Scientists discover genetic profile of an often-misdiagnosed chronic allergic disease of children

February 01, 2006

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.
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.

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).

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at

NIH/National Institute of Allergy and Infectious Diseases

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