Unexpectedly, antibodies work inside cells to defeat pathogens

My latest Mind and Matter column in the Wall Street Journal is on a surprising discovery about antibodies and the immune system:

It isn't often that an entire field of medical science gets turned on its head. But it is becoming clear that immunology is undergoing a big rethink thanks to the discovery that antibodies, which combat viruses, work not just outside cells but inside them as well. The star of this new view is a protein molecule called TRIM21.

Until recently, the conventional wisdom was that the body fights off infection in two separate ways. First is the adaptive immune system, which works outside the cell. It generates antibodies to intercept specific invaders, locking onto them like a tracking missile and preventing them from entering the cell. A second line of defense, the innate immune system, operates within the cell; it is like an expansive air-defense network, blasting away at all invaders.

Three years ago work by Leo James, William McEwan and their colleagues at the Laboratory of Molecular Biology in Cambridge revealed that this understanding was incomplete. They found that the neutralization of adenoviruses (common viruses causing colds and other infections) by antibodies was happening mainly inside the cell, not outside, and by an unexpected mechanism.

Their announcement—a challenge to the entire field of immunology—elicited a predictable immune reaction of its own from the establishment. Sure enough, leading journals rejected the Cambridge group's paper, sometimes without even reviewing it, while key funding agencies turned down the group's grant applications.

Gradually, though, the authors have won the argument. New papers from the group have pinned down what is going on. They describe a potent detection mechanism that links the antibodies outside a cell with its innate immunity, somewhat dissolving the distinction between the two.

Dr. James's team has shown that if an adenovirus enters the cell with antibodies attached, those antibodies will attract TRIM21 molecules, which pull the virus into a disposal system and send danger signals to put the whole cell in a state of antiviral alert. This explains the hitherto baffling finding that just one or two antibody molecules can neutralize a virus 1,000 times their size.

The significance of the group's finding is just sinking in. It gives medicine a whole new angle on infection, and it just might crack the hitherto almost insuperable problem of how to cure viral infections, rather than just prevent them by vaccination. Though treatments do exist for viruses such as HIV, they are neither as common nor as effective as antibiotics for bacterial infections. No effective remedy exists, for example, for the many kinds of common cold, whatever your grandmother says.

Perhaps the new knowledge that TRIM21 and other molecules like it are key antiviral defenders will lead to a true antiviral therapy, though if it was as easy as turning up the volume of TRIM21, then cells would surely be doing it. And it's worth noting that some viruses (including HIV) use a tactic for getting into cells that allows them to evade TRIM21.

The discovery may aid vaccine design and begins to explain why gene therapy has often run into trouble. Such therapy uses adenoviruses to carry new genes into cells, but frequently this provokes a strong native-immune response. TRIM21 possibly plays a part in this. Finally, there is a chance that TRIM21 will help to explain autoimmune diseases, in which the body attacks itself. TRIM21 itself is a target of autoantibodies in autoimmune conditions such as lupus.

In short, we will be hearing more from this molecule.