Innate Immune Activation and Circulating Inflammatory Markers in Preschool Children

Early childhood is characterised by repeated infectious exposures that result in inflammatory responses by the innate immune system. In addition, this inflammatory response to infection is thought to contribute to the epidemiological evidence linking childhood infection and adult non-communicable diseases. Consequently, the relationship between innate immune responses and inflammation during early life may inform prevention of NCDs later in life. In adults, non-genetic host factors such as age, sex, and obesity, strongly impact cytokine production and circulating mediators, but data in children are lacking. Here, we assessed cytokine responses and inflammatory markers in a population of healthy preschool children (mean age 4.2 years). We studied associations between cytokines, plasma inflammatory markers and non-genetic host factors, such as sex, age, adiposity, season, and immune cell composition. Similar to adults, boys had a higher inflammatory response than girls, with IL-12p70 and IL-10 upregulated following TLR stimulation. Adiposity and winter season were associated with increased circulating inflammatory markers but not cytokine production. The inflammatory markers GlycA and hsCRP were positively associated with production of a number of cytokines and may therefore reflect innate immune function and inflammatory potential. This dataset will be informative for future prospective studies relating immune parameters to preclinical childhood NCD phenotypes.

[1]  K. Carter,et al.  Mode of birth and risk of infection-related hospitalisation in childhood: A population cohort study of 7.17 million births from 4 high-income countries , 2020, PLoS medicine.

[2]  Daniel C. Casey,et al.  Burden of non-communicable diseases from infectious causes in 2017: a modelling study , 2020, The Lancet. Global health.

[3]  J. Aerssens,et al.  Biomarkers for Disease Severity in Children Infected With Respiratory Syncytial Virus: A Systematic Literature Review. , 2020, The Journal of infectious diseases.

[4]  J. Carlin,et al.  Body Mass Index From Early to Late Childhood and Cardiometabolic Measurements at 11 to 12 Years , 2020, Pediatrics.

[5]  X. Correig,et al.  Human Serum/Plasma Glycoprotein Analysis by 1H-NMR, an Emerging Method of Inflammatory Assessment , 2020, Journal of clinical medicine.

[6]  Alejandro Lucia,et al.  Chronic inflammation in the etiology of disease across the life span , 2019, Nature Medicine.

[7]  Karel G. M. Beenakker,et al.  Men Have a Stronger Monocyte-Derived Cytokine Production Response upon Stimulation with the Gram-Negative Stimulus Lipopolysaccharide than Women: A Pooled Analysis Including 15 Study Populations , 2019, Journal of Innate Immunity.

[8]  A. Ponsonby,et al.  Glycoprotein acetyls (GlycA) at 12 months are associated with high-sensitivity C-reactive protein and early life inflammatory immune measures , 2019, Pediatric Research.

[9]  T. Lehtimäki,et al.  Biomarker Glycoprotein Acetyls Is Associated With the Risk of a Wide Spectrum of Incident Diseases and Stratifies Mortality Risk in Angiography Patients , 2018, Circulation. Genomic and precision medicine.

[10]  F. Buntinx,et al.  Point-of-care CRP matters: normal CRP levels reduce immediate antibiotic prescribing for acutely ill children in primary care: a cluster randomized controlled trial , 2018, Scandinavian journal of primary health care.

[11]  W. Kraus,et al.  Association of the Composite Inflammatory Biomarker GlycA, with Exercise-Induced Changes in Body Habitus in Men and Women with Prediabetes , 2017, Oxidative medicine and cellular longevity.

[12]  F. Corazza,et al.  Sex Differences in Inflammatory Response and Acid–Base Balance in Prepubertal Children with Severe Sepsis , 2017, Shock.

[13]  Richard A. Notebaart,et al.  Host and Environmental Factors Influencing Individual Human Cytokine Responses , 2016, Cell.

[14]  R. Perera,et al.  Should all acutely ill children in primary care be tested with point-of-care CRP: a cluster randomised trial , 2016, BMC Medicine.

[15]  A. McMichael,et al.  Evolution of the immune system in humans from infancy to old age , 2015, Proceedings of the Royal Society B: Biological Sciences.

[16]  M. Wake,et al.  Do Childhood Infections Contribute to Adult Cardiometabolic Diseases? , 2015, The Pediatric infectious disease journal.

[17]  K. Ridge,et al.  Influenza A Virus Infection, Innate Immunity, and Childhood. , 2015, JAMA pediatrics.

[18]  T. Lehtimäki,et al.  Infection-Related Hospitalization in Childhood and Adult Metabolic Outcomes , 2015, Pediatrics.

[19]  F. Stanley,et al.  Childhood Hospitalisation with Infection and Cardiovascular Disease in Early-Mid Adulthood: A Longitudinal Population-Based Study , 2015, PloS one.

[20]  J. Carlin,et al.  The ontogeny of naïve and regulatory CD4+ T-cell subsets during the first postnatal year: a cohort study , 2015, Clinical & translational immunology.

[21]  Thomas J. Bollyky,et al.  The Emerging Global Health Crisis: Noncommunicable Diseases in Low- and Middle-Income Countries , 2014 .

[22]  Stephanie M. Tortorella,et al.  The early life origin theory in the development of cardiovascular disease and type 2 diabetes , 2014, Molecular Biology Reports.

[23]  E. Mylonakis,et al.  The Role of TLR4 896 A>G and 1196 C>T in Susceptibility to Infections: A Review and Meta-Analysis of Genetic Association Studies , 2013, PloS one.

[24]  N. Lefèvre,et al.  Sex Differences in Inflammatory Cytokines and CD99 Expression Following In Vitro Lipopolysaccharide Stimulation , 2012, Shock.

[25]  M. Gaestel,et al.  Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines. , 2011, Biochimica et biophysica acta.

[26]  P. Doevendans,et al.  Toll-like receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis. , 2011, Clinical science.

[27]  Samit R. Joshi,et al.  Dysregulation of human Toll-like receptor function in aging , 2011, Ageing Research Reviews.

[28]  N. Lefèvre,et al.  Gender differences and inflammation: an in vitro model of blood cells stimulation in prepubescent children , 2010, Journal of Inflammation.

[29]  C. Hermann,et al.  Gender difference in cytokine secretion on immune stimulation with LPS and LTA. , 2006, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[30]  H. Tilg,et al.  Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. , 2004, Biochemical and biophysical research communications.

[31]  I. Porto,et al.  Monocyte proinflammatory cytokine release is higher and glucocorticoid sensitivity is lower in middle aged men than in women independent of cardiovascular risk factors , 2004, Heart.

[32]  S. Ima-Nirwana,et al.  Toll-like Receptor as a Molecular Link between Metabolic Syndrome and Inflammation: a Review. , 2019, Current drug targets.

[33]  J. Carlin,et al.  Cohort Profile Cohort Profile : The Barwon Infant Study , 2015 .

[34]  J. Camps,et al.  Introduction: oxidation and inflammation, a molecular link between non-communicable diseases. , 2014, Advances in experimental medicine and biology.

[35]  P. Glendenning,et al.  Endotoxin induced TNF and IL-10 mRNA production is higher in male than female donors: correlation with elevated expression of TLR4. , 2008, Cellular immunology.