Effects of nongenetic factors on immune cell dynamics in early childhood: The Generation R Study

Publication date: Available online 29 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Diana van den Heuvel, Michelle A.E. Jansen, Kazem Nasserinejad, Willem A. Dik, Ellen G. van Lochem, Liesbeth E. Bakker-Jonges, Halima Bouallouch-Charif, Vincent W.V. Jaddoe, Herbert Hooijkaas, Jacques J.M. van Dongen, Henriëtte A. Moll, Menno C. van Zelm
Background. Numbers of blood leukocyte subsets are highly dynamic in childhood and differ greatly between individuals. Inter-individual variation is only partly accounted for by genetic factors.ObjectiveDetermine which nongenetic factors affect the dynamics of innate leukocytes, and naive and memory lymphocyte subsets.Methods. We performed six-color flow cytometry and linear mixed effect modeling to define the dynamics of 62 leukocyte subsets from birth to 6 years of age in 1,182 children with one to five measurements per individual. Subsequently, we defined the impact of prenatal maternal lifestyle-related or immune-mediated determinants, birth characteristics and bacterial/viral exposure-related determinants on leukocyte subset dynamics.Results. Functionally similar leukocyte populations were grouped by unbiased hierarchical clustering of patterns of age-related leukocyte dynamics. Innate leukocyte numbers were high at birth and were predominantly affected by maternal low education level. Naive lymphocytes peaked around 1 year, while most memory lymphocyte subsets more gradually increased during the first 4 years of life. Dynamics of CD4⁺ T cells were predominantly associated with gender, birth characteristics, and persistent infections with cytomegalovirus (CMV) or Epstein Barr virus (EBV). CD8⁺ T cells were predominantly associated with CMV and EBV infections, and TCRγδ⁺ T cells with premature rupture of membranes and CMV infection. B-cell subsets were predominantly associated with gender, breastfeeding and Helicobacter pylori carriership.Conclusions. Our study identifies specific dynamic patterns of leukocyte subset numbers, as well as nongenetic determinants that affect these patterns, thereby providing new insights into the shaping of the childhood immune system.

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Capsule Summary: Human inter-individual immunological diversity can only partly be explained by genetic factors, indicating an important contribution of nongenetic factors. We here analyzed leukocyte dynamics in 1,182 children of the Generation R Study and determined the effect of 26 nongenetic factors on inter-individual immunological diversity.


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