A molecular basis for the farm effect
Children who grow up on dairy farms have a significantly lower risk of developing asthma and allergies than kids reared in urbanized areas. A new collaborative study involving LMU researchers reveals a mechanistic basis for this phenomenon.
A body of epidemiological data has accumulated which indicates that children who regularly come into contact with dairy herds are less likely to develop asthma and allergies: Much of the evidence for this farm effect comes from studies carried out by LMU researcher Professor Erika von Mutius and her colleagues. Children growing up on farms are exposed to dust that contains high levels of so-called endotoxins – biomolecules found in the cell walls of bacteria – which they inhale. These substances are known to stimulate the immune system, and are thought to inhibit development of misdirected immune responses to innocuous agents. “However, the mechanism actually responsible for this protective effect has remained unidentified until now,” says von Mutius, who heads the Outpatient Clinic for Asthma and Allergies at Dr. von Hauner’s Children’s Hospital in Munich. But a new collaborative study by an international team of researchers, including von Mutius and members of her group, demonstrates that an enzyme called A20 plays a critical role in mediating the effect. Furthermore, a genetic mutation in the gene for A20 increases the risk of asthma in humans. The results of the study appear in the latest issue of the journal “Science”.
Allergic asthma is the result of a complex interplay between inborn genetic factors and environmental influences. The condition arises when the immune system overreacts to activation by respiratory allergens, such as mites found in household dust, by triggering a signal cascade that ultimately leads to chronic inflammation of the airways. Using the mouse as an experimental model, the investigators have shown that airborne endotoxins found in farm dust inhibit the development of allergic asthma by activating an enzyme called A20 in the epithelial cells of the airways. This protein in turn blocks the function of a transcription factor that is required to activate the inflammatory responses to house dust mites. Moreover, A20 seems essential for the protective effect, for mice that lack A20 in the airway epithelial cells go on to develop asthma when exposed to mite allergens, despite receiving regular doses of endotoxin or farm dust. In addition, these animals were more sensitive to the allergens than mice that expressed A20 in the airway cells.
Experiments with bronchial epithelial cells confirmed that A20 also plays a role in mediating protection in humans: Following stimulation with endotoxins, cells obtained from healthy control subjects expressed higher levels of A20 than cells isolated from asthmatic patients. In humans, A20 is encoded by the gene TNFAIP3. Several forms of TNFAIP3, which differ from each other at certain positions within the gene, are found in humans. The LMU researchers focused on the question whether these variations, called SNPs, might represent a genetic component associated with the relative risk of asthma in farm children. “And indeed, with the aid of data from earlier studies, we were able to show that one particular SNP in TNFAIP3 is associated with increased risk of asthma and allergies,” von Mutius says. Not only that, the degree of protection provided by farm exposure was found to depend on the specific mutation: In carriers of one variant, asthma was almost completely inhibited by farm upbringing, while a different variant conferred only 30% protection.
“These results constitute a great advance in our understanding of the link between the protective effect of farm exposures and endotoxins,” von Mutius affirms. The findings also open up opportunities for the development of novel therapies for allergic conditions. Pharmacological activators of A20, for instance, would be expected to restrain immune responses to allergens and thus confer protection on people who are particularly at risk.