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Key messages
Perinatal immune development and its role in atopy development
(ii) the rate of postnatal matu- ration of Th-cell functional competence (as measured by capacity to generate “bal- anced” Th1/Th2 cytokine re- sponses) is slower in children at high risk for allergy devel- opment;
(iii) subsequent studies have ex- tended the range of cell types manifesting atopic risk-asso- ciated developmental defi- ciencies to additional popu- lations within the innate and adaptive immune system in- cluding monocytes, dendritic cells and Tregs.
Following the advent of the Hy- giene Hypothesis in the late 1980s, interest has progressively increased in the role of the gut mi- crobiome as the “driver” of postna- tal development of immunocom- petence. Recent findings suggest a link between postnatal devel- opment of immunity to organisms within the respiratory microbiome and risk for atopic asthma.
Since many of these functional deficiencies are already evident in cord blood the trajectory for post- natal immune maturation seems at least partially preset before birth. Observations stemming from the “farm barn” studies in Europe
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have identified TLR-dependent microbial signaling to innate immune cells in the maternal decidua as the potential mecha- nism: this may result in stabiliza- tion of the immunological milieu in the placenta, contributing to protection of the integrity of the local vasculature responsible for delivering nutrients to the fetus, thus optimizing in utero growth and development (Figure 2).
KEY REFERENCES
1. Holt PG, Clough JB, Holt BJ, Baron-Hay MJ, Rose AH, Robin- son BWS et al. Genetic risk for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy 1992;22:1093-1099.
2. Holt PG, Strickland DH, Bosco A, Jahnsen FL. Pathogenic mecha- nisms of allergic inflammation: atopic asthma as a paradigm. In: Advances in Immunology. Eds: FW Alt. 2009;51-113.
3. Holt PG, Rowe J, Kusel M, Par- sons F, Hollams E, Bosco A, et al. Towards improved predic- tion of risk for atopy and asthma amongst preschoolers: a pro- spective cohort study. J Allergy
Clin Immunol 2010;125:645-651.
4. Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulato- ry T cells. J Allergy Clin Immunol 2009;123:774-782.
5. Holt PG, Strickland DH. Sooth- ing signals: transplacental transmission of resistance to asthma and allergy. J Exp Med 2009;206:2861-2864.
6. Holt PG, Strickland DH, Hales BJ, Sly PD. Defective “immune sur- veillance” of respiratory mucosal surfaces: a primary causal factor in asthma onset and progression.
Chest 2014;145:370-378.
Figure 1 Postnatal development of sensitization versus tolerance to house dust mite (HDM). Fluctuations in HDM-specific IgE titers in individual children
who were not (left) or were (right) sensitized at age 5 years. The dotted line indicates the 0.35 kU/L sensitization threshold. Note “cycling” of IgE production,
particularly in non atopics, reflecting underlying competitive interactions between regulatory and helper T-cell populations. ( Holt et al 2010 originally
published in J Allergy Clin Immunol 125(3), 645-651. Reprinted under Rightslink Lic No 3346780104940.)
Figure 2 Proposed mechanisms by which maternal exposure to bacteria protects against allergies in offspring. A multi-step process may be involved: (i) initial mild-to-moderate inflammation in the lungs induced by aerosol exposure to microbe-containing dust; (ii) resultant cytokine signals translocate from lung to placenta via the bloodstream, where they attenuate local TLR expression and modulate resident myeloid cell functions; (iii) circulating cytokines enter the maternal bone marrow, where they “program” myeloid precursors that subse- quently traffic to the decidua to replenish resident myeloid populations and influence the local inflammatory milieu. (Reproduced with permission from Patrick
G. Holt, et al. Soothing signals: transplacental transmission of resistance to asthma and allergy. J Exp Med. 2009;206(13):2861-2864.)
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• The development and phenotypic expression of allergic disease depends on a complex interaction between genetic factors, environmental factors (food or inhalant allergen exposure) and risk/protective factors
• The concept of the hygiene hypothesis has been extensively investigated and has influenced our understanding of early-life events
• Some susceptible/predisposed individuals may benefit from reduction of allergen exposure
• Exposure to food or inhalant allergens cannot be totally avoided, and observational and interventional studies on avoidance/ reduction of exposure have not shown convincing results • Multifaceted allergy avoidance during infancy with avoidance of
both foods and airborne indoor allergens have shown a persisting reduction of asthma
The development and phenotypic expression of allergic disease de- pends on the interaction between genetic and environmental factors such as exposure to allergens to- gether with risk and/or protective factors (Table 1). Over the last decades an increase in the preva- lence of allergic diseases has been reported worldwide. From pro- spective birth cohort studies, pos- sible protective and risk factors have been identified (Table 2, 3). A family history of allergic disease (asthma, allergic rhinoconjunctivi- tis, atopic eczema or food allergy) in first degree relatives, is strongly associated with an increased risk for allergic disease.
Considering that the increase in the prevalence of allergic diseas- es cannot be ascribed solely to genetic factors, most studies on development of allergic diseases have focused on the influence of in environmental factors, e.g. ear- ly feeding (breastfeeding vs. cow’s milk formula), diets/nutrients, exposure to allergens, tobacco smoking, pollution, farm vs. urban environment, and infectious load. Many hypotheses have been pro- posed based on observed asso- ciations between environmental factors and development of aller-