Early life factors that affect allergy development

Key Points

  • The recent rise in the incidence of allergic disease suggests that changing environmental factors can influence the risk of allergic sensitization. Environmental exposures that occur during the first few months of life can influence the risk of allergy development in later childhood.

  • The timing of the first exposure to potential allergens, as well as the route of the first exposure, can influence whether tolerance or allergic sensitization occurs. Cutaneous antigen exposure predisposes towards a T helper 2 (TH2) cell-skewing environment, which leads to allergic sensitization, whereas oral antigen exposure predisposes towards tolerogenic responses that are mediated by retinal dehydrogenase 2 (RALDH2)-expressing CD103+ dendritic cells.

  • Exposure to microbial endotoxins alongside potential allergens can protect against allergic sensitization through the stimulation of innate pattern recognition receptors.

  • Many of the environmental factors that are associated with allergy development modify the composition and diversity of the microbiota. Recent studies have demonstrated that the microbiota composition in the first few months of life can be predictive of allergy development in later childhood, and studies in mice have demonstrated that the absence of key bacterial microbiota species can be a driving factor in allergy development.

  • Infection with pathogens can protect against allergic sensitization by promoting tolerogenic responses or can exacerbate existing disease by promoting the release of TH2 cell-skewing cytokines. Fungal infections and certain bacterial and viral species are associated with the exacerbation of existing allergies, whereas helminth species and certain bacterial and viral species are associated with protection against allergic sensitization.

  • It is clear that there are notable differences in the quality of immune responses to foreign antigens and stimuli even in the few weeks after birth in mice; how this developmental time window translates into the setting of human neonates is not yet clear. Both microorganism-derived and helminth-derived molecules have great potential for therapeutic and prophylactic use in infants who are at a high risk of developing allergies.

Abstract

The incidence of allergic disease continues to rise in industrialized countries. The rapid increase in the incidence of allergic disease throughout the past half century suggests that recently altered environmental factors are driving allergy development. Accumulating evidence suggests that environmental experiences that occur during the first months of life can influence the risk of allergic sensitization. In this Review, we present the evidence relating to specific early life exposures that affect future allergy development, and discuss how these exposures may promote either tolerance or allergic sensitization.

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Figure 1: The route of antigen exposure influences immune priming.
Figure 2: A diverse microbiota can inhibit allergic sensitization.
Figure 3: Developmental time windows in early life affect adult allergic sensitization in mice.

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Acknowledgements

The authors gratefully acknowledge support from their funders. Work in the laboratory of B.B.F. is supported by operating grants from the Canadian Institutes of Health Research (CIHR). B.B.F. is a Canadian Institute for Advanced Research Senior Fellow and the University of British Columbia Peter Wall Distinguished Professor. L.A.R. was supported by postdoctoral fellowship awards from the CIHR and the Michael Smith Foundation for Health Research in partnership with the Allergy, Genes and Environment Network (AllerGen).

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Correspondence to B. Brett Finlay.

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Glossary

Atopic

Describes a state of heightened immune responsiveness to foreign antigens that is mediated by the production of IgE antibodies.

Allergen

A type of antigen that elicits an inappropriate immune response to an otherwise harmless substance.

Airway hyper-reactivity

A typical characteristic of patients with asthma in which the airways constrict in response to a variety of inhaled stimuli. This can be measured in people and in laboratory mice by changes in airway resistance that are induced by inhaled methacholine.

Allergic sensitization

The process of generating antigen-specific IgE antibodies against an allergen.

Lymphocyte anergy

An unresponsive state that can be induced in B cells or T cells that have been chronically stimulated, or when their antigen receptor is stimulated in the absence of co-stimulatory signals.

Regulatory T cell

(Treg cell). A specialized type of CD4+ T cell that suppresses the activity of other immune cells.

Signal transducer and activator of transcription 6

(STAT6). A transcription factor that is required for the differentiation of T helper 2 cells.

Microorganism-associated molecular patterns

(MAMPs). Highly conserved patterns that are found within microbial molecules such as components of bacteria cell walls and are recognized by host innate immune cells through pattern recognition receptors.

Germ-free mice

Mice that are not colonized by any microorganisms and so do not have a microbiota.

Gnotobiotic

Colonized with a known microbiota composition.

Specific pathogen-free mice

(SPF mice). Mice that are free from colonization by particular pathogens but that have a microbiota.

Pathobiont

An organism that can exist as an innocuous member of the microbiota but that in some circumstances can cause pathogenesis.

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Reynolds, L., Finlay, B. Early life factors that affect allergy development. Nat Rev Immunol 17, 518–528 (2017). https://doi.org/10.1038/nri.2017.39

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