Self & Other
6. The ID Check
In 1958, a young French researcher named Jean Dausset was studying the blood of patients who had received many transfusions. Some of them, he noticed, had developed strange antibodies in their blood — antibodies that didn’t react against bacteria, didn’t react against viruses, didn’t seem to react against anything in the outside world. They reacted against the white blood cells of other people.
The patients themselves were fine. Their own white blood cells were untouched. But put a sample of someone else’s white blood cells into a tube of their blood, and the antibodies would clump onto the foreign cells with obvious enthusiasm. Different patients had antibodies against different sets of donors. The pattern was consistent, repeatable, and — in a way Dausset could feel but not quite explain — important.
What he had stumbled into was the molecular answer to Medawar’s puzzle from Chapter 1. Why does borrowed skin get rejected? Why does your body know that someone else’s tissue isn’t yours? What, at the level of actual molecules, makes you you?
The answer turned out to be a set of proteins so distinctive, so individual, that they function as a kind of molecular fingerprint. Every cell in your body wears them. Almost no one else on earth wears the same combination. Your body checks for them constantly, and treats anything wearing the wrong ones as suspicious. Dausset spent the next thirty years working out what they were and how they worked. He shared the 1980 Nobel Prize for it.
In humans, the proteins are called HLA, for human leukocyte antigens — because Dausset first found them on white blood cells, which are also called leukocytes. In other animals, and in the immunology textbooks, the more general name for the same family of proteins is MHC, for major histocompatibility complex. Different name, same molecule. We’ll mostly call them MHC molecules in this book, because that’s the name that travels.
This is the chapter where we meet them properly. They are, arguably, the most important set of proteins in the entire immune system, and the reason transplants are hard, and the reason your body can spot a virus hiding inside one of its own cells, and the reason — we’ll see in Chapter 7 — some people develop autoimmune disease and others don’t.
The Card-Holding Cells
In Chapter 3, when we met T cells, we said something that probably sounded a little weird at the time. T cells, we said, do not recognize whole molecules floating in the blood. T cells recognize fragments of molecules being held up by other cells, like cards.
The cards are MHC molecules.
Imagine, for a moment, that you are a cell. You are sitting in a tissue — the lining of your throat, say, or the inside of your liver. You are doing whatever it is your kind of cell does. While you do this, you are also — constantly, automatically, as part of your normal cellular housekeeping — chopping up small samples of the proteins inside you and shoving them up onto your surface, held in the grip of MHC molecules, like a person holding up flashcards.
Most of the protein samples in those cards are samples of you. They are bits of your normal proteins, the ones every cell makes. T cells walking past read the cards, see normal you-shaped fragments, and walk on. Nothing happens.
But suppose a virus has gotten inside this cell. Now the cell is making viral proteins, too — because that’s what viruses do, they hijack the cellular machinery to make more virus. The cell has no way of knowing this is happening, in the sense that there’s no mind in there to be aware. But it doesn’t matter, because the cell does what it always does. It chops up samples of all its proteins, including the viral ones, and shoves them up onto its surface in MHC molecules. It holds up the flashcards.
Now a passing T cell reads the cards and sees something not-you. A killer T cell whose receptor happens to fit the viral fragment binds to it. The cell holding the card is killed by apoptosis, taking the virus with it.
This is the trick. This is how your body finds infections inside its own cells. The infected cells, in effect, snitch on themselves. Their normal housekeeping process — chopping up internal proteins and displaying them on the surface — makes it impossible for them to hide what they’re carrying.
Class I and Class II
There are two main flavors of MHC molecule, and the difference matters because it tells you what kind of trouble each one reports.
MHC class I is worn by almost every cell in your body — every cell that has a nucleus, anyway, which is to say almost every cell except mature red blood cells. (Red blood cells are weird. We won’t dwell on it.) Class I molecules display fragments of proteins from inside the cell. If the cell is healthy, the fragments are healthy. If the cell is infected with a virus, the fragments include viral pieces. If the cell has turned cancerous and is making mutant proteins, the fragments include the mutants.
Class I is read by killer T cells, which are looking for cells that need to be eliminated. The flashcard system here is, essentially, a way for every cell in your body to continuously prove it’s still healthy. A cell that displays normal you-fragments lives. A cell that displays foreign or mutant fragments gets killed. The check happens, on every cell, every few minutes, your whole life.