Self & Other · The ID Check
The Variation
This is, when you sit with it, an extraordinary arrangement. Right now, every cell in your body is holding up cards saying “I’m fine, I’m fine, I’m fine,” and somewhere in your tissues there are T cells walking past reading the cards and confirming the message. The moment a cell stops being able to put up convincing fine-cards, it doesn’t survive long.
MHC class II is worn by a smaller, specialized set of cells — mainly dendritic cells, macrophages, and B cells. (You may notice these are exactly the cells we’ve been calling the “evidence gatherers” throughout the book.) Class II molecules display fragments of proteins that the cell has eaten from outside, not made inside. If a macrophage swallows a bacterium, it chops the bacterial proteins up and displays the fragments on class II molecules.
Class II is read by helper T cells, the conductors of the orchestra. When a helper T cell sees a class II molecule with a foreign fragment in it, it knows: this cell has eaten something dangerous, and the immune system needs to respond. The flood of cytokines we described in Chapter 3 begins.
So the two classes report two different kinds of trouble. Class I says: there’s something wrong inside this cell. Class II says: there’s something wrong out in the tissue, and I’ve eaten a sample of it.
Together, they cover the body. Inside-the-cell threats and outside-the-cell threats both eventually get reported through this single, elegant flashcard system. The whole adaptive immune response, in some sense, runs on it.
The Variation
Here is where the system gets strange.
Most of the genes in your body are roughly the same as the genes in everyone else’s body. There are versions — your eye color, your blood type, your earlobe shape — but for any given gene, the differences across the human species are usually small. We’re a remarkably similar species at the genetic level, more similar than chimpanzees are to each other.
Except for the MHC genes.
The MHC genes are the most variable genes in the entire human genome. There are thousands of different versions of each MHC gene circulating in the human population. The combination of MHC versions you carry — inherited half from one biological parent, half from the other — is, in practice, almost unique to you. Identical twins share an MHC profile. Full siblings have a one-in-four chance of matching each other. Anyone less related than that is almost certainly a mismatch.
This is why transplants are hard. When a kidney from a donor is sewn into a recipient, the kidney cells continue, dutifully, to do what cells do: hold up flashcards displaying their internal proteins, including the MHC molecules themselves. The recipient’s T cells walk past, read the cards, and see MHC molecules that look subtly wrong — not the recipient’s pattern. The cards themselves, in this case, are foreign. The T cells respond as if every cell in the new kidney were displaying a virus. Within a few days, an enormous immune response begins, and unless powerfully suppressed by drugs, it will destroy the transplant.
This was Medawar’s puzzle in 1940, and now we can name the molecules involved. The pilot’s body wasn’t reacting to the borrowed skin in some vague sense. It was reacting to specific MHC molecules that didn’t match its own.
Modern transplant medicine is, more or less, the engineering problem of getting around this. Donors and recipients are matched as closely as possible at the MHC level, often through donor registries that scan thousands of people looking for one whose MHC profile is close to a particular patient’s. Even after the closest possible match, recipients usually take immunosuppressive drugs for the rest of their lives, to keep the residual mismatch from triggering rejection. It is one of the more delicate balancing acts in medicine: enough suppression to keep the transplant alive, not so much that ordinary infections become deadly.
Why So Variable?
The obvious question, once you know how variable MHC genes are, is: why? Why doesn’t every human have the same MHC molecules, the way we mostly have the same hemoglobin? It would make transplant medicine vastly easier. It would make a lot of immunology simpler. What’s the variation for?
The answer is one of the more elegant arguments in evolutionary biology, and it goes like this.
Each MHC molecule has a particular shape — a particular groove on its top surface, where it grips protein fragments and holds them up for inspection. The shape of that groove determines which fragments fit into it. Different MHC versions have differently shaped grooves, which means they can hold up different sets of fragments. Some MHC molecules are great at gripping fragments from certain viruses. Others are great at fragments from certain bacteria. None of them can hold up everything.
If every human had the same MHC molecules, then every human would have the same blind spots. Any pathogen that happened to be invisible to that one MHC profile — a virus whose key proteins didn’t fit into the groove — could sweep through the entire species. There would be no genetic variation to fall back on. The whole species would, in immunological terms, have one immune system, and a smart enough pathogen could defeat all of us at once.
Instead, the MHC system is wildly variable. Some people’s MHC molecules are great at displaying COVID fragments. Others are better at displaying HIV fragments. Others handle measles particularly well. No one’s MHC profile is best at everything. But across the population as a whole, almost any pathogen that comes along will find some humans whose MHC molecules can hold up its fragments and trigger a strong immune response. Those humans survive. The species survives. The pathogen, even if it’s terrible, doesn’t win against everyone.