NEW YORK CITY—Does genetics play a role in the development of asthma? Why do some people develop tolerance to allergens? How do microbes influence asthma and allergies? Allergic disease experts attempted to answer these questions at the recent annual meeting of the American Academy of Allergy, Asthma, & Immunology in New York City.[1]

Genetics strongly influences asthma risk, said Lyle J. Palmer, PhD, Assistant Professor of Medicine and Director of Statistical Genomics in the Channing Laboratory at Harvard Medical School in Boston. Studies have shown that having a parent with a history of asthma multiplies a child’s asthma risk by two to three times, he reported. The risk is increased four to eight times if both parents have asthma.

A particularly robust maternal influence on asthma development has been observed in many epidemiologic studies. “The differential in the risk of transmission from mother versus father may be fourfold,” Dr. Palmer said.

Twin studies have also demonstrated asthma’s genetic component; they show much higher concordance rates for asthma among monozygotic than dizygotic twins. The finding persists even when twins are reared apart.

Estimates of asthma heritability range from 36% to 75% in twin and pedigree investigations. Similar heritability has been observed for asthma-associated phenotypes, including atopy, eosinophilia, airway responsiveness, and impaired lung function.

Inherited risk factors for the disease begin to exert their influence in early infancy, Dr. Palmer stressed. “There is a strong clinical utility to taking a family history,” he concluded.

It is often assumed that exposure to high allergen levels increases the risk of sensitization. “But several studies now suggest that this is not true for all allergens,” said Judith A. Woodfolk, MBChB, PhD, an Assistant Professor in the Asthma and Allergic Disease Center at the University of Virginia in Charlottesville.

These studies have identified a modified T-helper cell 2-type (TH2) response to the major cat allergen Fel d 1 in children exposed to high levels of this allergen.[2] The response is characterized by the presence of serum immunoglobulin G (IgG) and IgG4 antibodies to Fel d 1. An interesting feature of this response is the lack of measurable serum IgE, which is associated with negative skin test reactivity, and no allergic symptoms. Furthermore, there is evidence to suggest that the modified TH2 response is present early in life and persists into adulthood.

“This phenomenon of [allergen] tolerance may not be restricted to cat allergen,” Dr. Woodfolk said. The immune response to allergens from rat, dog, and bee venom may also show features consistent with a modified TH2 response.

Production of high levels of the anti-inflammatory molecule interleukin (IL) 10 is associated with the modified TH2 response. IL-10 has been shown to inhibit both cytokine manufacture in TH1 and TH2 cells and allergen-specific T-cell proliferation in mice and humans; it has also been found to reduce mast cell activation in humans. Thus, “peptides with potent IL-10–inducing properties are attractive candidates for incorporation into a peptide [allergy] vaccine,” Dr. Woodfolk suggested.

Allergens are ubiquitous, so why do only about a third of us have allergies? Another answer may lie in the gut microflora, said Bengt Björkstén, MD, PhD, Executive Director of the Center for Allergy Research at the Karolinska Institute in Stockholm, Sweden.

Population-based studies suggest that the intestines of nonallergic children undergo greater bacterial colonization during infancy than do those of allergic children. For example, gut levels of bifidobacteria and enterococci during the first year of life are higher in infants from Estonia (where allergic disease prevalence is low) than in infants from Sweden, which has high allergy rates.[3] Gut colonization with lactobacilli has also been linked with protection from allergies; in contrast, allergic children tend to have higher intestinal levels of Clostridium difficile than do nonallergic children.

Interestingly, some data indicate that there are no significant differences between the gut microflora of allergic and nonallergic children older than 3 months. This suggests that if gut colonization is necessary for allergy protection, it must occur very early in life.

In Sweden, an inverse relationship exists between environmental endotoxin levels and skin-prick test positivity, whereas the two are unrelated in Estonia. It may be, said Dr. Björkstén, that endotoxin influences allergic sensitization in Western societies because it is present at very low levels; these low levels, ironically, appear more likely to cause sensitization than do very high levels. “In traditional societies, [endotoxin] is everywhere at high enough levels not to present a risk to individuals,” he stated.

Age and virus type are key determinants of which children with viral infections will subsequently develop asthma, said Scherer P. Sanders, PhD, an Associate Professor of Medicine at the Asthma and Allergy Center of Johns Hopkins University in Baltimore. Indeed, among those younger than 3 years, repeated herpes infection has been associated with reduced asthma risk, and repeated lower respiratory tract infection has been linked to increased risk.

In addition, exposure to older siblings and entering day care before age 6 months seem to lower the asthma risk. Thus, “repeated viral infections early in life may stimulate the immature immune system toward a TH1 phenotype and reduce the risk of asthma,” Professor Sanders speculated.

However, viral infections later in life may be more harmful. Recent data show that up to 80% of asthma exacerbations are associated with viruses—usually rhinovirus but also coronavirus, influenza, parainfluenza, and respiratory syncytial virus. Furthermore, asthma hospitalization rates correlate strongly with seasonal peaks in viral upper respiratory infections, Professor Sanders related.

Interestingly, in vitro and in vivo studies suggest that rhinovirus infection stimulates production of nitric oxide, which then inhibits viral replication and virus-induced cytokine release. It may, therefore, be possible to use nitric oxide donors as a novel therapy for rhinovirus infection and virus-related asthma exacerbations.[4]

—Timothy Begany