By Andy Coghlan
SOME very strangely behaved antibodies could force immunologists to rewrite
their textbooks. The discovery of these freakish proteins, by a team in
Amsterdam, might also help explain some of the mysteries surrounding
allergies.
Antibodies, the sentinels of the immune system, are Y-shaped proteins made by
a class of white blood cells called B lymphocytes. At the tip of each arm, an
antibody has a pair of molecular tweezers known as an antigen-binding site.
These grasp a specific target antigen, such as a protein found on the surface of
a bacterium.
The textbooks all say that the tweezers on the two arms are
identical—making the "Y" symmetrical and allowing the antibody to grab two
copies of the same antigen. But Rob Aalberse and his colleagues at the
University of Amsterdam are challenging this dogma. Working with the Dutch Red
Cross Blood Transfusion Service, they claim to have discovered natural
antibodies with a different set of tweezers on each arm.
Aalberse scented something odd a decade ago, while studying immunoglobulin G4
(IgG4) antibodies, which are involved in allergic reactions. When exposed to
what was presumed to be their only target antigen, some of these antibodies
seemed capable of picking up only one antigen molecule, rather than two.
Now, Aalberse and his colleagues believe they have established why, after
studying IgG4 antibodies from patients who had been treated for combined allergy
to grass pollen and house dust mites. Aalberse had the heretical hunch that the
patients had produced IgG4 antibodies with two different antigen-binding sites
capable of binding to both antigens at once.
To put this to the test, the researchers stuck pollen antigens to the inner
surface of a test tube and rinsed it out with antibodies which bound to the
pollen. Then they washed the tube with a solution containing dust mite antigens,
each marked with radioactive iodine. The radioactively labelled antigens also
stuck to the test tube, showing that the antibodies were simultaneously bound to
both antigens (Immunology, vol 97, p 693).
Since then, Aalberse and his colleagues have found other double-barrelled
IgG4 antibodies. Some bind simultaneously to diptheria and tetanus toxins.
Others capture banana antigens and cat dander antigens. "There are loads of
combinations," he says.
The puzzle is to work out how and why the body makes these unusual
antibodies. Aalberse speculates that they start life as normal, symmetrical
antibodies but are later pulled apart and reassembled to produce mix-and-match
variants.
This could help limit the damage caused by allergies. Normal antibodies clump
together whenever they capture and accumulate antigens, and these clumps can
damage the kidneys. The mix-and-match antibodies don't clump so readily
(see Diagram).
This may prevent kidney damage during a severe allergic reaction. The
asymmetric antibodies might also help explain why some people show similar
allergic reactions to two different antigens that aren't obviously related.FIG-22040301.jpg
Ivan Roitt, an immunologist at University College London, says he wants to
see more evidence that the antibodies really are asymmetrical—rather than
possessing identical antigen binding sites that happen to be able to grab
molecules with slightly different structures.
But other researchers are intrigued. "This is a very interesting observation
because it raises a host of questions about the possible biological role of IgG4
antibodies," says Greg Winter, an antibody engineer at the Medical Research
Council's Laboratory of Molecular Biology in Cambridge.
Editorial : If at first you don't succeed . . .
All bets are off