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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

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

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

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

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.

By Matt Ridley | Tagged:  rational-optimist  wall-street-journal