Madrid-"We should not underestimate the importance of the prenatal environment and postnatal immunologic development in very early life, because changes occurring during those times set the scene for what happens thereafter," said Susan Prescott, MD, PhD, who is a senior lecturer in pediatrics at the University of Western Australia in Perth. "Once we can define what is going on during those periods, we may be able to intervene before disease develops and thereby prevent atrophy."

Dr. Prescott outlined the link between asthma and allergy at the Annual Congress of the European Respiratory Society (ERS) held recently in Madrid. "It is becoming increasingly important to characterize T-cell responses in early life, in light of the fact that we now understand asthma to be an inflammatory condition and that there are strong links between allergy and asthma," she explained.

Dr. Prescott and colleagues are seeking to characterize early immune responses to allergens to determine how the immune system develops and what factors influence that development. "Whatever these factors are, they may be, at least in part, responsible for the dramatic increase we've seen in allergy sensitization," she said.

Early life appears to be critical to sensitization because "it is when both structural and immunologic development occur," Dr. Prescott noted. "The developing human is more vulnerable to environmental and genetic influences, which may shape the later paths of immune response to our environment."

INNATE IDEAS OF ALLERGENS

Recent studies by Dr. Prescott's group have added to the accumulating evidence that allergen-specific cellular memory is initiated before birth. "We begin to develop our memory to allergens before we are born," she said. Furthermore, "all of us have a type 2 skew during that period. Although in mature individuals this pattern of immune response is associated with allergy, it appears to be a normal process that protects the fetus from the mother."

Although babies respond to allergens at birth, this doesn't mean that allergy is present (or will ever be); it is only a measure of immunologic memory. "Even in adults, immune responses to allergens (such as house dust mites) are almost universal, regardless of whether the individual has an allergy," Dr. Prescott explained. "It is the dominant type of T-cell response (ie, type 1 or type 2) that determines whether or not we develop allergy."

After birth, normal individuals "switch off" this neonatal type 2 immune response-a process that underscores the importance of both the intrinsic and environmental type 1 triggers. In contrast, allergic infants have weaker type 1 responses (which are already detectable at birth), and they fail to "switch off" the newborn type 2 responses. This may be due to genetic and environmental factors that affect the infants' capacity to downregulate type 2 responses.

The dramatic increase in allergic diseases in the last few decades has highlighted the need to understand potential environmental factors that may be responsible. There are now many studies investigating the role of such environmental factors as bacterial infections, allergen exposure, pollutants, and dietary antioxidants.

NATURE OR NURTURE

The role of allergen exposure in early life remains a controversial area. Practitioners remain uncertain about the role of allergen avoidance during pregnancy. "We still don't know whether allergen avoidance is going to be a good thing or a bad thing," Dr. Prescott explained. "Although some doctors are telling their patients to avoid peanuts, for instance, there is no hard evidence that one benefits by avoiding these allergens early in life. Nonetheless, we can postulate that individuals who have marked 'type 1 immaturity' in early life might benefit from delayed encounter with these allergens until such time as their immune responses have matured."

There are a number of ongoing studies that may further clarify these issues, Dr. Prescott noted, but "for now, the jury is still out," she said. At this stage, allergen avoidance for primary allergy prevention is "almost impossible to achieve and appears of limited benefit so far."

Other dietary factors (apart from allergens in food) may also contribute to a proinflammatory tendency. Levels of "anti-inflammatory" omega-3 dietary fatty acids (found in oily fish) and vitamin C have fallen in our diets. Dr. Prescott and colleagues are currently evaluating the effect of these dietary changes on the developing immune response, and they are trying to determine whether early dietary supplementation can protect against later allergy.

Other studies are investigating the relationship between microorganisms and allergic disease. The types of bacteria in a person's gut "may be very important for influencing the immune system or giving it the proper signals as it matures," Dr. Prescott explained. "These bacteria stimulate the monocyte system, which steers the development of T-cell responses."

Bacterial antigens (from both pathogens and commensals) stimulate type 1 differentiation and may protect from allergy. "There is concern that with the increasing use of antibiotics and improved public health, we might be reducing this vital type 1 drive and favoring the development of the type 2 responses, which lead to allergies," she said. A number of recent studies have examined the use of bacterial adjuvants (such as bacillus Calmette-Guérin vaccination) in infancy to favor type 1 immune maturation and prevent allergy. "But so far, these studies have not shown any benefit," Dr. Prescott reported.

The role of other, less well-defined environmental factors (such as increased environmental estrogen levels and greater exposure to biologically active compounds in our food supplies and homes) is unknown. "Many of these compounds have hormonal effects and could therefore have type 2 influences on immunologic development, but no one has looked at this yet," she noted. The fact that no one strong factor appears to be responsible for the increase in allergic disease emphasizes that this is likely to be "a result of complex interaction between multiple environmental and genetic factors," said Dr. Prescott.

It is important for physicians to realize that the balance between type 1 and type 2 responses is not as clear-cut as some would believe. "It is a very subtle balance," Dr. Prescott said. "Just aiming to 'push' the immune response in a type 1 direction could have other serious consequences that we don't understand."

Overall, Dr. Prescott explained, "if we can determine the environmental causes, we will be much better off using noninvasive strategies on a population level than using invasive immunotherapy in targeted individuals." She concluded, "we need a much better understanding of this area before we will be in a position to propose interventions."

-Bob Kronemyer

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