Cytokine soluble receptors in perinatal and early neonatal life.

BACKGROUND: In contrast to cellular receptors, soluble receptors do not enhance the cellular activation because they do not have transmembranic and cytoplasmic parts, acting thereby as endogenous regulatory mechanisms against systemic functions of cytokines. AIM: To measure serum concentrations of the soluble interleukin-2 receptor (sIL2R), soluble interleukin-4 receptor (sIL4R), soluble interleukin-6 receptor (sIL6R), and soluble tumor necrosis factor-alpha receptor I and soluble tumor necrosis factor-alpha receptor II, during the perinatal and early neonatal period, in order to evaluate their role in activation of immune response in labor and the first days postpartum. METHODS: Soluble receptor serum concentrations were determined by enzyme-linked immunosorbent assay, in 45 healthy, full-termed neonates during the first and fifth days after birth, in 25 of their mothers (MS), in 25 samples of umbilical cords (UC) and in 25 healthy adult donors age-matched with the mothers (controls). RESULTS: Soluble receptor serum concentrations showed considerable changes during labor and early neonatal life, being significantly higher both in MS (except sIL6R) and in neonatal sample UC, first and fifth days after birth, compared with controls (p<0.0001). Neonatal serum sIL2R and sIL6R increased significantly from birth to the fifth day, while the remaining receptors showed a rapid increase in the first day (p<0.0001), declining significantly thereafter (p<0.0001). CONCLUSION: Our findings suggest that the elevated concentrations of all studied soluble cytokine receptors reflect the activation of immune response, and represent also regulatory protective mechanisms for mother and fetus-neonate against the systemic function of cytokines during labor and early neonatal life

Age-related differentiations of Th1/Th2 cytokines in newborn infants.

OBJECTIVE: To evaluate age-related differentiation of immune response in newborns by measuring serum concentrations of interleukin-2 (IL-2), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) during the perinatal period. SUBJECTS AND METHODS: Fifty-seven healthy term neonates, their mothers and 25 healthy adults (controls) age-matched to the mothers were included in the study. Cytokine concentrations were measured in the umbilical cord (UC), and in first-day (1N) and fifth-day (5N) neonatal samples, compared with those in maternal serum (MS) and control serum samples. RESULTS: Serum IL-2 concentrations in the UC were markedly elevated compared with those in MS and controls (p < 0.0001), decreasing significantly thereafter up to 5N (p < 0.001). IL-4 serum concentrations did not differ significantly between the UC, 1N and 5N samples; they were, however, markedly elevated compared with those in MS (p < 0.001, p < 0.0007 and p < 0.0001, respectively) and controls (p < 0.05, p < 0.01 and p < 0.006, respectively). IFN-gamma serum concentrations were significantly lower in the UC compared with those in controls (p < 0.04), increasing significantly up to 5N (p < 0.03). Both IFN-gamma/IL-2 and IFN-gamma/IL-4 ratios increased significantly in 5N, compared with those in the UC (p < 0.001 and p < 0.03). CONCLUSION: Our findings indicate a differential cytokine balance at birth with enhanced expression of IL-2 and IL-4 against IFN-gamma. However, a regularization of immune response seems to proceed quickly during the early neonatal life

Associations of Maternal Educational Level, Proximity to Green Space During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood:A Proof-of-Concept Federated Analysis in 18 Birth Cohorts

International sharing of cohort data for research is important and challenging. We explored the feasibility of multicohort federated analyses by examining associations between 3 pregnancy exposures (maternal education, exposure to green vegetation, and gestational diabetes) and offspring body mass index (BMI) from infancy to age 17 years. We used data from 18 cohorts (n = 206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13, and 14-17 years. Associations were estimated using linear regression via 1-stage individual participant data meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z score comparing low with high education, at age 2-3 years = 0.03 (95% confidence interval (CI): 0.00, 0.05), at 4-7 years = 0.16 (95% CI: 0.14, 0.17), and at 8-13 years = 0.24 (95% CI: 0.22, 0.26)). Gestational diabetes was positively associated with BMI from age 8 years (BMI z score difference = 0.18, 95% CI: 0.12, 0.25) but not at younger ages; however, associations attenuated towards the null when restricted to cohorts that measured gestational diabetes via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age 1 year but not at older ages. Opportunities of cross-cohort federated analyses are discussed.</p

Associations of maternal education, area deprivation, proximity to greenspace during pregnancy and gestational diabetes with Body Mass Index from early childhood to early adulthood: A proof-of-concept federated analysis in seventeen birth cohorts

Background: International sharing of cohort data for research is important and challenging. The LifeCycle project aimed to harmonise data across birth cohorts and develop methods for efficient federated analyses of early life stressors on offspring outcomes. Aim: To explore feasibility of federated analyses of associations between four different types of pregnancy exposures (maternal education, area deprivation, proximity to green space and gestational diabetes) with offspring BMI from infancy to 17 years. Methods: We used harmonised exposure and outcome data from 17 cohorts (n=200,650 mother-child pairs) from the EU Child Cohort Network. For each child, we derived BMI at five age periods: (i) 0-1 years, (ii) 2-3, (iii) 4-7, (iv) 8-13 and (v) 14-17 years. Associations were estimated using linear regression via one-stage individual participant data meta-analysis using the federated analysis platform DataSHIELD. Results: Associations between lower maternal education and higher child BMI emerged from age 4 years and increased with age (difference in BMI z-score comparing low with high education age 0-1 years = 0.02 [95% CI 0.00, 0.03], 2-3 years = 0.01 [CI -0.02, 0.04], 4-7 years = 0.14 [CI 0.13, 0.16], 8-13 years = 0.22 [CI 0.20, 0.24], 14-17 years = 0.20 [CI 0.16, 0.23]). A similar pattern was found for area deprivation. Gestational diabetes was positively associated with BMI from 8 years (8-13 years = 0.17 [CI 0.10, 0.24], 14-17 years = 0.012 [CI -0.13, 0.38]) but not at younger ages. The normalised difference vegetation index measure of maternal proximity to green space was weakly associated with higher BMI in the first year of life but not at older ages. Conclusions: Associations between maternal education, area-based socioeconomic position and GDM with BMI increased with age. Maternal proximity to green space was not associated with offspring BMI, other than a weak association in infancy. Opportunities and challenges of cross-cohort federated analyses are discussed

Associations of maternal educational level, proximity to greenspace during pregnancy, and gestational diabetes with body mass index from infancy to early adulthood: a proof-of-concept federated analysis in 18 birth cohorts

International sharing of cohort data for research is important and challenging. We explored the feasibility of multi-cohort federated analyses by examining associations between three pregnancy exposures (maternal education, exposure to green vegetation and gestational diabetes) with offspring BMI from infancy to 17 years. We used data from 18 cohorts (n=206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13 and 14-17 years. Associations were estimated using linear regression via one-stage IPD meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z-score comparing low with high education age 2-3 years = 0.03 [95% CI 0.00, 0.05], 4-7 years = 0.16 [95% CI 0.14, 0.17], 8-13 years = 0.24 [95% CI 0.22, 0.26]). Gestational diabetes was positively associated with BMI from 8 years (BMI z-score difference = 0.18 [CI 0.12, 0.25]) but not at younger ages; however associations attenuated towards the null when restricted to cohorts which measured GDM via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age one but not at older ages. Opportunities of cross-cohort federated analyses are discussed.</p

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations. (J Allergy Clin Immunol 2021;148:1332-41.