Leukocyte activation in newborns in relation to prenatal stress

The aim of this project is to describe the pattern of innate immunity responses at birth with focus on the recruitment of leukocytes such as eosinophils and neutrophils and their content of cathelicidin antimicrobial peptide LL-37 associated to different degrees of fetal stress and delivery modes.

We know that delivery is associated to fetal stress including release of cortisol and cathecolamines. Stress has profound effects on the immune system, also by acting on the trafficking of leukocytes, a process in which adhesion and chemotaxis are primordial and critical events for the development of effective antimicrobial defences.

Birth and postnatal adaptation are associated with leukocyte recruitment and activation, an acute phase response and inflammatory skin reactions in the human newborn, all together indicating an enhanced innate immunity at that time-point in life.

We found that with a progressive increase in fetal stress, there are significant elevations in total white blood count, in particular neutrophils and monocytes, as well as an enhanced IL-8 and soluble ESelectin level. Assisted delivery, associated with the highest degree of fetal stress in addition has an increased Interferon-gamma level. The direct correlation between specific leukocytes and Interferon-gamma respectively, with stress markers such as cortisol, beta-endorphin and cathecolamines reflects the impact of stress on fetal immunity.

Also, after normal delivery cord plasma LL-37 levels were 3 times higher compared to C-section indicating fetal peptide release. Neutrophils from cord blood after normal delivery contain 10 times more cytoplasmatic cathelicidin peptide compared to corresponding cells after C-section where a strict granular localization is found, a possible sign of cell activation. A highly significant correlation was observed between maternal and cord plasma LL-37 levels, most probably reflects maternal cathelicidin placental transfer.

We also could show that cord eosinophils contain and to some degree release LL-37. Interesting, cord eosinophils contain 3 times more LL-37 compared to adults. Thus, it seems reasonable to deduce that these cells may exert important regulatory functions during the neonatal period, also including antimicrobial activity and immunomodulatory effects by peptide LL-37.

Our data analysis shows gene expression differences in eosinophils between the two delivery modes. We have identified the genes with most significant expression difference in C-section eosinophils compared to normal delivery eosinophils, here, being IFN-gamma receptor and STAT1. Our RT-PCR data confirms the upregulation of these genes in eosinophils from cord blood compared to normal delivery. This indicates a more enhanced immunity in eosinophils after normal delivery.

This study assembles a picture of newborn infant s ability to mount a powerful inflammatory immune response at birth and that the stress of normal labor and terrestrial adaptation induces profound structural and functional changes in fetal leukocytes.

List of scientific papers

I. Yektaei-Karin E, Moshfegh A, Lundahl J, Berggren V, Hansson LO, Marchini G (2007). The stress of birth enhances in vitro spontaneous and IL-8-induced neutrophil chemotaxis in the human newborn. Pediatr Allergy Immunol. 18(8): 643-51.
https://doi.org/10.1111/j.1399-3038.2007.00578.x

II. Mandic Havelka A, Yektaei-Karin E, Hultenby K, Sørensen OE, Lundahl J, Berggren V, Marchini (2009). Maternal plasma level of antimicrobial peptide LL37 is a major determinant factor of neonatal plasma LL37 level. Acts Paediatrica. [Accepted]
https://doi.org/10.1111/j.1651-2227.2010.01726.x

III. Yektaei-Karin E, Moshfegh A, Hultenby K, Andersson E, Selvanesan Blesson C, Mandic Havelka A, Lundahl J, Marchini G (2009). The cathelicidin antimicrobial peptide LL-37 is present in eosinophils isolated from human umbilical cord blood. [Submitted]

IV. Yektaei-Karin E, Lundahl J, Marchini G, Moshfegh A (2009). Gene expression pattern of cord blood eosinophils in normal delivery compared to cesarean section. [Manuscript]