Allergic disease can be viewed as an early manifestation of immune dysregulation. Environmental exposures including maternal inflammation, diet, nutrient balance, microbial colonization and toxin exposures can directly and indirectly influence immune programming in both pregnancy and the postnatal period. The intrauterine microclimate is critical for maternal and fetal immunological tolerance to sustain viable pregnancy, but appears susceptible to environmental conditions. Targeting aspects of the modern environment that promote aberrant patterns of immune response is logical for interventions aimed at primary prevention of allergic disease. Defining the mechanisms that underpin both natural and therapeutic acquisition of immunological tolerance in childhood will provide insights into the drivers of persistent immune dysregulation. In this review, we summarize evidence that allergy is a consequence of intrauterine and early life immune dysregulation, with specific focus on contributing environmental risk factors occurring preconception, in utero and in the early postnatal period. We explore the immunological mechanisms which underpin tolerance and persistence of allergic disease during childhood. It is likely that future investigations within these two domains will ultimately provide a road map for the primary prevention of allergic disease.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/cea.12531

Mechanisms of allergic disease - environmental and genetic determinants for the development of allergy.

Epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exert a profound influence on physiological function and risk of diseases in adult life. The concepts of the 'developmental programming' and Developmental Origins of Health and Diseases (DOHaD) have become well accepted and have been applied across almost all fields of medicine. Adverse intrauterine environments may have programming effects on the crucial functions of the immune system during critical periods of fetal development, which can permanently alter the immune function of offspring. Immune dysfunction may in turn lead offspring to be susceptible to inflammatory and immune diseases in adulthood. These facts suggest that inflammatory and immune disorders might have developmental origins. In recent years, inflammatory and immune disorders have become a growing health problem worldwide. However, there is no systematic report in the literature on the developmental origins of inflammatory and immune diseases and the potential mechanisms involved. Here, we review the impacts of adverse intrauterine environments on the immune function in offspring. This review shows the results from human and different animal species and highlights the underlying mechanisms, including damaged development of cells in the thymus, helper T cell 1/helper T cell 2 balance disturbance, abnormal epigenetic modification, effects of maternal glucocorticoid overexposure on fetal lymphocytes and effects of the fetal hypothalamic-pituitary-adrenal axis on the immune system. Although the phenomena have already been clearly implicated in epidemiologic and experimental studies, new studies investigating the mechanisms of these effects may provide new avenues for exploiting these pathways for disease prevention.

/pdf/developmental-origins-of-inflammatory-and-immune-diseases-4615qvn69j.pdf

Developmental origins of inflammatory and immune diseases.

During the last 50 years there has been a significant increase in Western societies of atopic disease and associated allergy. The balance between functional subpopulations of T helper cells (Th) determines the quality of the immune response provoked by antigen. One such subpopulation - Th2 cells - is associated with the production of IgE antibody and atopic allergy, whereas, Th1 cells antagonize IgE responses and the development of allergic disease. In seeking to provide a mechanistic basis for this increased prevalence of allergic disease, one proposal has been the 'hygiene hypothesis', which argues that in Westernized societies reduced exposure during early childhood to pathogenic microorganisms favours the development of atopic allergy. Pregnancy is normally associated with Th2 skewing, which persists for some months in the neonate before Th1/Th2 realignment occurs. In this review, we consider the immunophysiology of Th2 immune skewing during pregnancy. In particular, we explore the possibility that altered and increased patterns of exposure to certain chemicals have served to accentuate this normal Th2 skewing and therefore further promote the persistence of a Th2 bias in neonates. Furthermore, we propose that the more marked Th2 skewing observed in first pregnancy may, at least in part, explain the higher prevalence of atopic disease and allergy in the first born.

T helper cell 2 immune skewing in pregnancy/early life: chemical exposure and the development of atopic disease and allergy

Background Parental history of atopic disease is a well-established risk factor for the development of atopic dermatitis (AD), but several aspects of this association remain unclear. Objective We sought to determine the association of parental history of atopic disease with AD in offspring. Methods We searched PubMed and EMBASE through June 2018 for relevant records and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled odds ratios (ORs) with 95% CI were calculated using random-effects models. Results A total of 163 records covering 149 unique studies were included. Of these, 119 studies were included in the meta-analysis. Individuals with parental history of atopic disease had increased odds of AD (OR, 1.81; 95% CI, 1.65-1.99). Parental asthma (OR, 1.56; 95% CI, 1.18-2.05) and allergic rhinitis (OR, 1.68; 95% CI, 1.34-2.11) had a smaller effect than AD (OR, 3.30; 95% CI, 2.46-4.42). The effect of maternal and paternal history was comparable for all atopic diseases. An increase in odds was observed when comparing the effect of having 1 (OR, 1.30; 95% CI, 1.15-1.47) or 2 atopic parents (OR, 2.08; 95% CI, 1.83-2.36), as well as having a parent with 1 (OR, 1.49; 95% CI, 1.28-1.74) or more atopic diseases (OR, 2.32; 95% CI, 1.92-2.81). Conclusions This study provides evidence-based risk estimates that may guide physicians who counsel parents with a history of atopic disease about their children's risk of AD. This information is of particular importance for future efforts toward establishing prophylactic interventions for AD on a general population level.

How does parental history of atopic disease predict the risk of atopic dermatitis in a child? A systematic review and meta-analysis.

Regulatory T cells (Tregs ) control immune responses by suppressing various inflammatory cells. Tregs in newborn babies may play an important role in preventing excessive immune responses during their environmental change. We examined the number and phenotype of Tregs during the neonatal period in 49 newborn babies. Tregs were characterized by flow cytometry using cord blood (CB) and peripheral blood (PB) from the early (7-8 days after birth) and late (2-4 weeks after birth) neonatal periods. CD4+ forkhead box protein 3 (FoxP3+ ) T cells were classified into resting Tregs (CD45RA+ FoxP3low ), activated Tregs (CD45RA- FoxP3high ) and newly activated T cells (CD45RA- FoxP3low ). Compared with CB and PB during the late neonatal period, the percentage of Tregs and all Treg subpopulations in the CD4+ lymphocyte population were increased significantly during the early neonatal period. Furthermore, the proportion and absolute number of activated Tregs were increased markedly compared with other Treg subpopulations, such as resting Tregs and newly activated T cells (non-Tregs ), in the early neonatal period. Increased Tregs concomitantly expressed the suppressive molecule cytotoxic T lymphocyte antigen-4 (CTLA-4). The up-regulated expression of chemokine receptor 4 (CCR4) and down-regulated expression of CCR7 were also observed in expanded Tregs . When cord blood cells were cultured in vitro with CD3 monoclonal antibodies (mAb) for 5 days, CD4+ CD45RA- FoxP3high cells were increased significantly during the culture. Thus, the presence of increased activated Tregs in early neonates may play an important role in immunological regulation by suppressing excessive T cell activation caused by the immediate exposure to ubiquitous antigens after birth.

/pdf/significant-augmentation-of-regulatory-t-cell-numbers-occurs-2ib5ow49zb.pdf

Significant augmentation of regulatory T cell numbers occurs during the early neonatal period

Background

This study aimed to investigate the influence of maternal allergy on cord blood regulatory and effector T cells and to evaluate their role as a predictor of atopic dermatitis (AD) during the first 2 yr of life.



Methods

Seventy mother–infant pairs were recruited in this prospective birth cohort study (21 allergic and 49 non-allergic mothers). Cord blood samples were collected and assayed for the percentage of regulatory T cells (Treg), interferon-γ (IFN-γ), and interleukin-4 (IL-4) producing T cells (Th1 and Th2, respectively) using flow cytometry. Experiments were undertaken to assess the function of cord blood CD4+CD25+CD127− Treg cells by cell proliferation and cytokine responses. Their offspring at the age of 2 yr old were evaluated by dermatologists to determine whether they had AD.



Results

During the first 2 yr of life, 15.7% of the children developed a physician-diagnosed AD. A significantly increased percentage of Th2 cell was observed in cord blood of newborns with maternal allergy. Treg/Th2 ratio significantly decreased among the offspring of allergic mothers. Treg cell-associated suppression of Th2 response was attenuated in Der p1-stimulated CD4+CD25− T cells from the offspring of allergic mothers. Children with reduced Th1/Th2 (p = 0.001, OR = 0.37) and Treg/Th2 (p = 0.001, OR = 0.47) ratio in cord blood had a higher risk of developing AD.



Conclusion

Maternal allergic status is associated with increased percentage of IL-4+CD4+ T cells and a reduced Treg/Th2 ratio in cord blood at their children's birth, which may predispose to an increased risk for developing AD.

T cell subsets in cord blood are influenced by maternal allergy and associated with atopic dermatitis

Efficient light-driven reductive amination of furfural to furfurylamine over Ruthenium-cluster catalyst

Co-thermal in-situ reduction of inorganic carbonates to reduce carbon-dioxide emission

Objective
To investigate the influence of maternal atopy on cord blood effector T cells and to identify these biologic markers as predictors of atopic dermatitis（AD）.


Methods
Seventy mother-infant pairs were recruited in this prospective birth cohort study.Suspected factors for allergy, including maternal allergic history, total serum IgE, and maternal age at birth, were collected.Mother peripheral blood samples and cord blood were obtained and assayed for the percentage of interferon -γ（IFN-γ） and interlukin 4 （IL-4） producing T cells（Th1 and Th2 respectively） using flow cytometry.Their offspring at the age of 2 years old were evaluated by their dermatologist whether they had AD.Statistical analysis was performed using multiple logistic regression models and receiver-operating characteristic curve was employed＆amp;nbsp;to predict atopic dermatitis.


Results
Twenty-one allergic and 49 nonallergic mothers were recruited in this study.During the first two years of life, 15.7%children （n=11） developed a physician-diagnosed AD （all children were the only child in the family ）.In group with maternal allergic rhinitis , a significantly increased percentage of Th2 was observed in peripheral blood of mother （ 7.10 [ 1.18;16.1 ]% vs.0.37 [ 0.25;0.72]%, U=10.0, P ＆lt;0.05 ） and cord blood of newborns （ 1.02 [ 0.57;1.34 ]% vs.0.21 [ 0.15;0.42]%, U=127.5, P＆lt;0.05）, respectively.Maternal atopic history did not affect the percentage of Th1cells in cord blood （0.69[0.40;1.12]% vs.0.50[0.31;0.66]%, U=361.0, P＆gt;0.05）.Children with reduced Th1/Th2 ratio in cord blood had a higher risk to develop AD （OR=1.72,P=0.001）.The model including Th1/Th2, maternal allergy, maternal age at birth and maternal total IgE showed high ability to discriminate children with and without AD.AUC was 0.907 （95% CI：0.804 -1.011, P＆lt;0.001）.


Conclusions
Elevated IL-4＋CD4＋T cells in cord blood were of relevance with maternal allergic history.Imbalance between Th1 cell and Th2 cell at birth are associated with maternal allergy and promoted subsequent AD development.


Key words: 
Rhinitis, allergic, perennial; Dermatitis, atopic; Fetal blood; Interferontype Ⅱ; Interleukin-4

Imbalance between Th1 and Th2 cells in cord blood is influenced by maternal allergic rhinitis and associated with atopic dermatitis during the first two years of life

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T cell subsets in cord blood are influenced by maternal allergy and associated with atopic dermatitis

Efficient light-driven reductive amination of furfural to furfurylamine over Ruthenium-cluster catalyst

Co-thermal in-situ reduction of inorganic carbonates to reduce carbon-dioxide emission

Imbalance between Th1 and Th2 cells in cord blood is influenced by maternal allergic rhinitis and associated with atopic dermatitis during the first two years of life