Self & Other · Inflammation: The Double-Edged Sword

Heart Disease

More surprising is what has been added to the list in the last twenty or thirty years.

Heart Disease

For most of the twentieth century, heart disease was understood as a plumbing problem. Cholesterol built up inside the walls of arteries; eventually the buildup got bad enough that an artery clogged or burst; you had a heart attack or stroke. The model was straightforward, and treatment focused on lowering cholesterol.

The current picture is more interesting. Cholesterol matters, but the buildup of plaque inside arteries turns out to be, in large part, an inflammatory process. The cholesterol gets inside the artery wall. Macrophages move in, in classic Chapter 2 fashion, and try to eat it. They eat too much, become engorged with cholesterol droplets, and turn into something biologists charmingly call foam cells. The foam cells release inflammatory cytokines. Other cells respond. The artery wall, instead of being a smooth tube, becomes a slow-motion battle zone. Eventually a plaque can rupture — not because it ran out of structural strength, but because the inflammatory chemistry inside it weakened the cap. The rupture causes a clot. The clot blocks the artery. You have a heart attack.

A clinical trial in 2017, called CANTOS, did something striking. It treated patients who had already had a heart attack with a drug that does nothing to cholesterol but blocks a single inflammatory cytokine called IL-1β. The patients on the drug had fewer subsequent heart attacks. The effect was modest but real. Inflammation, treated as a target on its own, mattered.

This does not mean cholesterol doesn’t matter — it does. It means cholesterol is part of a story in which inflammation is also a major character. Treating only the cholesterol leaves the other character in play.

The Brain

For decades, the brain was thought of as immunologically isolated — a privileged tissue that the rest of the immune system didn’t really enter. This turned out to be wrong, in important ways.

The brain has its own resident macrophages — microglia, which we met briefly in Chapter 2. Microglia patrol brain tissue the way other macrophages patrol other tissues. When something goes wrong — an injury, an infection, a buildup of damaged proteins — microglia respond. They produce cytokines, recruit other cells, and remodel their environment.

In Alzheimer’s disease, this response appears to play a complicated role. The classic story of Alzheimer’s is the buildup of certain abnormal proteins (amyloid plaques and tau tangles) in the brain. The newer story is that microglia respond to those proteins in ways that, over time, may damage neurons further. Inflammation in the brain seems to be part of how Alzheimer’s progresses, not just a side effect of it. There is genuine hope that anti-inflammatory approaches may eventually help, though no clear winner has emerged yet.

In depression, an even more provocative story has been developing. People with major depression often have elevated levels of certain inflammatory cytokines in their blood. People treated with cytokines for other diseases (interferon for hepatitis, for instance) sometimes develop classic symptoms of depression as a side effect. People with chronic inflammatory illnesses have higher rates of depression than people without them. None of this proves that inflammation causes depression in any simple way, and the field is still working out what does. But the old picture of depression as purely a chemical imbalance of mood neurotransmitters has given way to a picture in which the immune system is, somehow, also involved.

The connections between the brain and the immune system are real, surprising, and only beginning to be mapped. We’ll come back to them in Chapter 15, when we talk about stress and the vagus nerve. For now, the point is that inflammation does not stay where you would expect it. The same kinds of chemistry that make a sprained ankle hurt can, in low chronic doses, change how the brain works.

Inflammaging

As people age, baseline levels of certain inflammatory markers in the blood tend to drift slowly upward, even in the absence of any specific disease. The phenomenon has been given a slightly unfortunate but useful name: inflammaging.

No one is entirely sure why this happens. Older immune systems may be slightly less good at resolving inflammation cleanly. Older tissues accumulate more damaged cells and debris that the immune system has to clean up. The microbiome shifts with age. Lifelong exposures add up. Whatever the cause, the consequence appears to be a quiet, low-grade hum of inflammation that increases with age and seems to be involved in many of the diseases we associate with aging — cardiovascular disease, dementia, sarcopenia (the loss of muscle mass), frailty, certain cancers.

This is one of the most actively studied questions in current biology, partly because if you could find a way to dampen inflammaging without weakening the rest of immunity, you might genuinely slow some aspects of aging. There are early hints — from drugs like rapamycin, from certain dietary patterns, from regular moderate exercise — that this might be possible. There is also a great deal of overhype around it. We will try to be honest about both in Chapter 13.

The Cytokine Storm

There is one more inflammatory phenomenon worth mentioning, partly because the phrase has been so common in news headlines since 2020 that it deserves a careful definition.

A cytokine storm (more formally, cytokine release syndrome) is what happens when the inflammatory response loses its negative-feedback brakes and runs away. Cytokines summon immune cells. The immune cells release more cytokines. More cells arrive. More cytokines. A response that should have ramped up, dealt with the threat, and resolved itself instead spirals upward, recruiting more and more inflammatory machinery, until the body is doing systemic damage to itself in the name of fighting an infection that may have already been controlled.

Cytokine storms can occur in severe viral infections, in some autoimmune crises, in certain reactions to chemotherapy, and — in a manageable form — as a known side effect of some of the most exciting new cancer therapies, the CAR-T cell treatments we’ll meet in Chapter 12. In severe cases, cytokine storms can be deadly. Treatment usually involves drugs that block specific cytokines or specific cytokine receptors, breaking the feedback loop and giving the system a chance to reset.

The phrase has been somewhat overused in the popular press. Most severe inflammation is not a true cytokine storm in the strict clinical sense. But the underlying idea — that the inflammatory response can become its own problem, that the defense can hurt the defender — is real, and it is the same underlying idea that runs through all of chronic inflammation. The tools the immune system uses to defend you can, applied wrongly or for too long, harm you. The same fire that warms the house can burn the house down.

The Larger Pattern

If you stand back and look at the whole picture this chapter has assembled, a pattern emerges that is worth naming.

The immune system was shaped, evolutionarily, in a world where infection was the most dangerous thing that could happen to you. For most of human history, the average person fought off serious infections constantly, lost many of those fights, and rarely lived long enough for chronic diseases to become important. An immune system that responded vigorously, quickly, and at some cost to surrounding tissue was a good trade. The cost of inflammation was small compared to the cost of dying of plague at twenty-five.

The world we now live in is different. In wealthy countries, with sanitation and vaccines and antibiotics, most people are no longer dying of infections. They are living long enough to develop the diseases of an immune system applied to a longer life than it was designed for: chronic inflammation in arteries, in joints, in brains, in metabolic tissue. Many of the major killers of the modern world — heart disease, stroke, type 2 diabetes, Alzheimer’s, certain cancers — turn out to involve, somewhere in their causation, immune systems that are no longer cleanly resolving their responses.

This is not a moral failing of the immune system. It is, more or less, what happens when an evolutionary tool designed for one set of conditions is applied to a different set. The system that kept your ancestors alive at twenty-five is, in some of its modes, the same system that ages you at seventy-five.

Some of the things that affect chronic inflammation are within a person’s control. Some are not. Diet, sleep, exercise, social connection, stress, smoking, certain medications — these all shift the baseline, sometimes substantially. Genetics, age, certain past infections, the microbiome you happened to inherit — these are largely fixed. The honest version of the lifestyle conversation, which we’ll get to in Chapter 13, is that you can move your numbers in helpful directions but you cannot guarantee any particular outcome. The dice are weighted by your behavior. They are not loaded.

So this is the cost of having a defense. The same machinery that saves your life when you have a serious infection at thirty can, in chronic low-grade form, contribute to the diseases that take your life at eighty. The same cytokines that summon the cells that heal a wound can, in different concentrations or for too long, drive depression or atherosclerosis. The flame keeps the room warm, and sometimes it burns the curtains. There is no version of immunity that is free.

This is also, importantly, why “boosting” your immune system is the wrong goal. We’ve said this once already, but it bears repeating now that we have the picture. A boosted immune system would be an immune system more prone to inflammation, more prone to attacking things, more prone to overshooting. What you want is an immune system that responds well when it should, resolves cleanly when it can, and stays quiet otherwise. The technical word for that is regulated. Not strong. Regulated.

We have now, finally, all the pieces we need to talk about what happens when the regulation fails. Three failure modes are particularly worth understanding, because they account for a great deal of human disease and they sit very differently in the public imagination. The first is when the immune system attacks something harmless and treats it as dangerous. We call this allergy. The second is when the immune system attacks the body itself and treats parts of you as not-you. We call this autoimmune disease. The third is when the immune system fails to respond at all, leaving the body open to threats it should easily have handled. We call this immunodeficiency.

Each gets its own chapter. The first one is allergies, which is also, surprisingly, where some of the most interesting recent science has been happening.

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