Paul Noakes

Maternal smoking in pregnancy alters neonatal cytokine responses

Background: Maternal cigarette smoking in pregnancy is an important, common and avoidable exposure that has been linked with elevated cord blood (CB) immunoglobulin E levels and subsequent asthma and allergic disease in childhood. Despite this, there is still very little information about the immunological effects of maternal smoking on the fetus.

Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses

Infants of smokers have much higher rates of respiratory infection, asthma and airway disease. The current study assessed the effects of maternal smoking in pregnancy on neonatal toll-like-receptor (TLR)-mediated immune responses as a possible contributing factor to the elevated rates of respiratory illness. In a prospective birth cohort, the cord blood immune responses of neonates of smoking and nonsmoking mothers were compared. Maternal and cord serum cotinine were measured to confirm the level of cigarette smoke exposure. Neonatal cytokine responses were assessed to optimal doses of TLR2, TLR3, TLR4 and TLR9 ligands. Cotinine levels confirmed maternal reporting of cigarette smoking in pregnancy, with significantly higher cotinine levels in maternal and cord blood compared with the nonsmoking group. Infants of smoking mothers showed significantly attenuated innate TLR-mediated responses compared with infants of nonsmokers. The current findings indicate that in addition to effects on developing airways, maternal smoking also has significant immunological effects in pregnancy, which could contribute to the well recognised, subsequent increased risk of respiratory infections and asthma. These effects appear to be mediated through effects on toll-like receptor-mediated innate response pathways, which also promote regulatory pathways in the inhibition of allergic immune responses in the postnatal period, suggesting that other environmental interactions are highly relevant to the “hygiene hypothesis”.

Children with egg allergy have evidence of reduced neonatal CD4+CD25+CD127lo/− regulatory T cell function

BACKGROUNDnThe role of regulatory T (Treg) cells in allergic predisposition is not known.nnnOBJECTIVEnThis study compared the frequency and function of cord blood Treg cells from nonallergic children (n = 18) with those from children who have egg allergy (n = 15) in the first year of life.nnnMETHODSnCD4(+) effector T cells and autologous antigen-presenting cells isolated from cord blood mononuclear cells were cocultured with or without CD4(+)CD25(+)CD127(lo/-) Treg cells, and cytokine responses to staphylococcal endotoxin B were assessed after 48 hours.nnnRESULTSnThe addition of Treg cell populations to cord blood mononuclear cell cultures resulted in significant reduction in IL-10 (P = .002), IL-13 (P = .012), and IFN-gamma (P < .001) production. Consistent with other reports, effector CD4(+) T-cell responses (IFN-gamma and IL-13) tended to be lower in the allergic group. These neonates showed less significant Treg cell-associated suppression of IFN-gamma (P = .015) compared with that seen in the nonallergic group (P = .001). The allergic group was also less likely (44%) to show Treg cell-associated suppression of IFN-gamma effector responses compared with that seen in the nonallergic group (78%, P = .015). The magnitude of suppression (change in IFN-gamma level when CD4(+)CD25(+)CD127(lo/-) Treg cells were added to responding effector T-cell cultures) was significantly lower in the allergic group (P = .004). There were no between-group differences in the circulating CD4(+)CD25(+)CD127(lo/-) Treg cells (as a percentage of cord blood T cells) or in the FOXP3 expression of these cells.nnnCONCLUSIONnThis study confirms the presence and activity of Treg cells in cord blood and provides preliminary evidence of differences in neonates who progress to allergic disease in the first year of life.

The gut microbiota and inflammatory noncommunicable diseases : associations and potentials for gut microbiota therapies.

Rapid environmental transition and modern lifestyles are likely driving changes in the biodiversity of the human gut microbiota. With clear effects on physiologic, immunologic, and metabolic processes in human health, aberrations in the gut microbiome and intestinal homeostasis have the capacity for multisystem effects. Changes in microbial composition are implicated in the increasing propensity for a broad range of inflammatory diseases, such as allergic disease, asthma, inflammatory bowel disease (IBD), obesity, and associated noncommunicable diseases (NCDs). There are also suggestive implications for neurodevelopment and mental health. These diverse multisystem influences have sparked interest in strategies that might favorably modulate the gut microbiota to reduce the risk of many NCDs. For example, specific prebiotics promote favorable intestinal colonization, and their fermented products have anti-inflammatory properties. Specific probiotics also have immunomodulatory and metabolic effects. However, when evaluated in clinical trials, the effects are variable, preliminary, or limited in magnitude. Fecal microbiota transplantation is another emerging therapy that regulates inflammation in experimental models. In human subjects it has been successfully used in cases of Clostridium difficile infection and IBD, although controlled trials are lacking for IBD. Here we discuss relationships between gut colonization and inflammatory NCDs and gut microbiota modulation strategies for their treatment and prevention.

Presymptomatic differences in Toll-like receptor function in infants who have allergy.

BACKGROUNDnMicrobial exposure might play a key role in allergy development, but little is known about the role of Toll-like receptors (TLRs).nnnOBJECTIVEnThis study explored the association between neonatal TLR microbial recognition/function, allergy risk (maternal allergy), and prospective allergy development.nnnMETHODSnCord blood mononuclear cells (n = 111) were cultured either alone or with optimal concentrations of TLR ligands: lipoteichoic acid (TLR2), polyinosinicpolycytidylic acid (TLR3), LPS with IFN-gamma (TLR4), flagellin (TLR5), imiquimod R837 (TLR7), or CpG (TLR9). Cytokine responses were assessed in relation to allergy risk (maternal allergy) and allergy outcomes (sensitization, food allergy, and atopic dermatitis) at 12 months of age.nnnRESULTSnMaternal allergy (n = 59) was associated with significantly higher neonatal IL-12 and IFN-gamma responses to TLR2, TLR3, and TLR4 activation, whereas TNF-alpha and IL-6 responses to TLR2, TLR4, and TLR5 activation were significantly higher in newborns who subsequently had allergic disease (n = 32). Notably, consistent with previous reports, newborns who had disease had lower T(H)1 IFN-gamma response to mitogens (PHA).nnnCONCLUSIONnAllergic disease was associated with increased (rather than decreased) perinatal TLR responses. Further studies are needed to determine how these responses track in the postnatal period and whether this relative hyperresponsiveness is a product of intrauterine influences, including maternal atopy, functional genetic polymorphisms, or both.

Association of maternal smoking with increased infant oxidative stress at 3 months of age

Background: Cigarette smoke is a major source of free radicals and oxidative stress. With a significant proportion of women still smoking during pregnancy, this common and avoidable exposure has the potential to influence infant oxidative status, which is implicated in the increased propensity for airway inflammation and asthma. The aim of this study was to examine the effects of maternal smoking on markers of infant oxidative stress. Methods: The level of oxidative stress (using urinary F2-isoprostanes as a marker of lipid peroxidation) was compared in infants of smokers (nu200a=u200a33) and non-smokers (nu200a=u200a54) at 3 months of age. These groups were balanced for maternal atopy and socioeconomic status. Infant urinary cotinine levels were also measured as an indicator of early postnatal cigarette smoke exposure. Results: Maternal smoking was associated with significantly higher infant cotinine levels, despite the fact that most smoking mothers (83.8%) claimed not to smoke near their baby. Maternal smoking was associated with significantly higher markers of oxidative stress (F2-isoprostane) at 3 months of age. There was also a positive correlation between urinary F2-isoprostanes and infant urinary cotinine levels. Conclusions: Although this study does not separate the prenatal and postnatal effects of smoking, these findings indicate that environmental tobacco smoke in the early postnatal period adversely affects pro-oxidative/antioxidative status within weeks of life in very early infancy.

Maternal reactivity to fetal alloantigens is related to newborn immune responses and subsequent allergic disease

Background Maternal allergy confers stronger allergy risk (than paternal allergy) suggesting that maternal patterns of immune response can directly influence immune development in offspring. Women prone to allergic immune responses to allergens may also have altered immune responses to other antigens including fetal antigens.

The effects of maternal smoking on early mucosal immunity and sensitization at 12 months of age

With the dramatic rise in asthma and respiratory disease, there is an urgent need to determine the effects of common environmental exposures on early immune development. In this study, we examined the effects of maternal smoking as a major adverse exposure in early life, on mucosal immune function and allergen sensitization in the first year of life. A cohort of 60 smokers and 62 non‐smokers was recruited in pregnancy, and followed prospectively at 3 and 12u2003months of age for saliva collection [for immunoglobulin (Ig) A measurements], urine collection (for cotinine levels) and clinical assessments (for allergy and infection history). Allergen skin‐prick tests were also performed at 12u2003months of age. Specific IgA to common colonizing bacteria was measured on saliva samples, including pneumococcal polysaccharide (PS) serotype 14 and non‐typeable Haemophilus influenza (NTHI) outer membrane protein 6 (OMP6). Eighty‐two mothers and their infants completed the 12‐month follow‐up period – 56 in the maternal non‐smoking group and 26 in the maternal smoking group. Maternal smoking was associated with significantly higher total infant salivary IgA at 12u2003months of age (pu2003=u20030.026), and more chronic upper respiratory tract symptoms (pu2003=u20030.012). However, there were no differences in the level of specific IgA antibodies to common colonizing bacteria (pneumococcal PS serotype 14 and NTHI OMP6). In general, the IgA levels at 12u2003months were higher in children who had more chest infections in the first year (Kendalls tau b, 0.282; pu2003=u20030.003). There was also a trend of lower respiratory tract symptoms (wheeze) (pu2003=u20030.142) in infants of smokers. There were no effects of maternal smoking on the rates of allergen sensitization, atopic dermatitis and food allergy at 12u2003months of age. In conclusion, maternal smoking did not inhibit the production of anti‐microbial IgA, suggesting that other factors are responsible for the increased susceptibility to infection in these infants. The increased mucosal inflammation in these children was not associated with effects on early allergy propensity.

Epigenome-wide analysis of neonatal CD4+ T-cell DNA methylation sites potentially affected by maternal fish oil supplementation

Supplementation of fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFA) during pregnancy has been shown to confer favorable health outcomes in the offspring. In a randomized controlled trial, we have previously shown that n-3 PUFA supplementation in pregnancy was associated with modified immune responses and some markers of immune maturation. However, the molecular mechanisms underlying these heritable effects are unclear. To determine whether the biological effects of maternal n-3 PUFA supplementation are mediated through DNA methylation, we analyzed CD4+ T-cells purified from cryo-banked cord blood samples from a previously conducted clinical trial. Of the 80 mother-infant pairs that completed the initial trial, cord blood samples of 70 neonates were available for genome-wide DNA methylation profiling. Comparison of purified total CD4+ T-cell DNA methylation profiles between the supplement and control groups did not reveal any statistically significant differences in CpG methylation, at the single-CpG or regional level. Effect sizes among top-ranked probes were lower than 5% and did not warrant further validation. Tests for association between methylation levels and key n-3 PUFA parameters, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or total n-3 PUFAs were suggestive of dose-dependent effects, but these did not reach genome-wide significance. Our analysis of the microarray data did not suggest strong modifying effects of in utero n-3 PUFA exposure on CD4+ T-cell methylation profiles, and no probes on the array met our criteria for further validation. Other epigenetic mechanisms may be more relevant mediators of functional effects induced by n-3 PUFA in early life.

Direct infant UV light exposure is associated with eczema and immune development

Background Suboptimal vitamin D levels during critical periods of immune development have emerged as an explanation for higher rates of allergic diseases associated with industrialization and residing at higher latitudes. Objective We sought to determine the effects of early postnatal vitamin D supplementation on infant eczema and immune development. Methods By using a double‐blind randomized controlled trial, newborn infants were randomized to receive vitamin D supplementation (400 IU/d) or a placebo until 6 months of age. Some infants also wore personal UV dosimeters to measure direct UV light (290‐380 nm) exposure. Infant vitamin D levels were measured at 3 and 6 months of age. Eczema, wheeze, and immune function outcomes were assessed at 6 months of age. Results At 3 (P < .01) and 6 (P = .02) months of age, vitamin D levels were greater for the vitamin D–supplemented group than the placebo group, but there was no difference in eczema incidence between groups. Infants with eczema were found to have had less UV light exposure (median, 555 Joules per square meter [J/m2; interquartile range, 322‐1210 J/m2]) compared with those without eczema (median, 998 J/m2 [interquartile range, 676‐1577 J/m2]; P = .02). UV light exposure was also inversely correlated with IL‐2, GM‐CSF, and eotaxin production to Toll‐like receptor ligands. Conclusion This study is the first to demonstrate an association between greater direct UV light exposures in early infancy with lower incidence of eczema and proinflammatory immune markers by 6 months of age. Our findings indicate that UV light exposure appears more beneficial than vitamin D supplementation as an allergy prevention strategy in early life. Graphical abstract Figure. No Caption available.