Prenatal Antecedents of Allergies and Asthma

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While fetal growth is manifest clearly by infant size at birth, prenatal influences on other physiological systems are also occurring but are less overtly evident. For example, there is extensive evidence documenting the significance of prenatal priming for the developing immune system. It includes fetal exposure to allergens, which has a special relevance to pediatric medicine because it may contribute to the rising incidence of allergies and asthma worldwide. Although the placenta is usually an effective barrier that blocks the transfer of viruses and bacteria and keeps the fetal compartment sterile, the immune system actually starts to develop and become functional early in gestation. By 2 months after conception, the fetus has lymphocytes that can respond and proliferate. By mid-gestation, analyses of cell subsets in cord blood indicate the presence of activated T cells (Devereux et al, 2001; Warner et al, 2000). Some of this cellular activation is likely due to reactions to food proteins, such as ovalbumin and 6-lactoglobulin (Liobichler et al, 2002). Even some airborne allergens may reach the placenta via the mother. In addition, certain allergens, such as cat dander, can be pulled across the placenta as a conjugated complex with the IgG antibody (Casas and Brjorksten, 2001). In keeping with this evidence for fetal exposure to environmental allergens, analyses of cord blood from neonates across the year have documented that their cellular responses track seasonal variation in grass and tree pollen levels (Piccinni et al, 1993; Van Duren Schmidt et al, 1997).

As can be seen in Fig. 35.2, clinical allergists now believe that the initial biases toward atopic disorders and asthma begin before birth (Jones et al, 2000). Maternal exposure to allergens, tobacco smoke, and pollution increases the risk that infants will wheeze during the first year of life and subsequently develop asthma by 3-4 years of age. Early warning signs of being prone to atopy can often be detected in cord blood. Two neonatal indicators are (1) the presence of elevated levels of IgE, the antibody class associated with allergies and (2) a response bias toward Th2 cytokines when their mononuclear cells are stimulated in culture. If there is a high production of certain cytokines, such as interleukin-5 (IL-5), and relatively low levels of IL-12 and interferon-gamma, it is indicative of a Th2 cytokine or atopic profile. This type of infant is more likely to become asthmatic if subsequently exposed to a rearing environment with cockroaches, air pollution and second hand cigarette smoke, or opportunistically infected with rhi-noviruses on a repeated basis, or subjected to chronic familial stressors (Chen et al, 2007). Yet one more example that in utero and maternal factors influence the propensity for allergies is that a woman's parity status also affects the levels of IgE found in the neonate. While the first child of a woman who has allergies herself will be born with high IgE, the antibody levels in her next infants will then decline progressively with each subsequent birth (Karmaus et al, 2004).

While these associations between prenatal conditions and pediatric allergies may suggest prenatal stimulation is mostly bad, we have also come to realize that the immune system must normally rely on early priming to mature correctly. A total absence of antigenic exposure would result in even more aberrant immune responses. The consequences of under-stimulation can be readily seen in animals reared in the unique conditions of the gnotobiotic laboratory, where they live in sterile conditions without bacteria. Not only does their lymphoid tissue develop abnormally, they fail to establish normal mucosal immune responses, which then undermine the competent maturation of systemic immunity. In addition, even the basic structure of their gut anatomy becomes abnormal in the absence of the resident gastrointestinal micro-biota. Our awareness that some level of antigenic stimulation is critical during infancy has led to the formulation of an alternative idea that may seem counterintuitive: the 'hygiene hypothesis' of pediatric illness (Liu and Murphy, 2003). It proposes that there are some adverse unintended consequences of the modern rearing environment, which is now too clean and pathogen free.

Gestational Age

Fetal Growth _

Maternal Allergen Exposure Cytokine Profile of Mother

Intrauterine priming of fetus

Atopic Neonatal Phenotype Th2 Dominance (IFN^, IL-12 IL-5 Elevated IgE

Allergens, Pollutants Rhinovirus


Fig. 35.2 Many infants that develop allergies and asthma are already predisposed toward atopic conditions at birth. Prenatal exposure to allergens, prematurity, and

If over the course of many millennia, the immune system had become selected to rely on antigenic priming, a child may not be able fully achieve normal immune competence without some exposure to viral and bacterial pathogens. Now that we have vanquished so many of the common parasites and infectious pathogens to which humans used to be exposed, our children today grow up in a more germ-free and hygienic world than ever before. It could help to explain why increasing numbers of people worldwide now seem to be over-reactive to formerly benign food antigens and plant pollens. Specifically, lymphoid cells such as the eosinophil, which are the ones that responded to microfilaria worms and protozoan parasites like malaria, now may be redirected toward other environmental stimuli.

We still have much to learn about how prenatal conditions set the stage for subsequent reactions during early encounters with the postnatal world (Salk et al, 1974). Our laboratory investigated some of these questions in a primate model and demonstrated that disturbances of pregnancy affected many immune responses in infant rhesus monkeys (Coe et al, 2007). Some immune abnormalities were evident already being small or very large at birth are among the many factors that affect how a neonate will respond to the rearing environment and to respiratory infections at birth; others emerged as the infant monkey developed across the first year of life. For example, the infants established atypical profiles of gut bacteria, with lower concentrations of beneficial Lactobacilli and Bifidobacteria, when generated from stressed pregnancies (Bailey et al, 2004). In turn, with reduced numbers of the protective microbiota, the infants were more vulnerable to enteric pathogens like Shigella and Campylobacter, two diarrhea-causing bacteria, especially during the subsequent stressful event of weaning (Bailey and Coe, 1999).

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Coping with Asthma

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If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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