Allergy, Immunity and Tolerance in Early Childhood

The First Steps of the Atopic March

Hans Ulrich Wahn, Hugh A. Sampson

• Publisher: Academic Press
• Year: 2015
• Print ISBN:
  9780124202269
• eBook ISBN:
  9780127999302
• Topic: Medicine
• Subtopic: Immunology

Allergy, Immunity and Tolerance in Early Childhood: The First Steps of the Atopic March provides valuable insights on the atopic diseases, including asthma, allergic rhinitis, atopic dermatitis, and food allergies, which have developed into major health problems in most parts of the world. As the natural history of these chronic diseases has been extensively studied, including their major genetic, environmental, and lifestyle determinants and potential protective factors, the book presents tactics on how pediatric allergists can provide early intervention. In addition, the book unites key, global experts in the field who summarize their collective, and current, knowledge of the early stage of the "Atopic March", along with novel ideas for potential options of prevention. - Summarizes the current knowledge of the epidemiological, genetic, and cellular basis of allergic diseases - Ideal reference for the study of allergies in young children, atopic dermatitis, allergic rhinitis, childhood asthma, and food allergies - Provides landmark findings in the field of immunology and allergy development - Fulfills the need for a book that focuses on primary and secondary allergy prevention, especially during the first years of life - Unites key, global experts in the field who summarize their collective, and current, knowledge, along with novel ideas for potential options of prevention

1

The Maturation of Immune Function in Pregnancy and Early Childhood

Bianca Schaub^∗, and Susan L. Prescott^{§ ∗}Pediatric Pulmonary Division, University Children’s Hospital Munich, LMU Munich, Munich, Germany ^§School of Paediatrics and Child Health, Telethon KIDS Institute, University of Western Australia, Princess Margaret Hospital, Perth, WA, Australia

Abstract

Healthy immune development usually occurs with no intervention being based on the efficient interaction of innate and adaptive immune mechanisms. Environmental exposure interacting with a given genotype participates in shaping early immune maturation toward favorable, healthy development since the evolution. Certainly, microbes are one of the most relevant and abundant constituents of the environment. Any effects of microbial compounds stimulating innate immunity are based on a variety of factors including age, the host's genetic background, and additional environmental factors. Whereas the mucosa and epithelium are critical as the first contact site for microbes, the gut is particularly important as an organ with continuous exposure to microbial substances. Although the microbiota have emerged as arguably as the single most important factor in normal immune development, we know little about how this relationship evolves in pregnancy and how we can use it to prevent allergy and other noncommunicable diseases. In particular, we need to further explore the relationship between maternal gut flora in pregnancy and immune development. A better insight into the underlying mechanisms of immune response by exposure to microbes may result in novel therapeutic and preventive strategies that are relevant for different immune-mediated diseases including allergies. However, a critical issue will be to combine beneficial control of healthy immune mechanisms without suppressing other defense mechanisms against harmful microbes, other immune-mediated diseases, or cancer.

Keywords

Adaptive; Childhood; Immune; Innate; Maturation; Microbiome; Pregnancy

Introduction

“The first 1000 days” has become a core focus and a prominent catch phrase in growing efforts to understand the developmental programming of disease predisposition in early life. Spanning all aspects of health, the strong concept of the developmental origins of health and disease is based on clear evidence that events and exposures in early development can have lasting and sometimes latent effects on later health.^1,2 Although the early focus of this research was on later-onset cardiometabolic diseases, it is clear that earlier-onset noncommunicable diseases (NCDs) such as allergic diseases share similar risk factors and should be regarded as a core part of this agenda.³ Understanding the early environmental influences on early immune development is also a key element in disease prevention.

The immune system has a critical role in the development, homeostasis, and function of virtually all organ systems. Subtle early variations in the pattern of immune response can predispose to disease and influence both the propensity and the dynamics of inflammation in later life.⁴ The modern epidemic of infant allergic disease has drawn considerable attention to the importance of early immune development and the potential impact of modern environmental changes on the maturing immune system. In addition to its obvious role in the rising predisposition to allergic and autoimmune disease, early immune dysregulation is now implicated in a range of NCDs, including predisposition to mental health disorders and cardiovascular disease.^3,5 With economic prosperity and lifestyle changes, the rising propensity for inflammation is implicated in the rising burden of chronic disease and all-cause mortality in modern societies. It is therefore critically important to understand the normal processes and pathways that underpin the normal immune development, how these are modified by adverse early environmental exposures to lead to disease, and how these may be favorably modified to reduce that risk. Optimizing immune health in early life will reduce the risk of allergy and immune diseases, but it is also likely to reduce the burden of many other chronic inflammatory diseases. Because immune function is so responsive to the early environment, and because immune disease manifests so early, this provides an important early indicator for the effects of environment on human health.

Immune development in health and disease

Healthy immune maturation depends on efficient communication between the two pillars of immune regulation, the innate and adaptive immune systems, which are composed of a large number of involved cells (details are given in Ref. 6).

In brief, innate immune cells such as monocytes, granulocytes, dendritic cells (DC), natural killer (NK) cells, mast cells, thrombocytes, and locally relevant cells (e.g., pulmonary alveolar macrophages) are present during healthy immune maturation and are mostly active in some allergy-affected organs such as, for example, the skin and the respiratory tract.⁷

In addition, innate lymphoid type 2 cells, NK2 subsets, and regulatory NK and NK22 cells were shown to be involved in functional T cell responses, the production of immunoglobulin E (IgE), and the function of the epithelial cell barrier, are thus possibly involved in allergy development.^8,9 Also, precursors of innate bone marrow-derived mucosal DC and the NLRP3 inflammasome may be involved in either inflammatory signaling cascades after virus infections or airway inflammation,¹⁰ both of which are relevant for allergy development.

In close connection with innate immunity, the key players of adaptive immune regulation, namely different T cell subpopulations composed of Th2, Th1, and T_reg but also Th17, Th9, and Th22, and CD8+ cells, B cells, and regulatory B cells, are critical for healthy immune maturation and thus protection against allergic diseases.⁷

Early life immune regulation

The prenatal period is instrumental in shaping a child’s immune system (“programming”) influenced by a wide variety of factors elucidated below, including microbiome, nutrition, smoke exposure, and infection, among many others (Figure 1). This window of opportunity is thus critical for a wide range of risk and protective influences discussed in more detail below. Multifaceted effects on early immune programming can occur prenatally that are critical for effects on local tissues and relevant for risk for or protection from immune-mediated diseases, which may occur only several years later. Thus, an efficient interplay between innate and adaptive immune regulation can shape the maturing immune system, keeping it balanced over numerous years during childhood. Any default regulation affecting solely parts of the system or even cells can result in different immune-mediated diseases such as infections, more chronic diseases such as, for example, allergies, autoimmune diseases, or lack of tolerance.

Whereas bidirectional interactions between the fetus and mother seem critical for postnatal immune regulation, human studies on causal effects are complex because of multifaceted influences that are difficult to study at this time of maturation.

In addition to genetic factors such as “immutable footprints”, epigenetics, the environment, and their interactions influence early immune programming, subsequently affecting anatomical structures such as the mucosa and epithelium, and influencing barrier function.

Figure 1 Influences on prenatal and postnatal immune programming for the development of allergic diseases.

A wide range of environmental factors acting prenatally and/or postnatally are known to influence the maturation of immunological competence combined with genotype and epigenetics, and hence to modulate the risk for the development of allergic diseases. Reproduced with permission from Holt, Sly, Prescott, 2011. Early life origins of allergy and asthma (Figure 3). In: Stephen T., Holgate, Martin K., Church, David H., Broide, Fernando, D. (Eds.), Allergy: Principles and Practice, fourth ed. Elsevier Inc., Martinez.

The exact nature underpinning intrauterine modulatory mechanisms may be composed of the following: Although the amniotic fluid has been shown not to be sterile, direct and indirect modulation via fetoplacental transfer may occur. Decidual tissue maternal immune cells including macrophages, CD8⁺ and γδ-T cells, and large granulated lymphocyte cells are able to induce rejection of paternal histocompatibility antigens. Maternal–fetal tolerance to paternal alloantigens is actively mediated, involving pT_regs (peripheral T_regs) distinctly responding to paternal antigens for tolerance induction.¹¹ Generally, maturation of the infant adaptive immune system occurs from the 15th to 20th week of gestation and can be Ag-specific.

Postnatal immune maturation influences are comparable to before birth, with the major difference in the absence of direct maternal environment. Whereas effects on immune programming most likely happen continuously with different thresholds on several types of immune cells, numerous factors induce changes directly in the organs subsequently affect...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Introduction
• 1. The Maturation of Immune Function in Pregnancy and Early Childhood
• 2. Immunological Aspects of the Atopic March
• 3. Atopic Dermatitis in Infancy and Childhood
• 4. Adverse Reactions to Food
• 5. Viral-Induced Wheeze and Asthma Development
• 6. Infantile Lung Function and Airway Hyperresponsiveness
• 7. The Development of Allergic Rhinitis in Childhood
• 8. Genes and Atopic Phenotypes
• 9. Epigenetic Factors Before and After Birth
• 10. The Physiological Induction of Tolerance to Allergens
• 11. Microbiome and the Effect on Immune Response
• 12. Indoor Allergen Exposure
• 13. Microbial Influences on the Development of Atopy
• 14. Role of Vaccines
• 15. Breast—Always Best?
• 16. Dietary Interventions in Infancy
• 17. Allergen Exposure and Avoidance as Part of Early Intervention and Prevention
• 18. Pharmacotherapies Early in Life to Prevent the Atopic March
• 19. The Role of Antiviral Strategies for the Prevention of Childhood Asthma
• 20. Prevention of Allergy/Asthma—New Strategies
• 21. Antiallergic Strategies: Induction of Tolerance to Food
• Index