Stanford, Packard research draws link between cleanliness, hepatitis A, asthma

STANFORD, Calif. – Contrary to what your mother may have told you, it is, in fact, possible to be too clean. Mounting circumstantial evidence over the past several years has indicated that overly sanitary conditions, which result in fewer infections, render children more likely to develop eczema, allergies and asthma. Dubbed the “hygiene hypothesis,” no one knew exactly what caused the phenomenon or whether some infections provided more protection than others.

Recent findings by researchers at Lucile Packard Children's Hospital and the Stanford University School of Medicine illustrate the probable biological foundation for this effect, pinpointing one infectious culprit: the hepatitis A virus. The research suggests new ways to prevent or treat asthma and allergies.

“This is the first molecular explanation for how hygiene can affect allergies and asthma,” said Dale Umetsu, MD, PhD, professor of pediatrics. Umetsu, who is also chief of the division of allergy and immunology at Packard Children's Hospital, is the senior author on the study, which will appear in the Oct. 9 issue of Nature.

Hepatitis A causes an illness sometimes characterized by jaundice and flu-like symptoms. Nearly all people born before 1950 have been infected by the virus, which is usually spread by exposure to the stool from an infected person.

“As hygiene and sanitation have improved over the past several decades, the prevalence of hepatitis A infection has fallen dramatically,” said School of Medicine MD/PhD student and first author Jennifer McIntire. “However, rates of asthma and allergies have been rising sharply. This inverse relationship was not well understood; it's been a bit of a mystery as to what was happening.”

In a previous study, Umetsu and his colleagues, using a mouse model of asthma and allergy, discovered a family of genes called TIMs. One family member, TIM-1, predisposed mice to developing asthma and allergy. In humans, TIM-1 also serves as the receptor for the hepatitis A virus on both liver cells and T cells of the immune system. Because the same immune cells that express TIM-1 also play a critical role in the development of allergies and asthma, the researchers postulated that the hepatitis A virus protected against these diseases by killing or disabling these allergy-inducing T cells.

In the current study, the researchers examined the TIM-1 gene in nearly 400 people, about half of whom suffered from allergies or asthma. They found that, like many genes, TIM-1 can exist in several versions. People with the longer version of TIM-1 were significantly less likely to have asthma or allergies than those with the shorter version, but only if they had also been infected with the hepatitis A virus. In other words, a lucky cut of the genetic deck, in concert with a brush with hepatitis A, protected subjects with the long version of TIM-1 from the sniffling, sneezing, wheezing and worse experienced by those with the short form of TIM-1.

The researchers speculate that the long form of TIM-1 may enhance binding of hepatitis A to the immune cells, increasing the efficiency of T cell killing or down-regulation. More than 60 percent of Caucasians and African Americans, and 46 percent of Asian study subjects carried the protective version of the gene.

“Allergies, asthma and eczema all tend to run in families,” says Umetsu, “which indicates that a strong genetic component is responsible for these problems. But asthma and allergies are complex genetic traits, meaning that environmental factors such as allergens and infections are also involved. This complexity makes these diseases very difficult to study. What we've shown now is that TIM-1is a very important gene that regulates whether an individual gets allergies or not. In addition, we've shown that an environmental factor-hepatitis A infection-directly modulates the effect of this particular gene.”

In addition to discovering the molecular thread linking environment and genetics, the researchers hope their findings lead to practical treatments or preventives for asthma and allergies. They are curious as to whether a vaccine that protects against hepatitis A, which uses a killed version of the whole virus, may provide protection against asthma.

“Obviously you don't want to run out and try to get hepatitis A,” said Umetsu. “But as we find out more about how TIM-1 functions in the immune system, we may discover better ways to treat the disease. If we can design an antibody or drug to mimic the effect of hepatitis A, it may be a way to cure patients with allergies or asthma, regardless of which version of TIM-1 they carry.”

The Stanford University School of Medicine consistently ranks among the nation's top 10 medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://med.stanford.edu/about.html.