Self & Other · The Schools of Tolerance

When the System Holds, and When It Doesn’t

If a self-reactive T cell escapes the thymus and starts to react against your own tissue, Tregs are usually the first responders. They calm it down. They tell it to stand down. Most of the time, they succeed.

Tregs were properly identified only in the 1990s, after decades in which immunologists vaguely suspected something like them must exist but couldn’t find them. The researchers who eventually pinned them down — Shimon Sakaguchi in Japan, among others — had to fight an uphill battle against an established field that had grown skeptical of “suppressor T cells” after some earlier false starts. Tregs are now one of the most active areas of research in immunology, and likely a future Nobel topic. We are still learning what they do.

Beyond Tregs, there are other backup mechanisms — cells that can be made unresponsive rather than activated, signaling pathways that quiet down chronic responses, immune-privileged tissues like the eye and the brain that the immune system mostly leaves alone by design. The body has many ways of saying no. The thymus is the first and most dramatic. The Tregs, and the other quiet systems, are the ongoing daily maintenance.

When the System Holds, and When It Doesn’t

Most of the time, in most people, this whole layered system works. T cells with self-reactive receptors are deleted in the thymus. The few that escape are kept quiet by Tregs. The body lives, for decade after decade, in a state of immunological peace with itself.

Sometimes the peace breaks.

We are still working out, as a field, exactly why. The honest answer in 2025 — and the answer Jessica’s doctors would give if you asked them — is that the breakdown of self-tolerance, the failure that leads to autoimmune disease, is partly genetic, partly environmental, partly developmental, and partly random in ways we cannot yet predict. Different autoimmune diseases involve different failures of different parts of the tolerance system. Type 1 diabetes appears to involve T cells that escaped the thymus carrying receptors against insulin-producing cells in the pancreas. Multiple sclerosis appears to involve T cells against myelin, the insulating sheath around nerves. Hashimoto’s thyroiditis involves T cells and B cells against thyroid proteins. Lupus involves a more diffuse failure that produces antibodies against many different self-proteins at once. Each disease has its own particular pattern of which tolerance broke and which self-proteins are now under attack.

What seems to be going on, broadly, is some combination of:

Inherited variation. Some people are born with versions of MHC molecules — or versions of AIRE, or versions of the genes that control Tregs — that make their tolerance system slightly less reliable. We met some of these in the last chapter. Most people with the risky variants never develop autoimmune disease, but the variants tip the odds.

Environmental triggers. Certain infections, in certain people, seem to be able to set off an autoimmune response — sometimes because a viral or bacterial protein happens to look chemically similar to a human protein, so that T cells responding to the infection accidentally also respond to the body’s own tissue. This is called molecular mimicry, and it appears to play a role in some autoimmune diseases, possibly including some forms of type 1 diabetes and multiple sclerosis. Not all infections do this, and most people who get the relevant infections never develop autoimmunity. But for some, the trigger seems to matter.

Hormonal and developmental factors. Many autoimmune diseases are far more common in women than in men — by ratios of nine to one, in some cases. Some of this is probably hormonal. Some of it is probably related to the X chromosome, which carries a number of immune-related genes. Some of it we still don’t understand. Pregnancy can sometimes trigger autoimmune disease, and sometimes temporarily put it into remission. The relationship between sex and immunity is intricate and not yet fully mapped.

And, irreducibly, luck. Even with all the genetic and environmental factors accounted for, identical twins — who share all their genes — are often discordant for autoimmune disease. One twin gets type 1 diabetes; the other does not. One twin develops MS at thirty; the other lives a long healthy life. Whatever pushes a person from “carrying the risk” to “actually developing the disease” includes elements that, as far as we can tell, are genuinely random. Where in the body did a particular T cell get activated, on a particular day, in response to a particular infection? Did the Tregs get there in time? Tiny contingencies, multiplied over years, sometimes tip the system one way and sometimes the other.

This is, I think, one of the most important things to hold onto from this chapter, and one of the things that gets lost most often in popular writing about autoimmune disease. The development of an autoimmune condition is not a moral event. It is not the result of failing to do something, or failing to avoid something. It is the result of a system that protects you from infection at the cost of occasionally producing dangerous cells, a school that catches almost all of those cells but not all, a backup workforce that quiets almost all of the rest but not all, and a long roll of the dice that, for some people, eventually comes up wrong.

If it has come up wrong for you, or for someone you love, nothing in your behavior caused it. Nothing in your behavior could reliably have prevented it. The relevant decisions were made before you were born, or they happened in cells you would never have noticed, in moments you would never have known about. The only honest thing the science can say is: the system mostly works, and sometimes it doesn’t, and we are still learning why, and you are not at fault.

Hold this thought before we move on, because the next chapter is going to bring it forward in a different form.

The body’s defense against itself — negative selection in the thymus, regulatory T cells in the tissues, the whole quiet architecture of tolerance — is, in a way, the most thoughtful part of the immune system. It exists not to attack but to refrain from attacking. It is the part of you that has decided, every minute of every day, that the trillions of cells around it are family. The cost of that decision is a small but real risk that, somewhere, the system will fail and the family will be attacked. The benefit is that, for most people, most of the time, the body is at peace with itself.

There is a related cost, though, that we haven’t really discussed yet, and that turns up in different places throughout this book. The same machinery that defends you — the cytokines, the inflammation, the swarms of cells rushing to a wound or a virus — always damages tissue while it works. A small inflammation, well-resolved, is healing. A chronic inflammation, never quite resolved, is something else. Some of the most important chronic diseases of the modern world — heart disease, Alzheimer’s, depression, certain cancers — turn out to involve inflammation that has gone on too long.

That’s the next chapter. Inflammation, the double-edged sword. The cost of having a defense at all.

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