Scientists Discover Genetic
Profile of an
Often-Misdiagnosed Chronic
Allergic Disease of Children
Though many parents may never have heard of it, a severe and
chronic condition called eosinophilic esophagitis (EE) is recognized
by doctors as an emerging health problem for children. A disease
that was often misdiagnosed in the past, EE has been increasingly
recognized in the United States, Europe, Canada and Japan in the
last few years. Cases of the disease can be devastating since
children who suffer from it may have a host of lifelong problems.
Now, an interdisciplinary team of scientists funded in part by
the National Institute of Allergy and Infectious Diseases (NIAID)
and the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK), both components of the National Institutes of
Health (NIH), has published a major advance in understanding EE. In
the February 2006 issue of the
Journal of Clinical Investigation, the team reveals that
a highly specific subset of human genes plays a role in this
complicated disease.
“Understanding the genetic profile of a disease such as EE is an
important first step towards developing new ways to diagnose and
treat it,” says NIAID Director Anthony S. Fauci, M.D.
In EE, the esophagus (the muscular tube that connects the end of
the throat with the opening of the stomach) becomes inflamed—often,
but not always, due to allergic reactions to food. This inflammation
causes nausea, heartburn, vomiting and difficulty swallowing. In
advanced cases, children may suffer from malnutrition, often require
special liquid diets, and may need to have a feeding tube inserted
in order to receive nourishment. EE, first identified in 1977, has
been increasingly recognized since the advent of diagnostic
endoscopy, a procedure in which a flexible fiber-optic tube is
inserted down the throat to directly image and biopsy the esophagus.
Historically, part of the reason why the disease has been
misdiagnosed is that its symptoms are very similar to those of acid
reflux disease. However similar the two diseases are in terms of
symptoms, their underlying physiology is vastly different. Drugs on
the market for treating acid reflux do not abate the symptoms of EE,
which is not caused by production of stomach acid, but likely by
inflammation in the esophagus resulting from the abnormal
accumulation of immune cells know as eosinophils—hence its name
eosinophilic esophagitis. Eosinophils are white blood cells that
contain inflammatory chemicals, highly reactive proteins,
destructive enzymes, toxins, muscle contractors and signaling
molecules that can guide immune defenses to the site of infection.
At the Cincinnati Children’s Hospital Medical Center, Professor
of Pediatrics Marc E. Rothenberg, M.D., Ph.D., has seen patients
with EE for a number of years and pursued clinical and laboratory
research on the disease as well. To better understand the disease,
Dr. Rothenberg and his colleagues examined the gene expression in
tissue samples taken directly from the esophagus of individuals with
EE as well as from people without the disease. These individuals
were selected to represent a diverse sample with respect to age, sex
and disease state. Dr. Rothenberg and his colleagues found that a
particular set of 574 genes was expressed differently in people with
EE than in those without the illness.
This transcript signature, as they call it, yielded some
surprising findings; it was largely the same for every person with
EE, regardless of age and whether or not these people had food
allergies. This transcript signature was quite distinct from the
signature observed in patients with acid reflux disease, thus
allowing the two diseases to be easily discriminated. Although EE is
more common in males than in females, the genes expressed in the
esophagus did not vary dramatically between males and females with
EE. Of the 574 genes, the investigators found that the expression of
one gene in particular, termed eotaxin-3, was elevated in people
with EE compared to people without the disease--at up to more than
100-fold greater amounts in EE than in controls. Eotaxin-3, a factor
released from certain cells and tissues, acts to attract circulating
eosinophils, yet no one had previously observed that the local
levels of eotaxin-3 correlated directly with the number of
eosinophils in the esophagus.
In their paper, Dr. Rothenberg and his colleagues also
demonstrated that, in a mouse model of EE, mice lacking receptors
for eotaxin were protected against developing EE. These results,
when taken with those of the human studies, suggest that a drug to
block eotaxin-3 might have therapeutic value. Finally, by sequencing
the eotaxin-3 genes
of all the people in their study, the investigators identified
certain genetic variations known as single nucleotide polymorphisms
(SNPs)—particular spots within the DNA sequence of the gene where a
single base of DNA may vary from person to person. One particular
SNP in the gene appears to occur more frequently in patients with EE
than in controls, and, if this is confirmed, SNPs may provide a way
to determine if people are at risk for EE.
NIAID is a component of the National Institutes of Health, an
agency of the U.S. Department of Health and Human Services. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from
potential agents of bioterrorism. NIAID also supports research on
transplantation and immune-related illnesses, including autoimmune
disorders, asthma and allergies.
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Reference:
Blanchard et al.
Eotaxin-3 and a uniquely conserved gene expression profile in
eosinophilic esophagitis.
Journal of Clinical Investigation DOI: 10.1172/JCI26679
(2006).
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