculated that because the cells of different people reacted in different ways, the diseases presented with varied expressions. Virchow believed that social conditions more than anything else primed the body for these expressions: oppression would lead to more pronounced manifestations of disease, and justice would enable healing.63
Given his deep commitments to equality, Virchow was suspicious of racial categorizations and the hierarchies of supremacy they supported. At the dawn of the German nation-state, the political right championed scientific racism under the banner of Darwinism. This is why Virchow was a fierce anti-Darwinian.64 In a bid to disprove the scientific racism of the 1870s, he oversaw a study of 6,758,827 German schoolchildren, which measured the skull sizes of Jews and Aryans and showed that there was no such thing as a pure German race.65 (The Nazis would attack his work decades later.) But Darwin continued to cast a shadow over the study of the body’s defenses, including the question of how the body knows to muster a defense in the first place. In the conclusion of his epochal book On the Origin of the Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, he summarized the process of natural selection like this: “from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows.”66
When we think of the immune system, most of us think of war: our bodies defending against and destroying a foreign invader. It’s a startling, even unsettling militaristic image—one that can be traced from Darwin to a Russian scientist who attacked a starfish with a rose thorn.
METCHNIKOFF AND THE MACROPHAGE
In his autobiography, Ilya (Élie in translation) Metchnikoff, the Russian zoologist whose inquiries were foundational to modern immunology, recalls a fateful day in 1881:
When the whole family had gone to a circus to see some extraordinary performing apes, I remained alone with my microscope, observing the life in the mobile cells of a transparent star-fish larva, when a new thought suddenly flashed across my brain. It struck me that similar cells might serve in the defense of the organism against intruders.… I said to myself that if my supposition was true, a splinter introduced into the body of a star-fish larva, devoid of blood vessels or a nervous system, should soon be surrounded by mobile cells as is to be observed in a man who runs a splinter into his finger. This was no sooner said than done. There was a small garden to our dwelling … [and] I fetched from it a few rose thorns and introduced them at once under the skin of the beautiful star-fish larvae as transparent as water.67
When he put indigo on the tip of the offending thorn, he could see small cells from within the larva’s skin cluster around it and engulf the droplets of dye on the thorn’s surface, “eagerly devouring” the intruding enemy.68 How, Metchnikoff wondered, did the starfish know that the thorn didn’t belong inside its body, and why did it react the way it did? He wondered whether it was possible to devise a general theory of this reaction, looking not only at the redness and bleeding that signal an immune reaction in humans but more broadly at the web of life.69
These investigations, inspired by the starfish, were the basis of a series of remarkable lectures, “The Comparative Pathology of Inflammation,” that Metchnikoff gave at the Pasteur Institute in 1891.70 Alive with curiosity and scientific insight, he began the first lecture with the observation that infection is “a struggle between two organisms”—a nod to Darwin’s On the Origin of Species.71 Metchnikoff proposed to do for infection what Darwin had done for the struggle between species: “The phenomena of the active struggle among animals … being much more prominent, have attracted the attention of naturalists for years, whereas those of infection, which are far less on the surface, have been but rarely and insufficiently studied.”72
After announcing his ambition in the first lecture, he turned in the second to look at the smallest units of life. He saw a Darwinian struggle between individual single-cell creatures, which engage in complex chemical and biological warfare to preserve themselves and fend off attackers.73 In the third lecture, he moved from single-cell organisms to simple multicellular animals and plants.74 Although they could heal and regenerate, he found that plants showed no signs of inflammation.75 Their cells couldn’t engulf and devour enemy organisms because the cell walls were so thick, a result of having evolved for a static and defensive life. In other organisms, however, he saw a capacity for motion that allowed their cells to eat the various intruders he introduced to them. Cellular digestion, then, according to Metchnikoff, was the difference between a thick, woody knot on a wounded plant and a similar scar that formed on a person’s skin. Although these healings might look superficially similar, scar tissue in animals requires a star actor that doesn’t exist in plants: the phagocyte.76
Phagocytes are, literally, cells that eat. Phagocytosis involves engulfing things, such as bacteria or dead cells. Metchnikoff saw phagocytes as central to inflammation. When watching a hydra grow a new head, he observed “the regenerative side of inflammatory processes, but not the phenomena of inflammation itself or at least not the accumulation of phagocytes at the injured spot.”77 In other words, you know when inflammation is happening because the phagocytes show up. For Metchnikoff, inflammation was defined by the presence of “a phagocytic reaction on the part of the animal organism” to foreign parasites.78 Note that he wasn’t terribly interested in the healing part of inflammation. He didn’t say in his lectures whether his starfish larvae lived to be pierced another day.
Copyright © 2021 by Rupa Marya and Raj Patel
Copyright © 2014 by Allison Adelle Hedge Coke
