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 were expressed differently
in people with EE from people 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 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.
News releases, fact sheets and other NIAID-related materials are available on
the NIAID Web site at http://www.niaid.nih.gov.
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.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov. |