January 07, 1998
Breathing New Life into Allergy Research
Over the past several years, physicians have seen a dramatic rise in the
incidence of asthma and atopy, allergic conditions that affect about 40
percent of the population. Environmental factors are partially
responsible for the increase, but there is mounting evidence that some
individuals inherit susceptibility to these conditions.
In the December 11 issue of
The New England Journal of Medicine,
researchers at Washington University in St. Louis - including Talal
Chatila and Howard Hughes Medical Institute investigator Matthew Thomas -
present strong evidence that a mutant protein is associated with atopy, a
condition that causes hypersensitivity to common allergens such as cat
dander or dust mite feces.
Chatila and Thomas found that the mutation occurs in the interleukin-4
receptor (IL-4R), a protein found on the surface of B cells of the immune
system. When the receptor latches onto IL-4, a chemical secreted by T
cells, it transmits a signal to the nucleus of the B cell to stimulate
production of immunoglobulin E, IgE. Atopic individuals overproduce IgE,
resulting in an allergic reaction. "Much of atopy is essentially a
failure to regulate IL-4 signaling," said Thomas.
Searching for the cause of the IgE overproduction, the St. Louis
researchers examined the gene that codes for the alpha subunit of IL-4R.
They compared the DNA sequences of the alpha subunit gene from control
individuals to that from atopic patients, and found an alteration in the
amino acid sequenceroughly where the tail of the subunit protrudes
into the interior of the cell. Thirteen of 20 atopic individuals tested
had the amino acid arginine at this position (instead of the usual
glutamine), whereas only 5 of 30 control individuals had the same
Thomas and his colleagues examined the effect of the amino acid
substitution on IL-4R function, and found that the arginine mutation
caused a 50% increase in production of IgE. Thomas' and Chatila's groups
also showed that the altered tail of the IL-4R subunit was not as
effective as the normal subunit at binding SHP-1, a protein which Thomas
calls "one of the key negative regulators of receptors on all sorts of
These findings suggest that people with the arginine variant of IL-4R are
less able to bind SHP-1, which is likely to "put the brakes" on the IL-4
signaling pathway. "This could lead to the failure to regulate IL-4
signaling in an appropriate manner, which, in turn, results in the
overproduction of IgE," said Thomas.
Thomas noted that despite the excitement of these results, much remains
to be done. The data need to be confirmed and extended in larger groups
of individuals from different populations, he said. Thomas and Chatila
are gearing up to verify the functional effects of the amino acid
variants in physiologically relevant models.