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The intrauterine immune response and abnormal magnetic resonance images of the brain

Presented at the Neonatal Society 2003 Summer Meeting (programme).

Lall A1,2, Duggan P1,2, Kennea K1, Counsell S4, Allsop J4, Steel J3, Reynolds P1,2, Rutherford M4, Lombardi G2, Sullivan M3, Lechler R2, Edwards D1,4

1 Department of Paediatrics, Imperial College London, UK
Department of Immunology, Imperial College London, UK
Department of Obstetrics and Gynaecology, Imperial College London, UK
4 MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London, UK

Introduction: Chorioamnionitis and systemic fetal inflammation have been linked to increased risk of cerebral damage in preterm infants. No mechanism for this association has been defined, but activation of T cells in utero predicts abnormalities on magnetic resonance (MR) images acquired immediately after delivery, suggesting a role for the acquired immune system (1). Immune activation alters the phenotype of CD4+ T lymphocytes, which become CD45RO+, CD25+ and CD69+, and may display TH1 or TH2 dominance. In a TH1 dominant response effector T cells produce interferon-γ (IFN-γ, inducing predominantly cell mediated immunity and, in some animal models of infection, host tissue injury. TH2 dominant T cells produce interleukin-4 (IL-4) and a largely humoral response. TH1 and TH2 cells are mutually inhibitory, tending to progressive immune polarisation.

Aims: We addressed the question: are abnormalities on cerebral MR imaging in the perinatal period associated with chorioamnionitis and a coherent immune response in utero characterised by systemic inflammation and T cell activation. We speculated that TH1 dominance might increase the risk of cerebral injury.

Methods: 20 infants of median gestational age 28 (range 24-31) weeks were studied. Fetal systemic inflammation was assessed by measuring IL-1b and IL-6 with enzyme immunoassay of plasma separated from umbilical blood taken at delivery. To detect T cell activation CD4+ lymphocytes (106 cells.mlˉ) were isolated from umbilical blood and stained with the following antibodies: anti-CD4, anti-CD45RA, anti-CD45RO, anti-CD25 and anti-CD69. FITC, QR and RPE labelled murine immunoglobulins were used as isotype controls and the proportion of cells expressing the markers of interest was determined using flow cytometry. To determine the TH phenotype in cord blood samples, CD4+T cells were incubated in the presence of monensin (2mm), PMA (50ng/l) and ionomycin (1ug/l), fixed with paraformaldehyde and permeabilised with saponin, then stained with anti-CD4 and anti-IL-4 (TH2) and anti-IFN-γ (TH1), and analysed within 6 hours by three colour flow cytometry. To detect chorioamnionitis fetal membranes were assessed by microscopy. Brain MR images were obtained from all infants soon after delivery and localised abnormalities defined before immunological results were available. Groups were compared using non-parametric significance tests.

Results: Twelve infants had chorioamnionitis, and MR abnormalities were seen in six. The table gives median and range values for infants grouped by MR results. Abnormal images were associated with multiple markers of in utero T cell activation and systemic inflammation. All infants with MR abnormalities displayed chorioamnionitis, inflammation and immune activation although this was also seen in some infants without cerebral lesions. There was no evidence of TH1 or TH2 dominance.

Conclusions: Abnormal MR images are associated with chorioamnionitis, systemic fetal inflammation and activation of the acquired immune system in utero. Involvement of the acquired immune system in cerebral damage appears to be modulated by mechanisms other than TH1 or TH2 polarisation; these might include co-incident hypoxia-ischaemia or endogenous immune regulation to prevent self-harm.

1. Duggan, P, Maalouf, E. et al, (2001). Intrauterine T cell activation and increased pro-inflammatory cytokine concentrations in preterm infants with cerebral lesions. Lancet 358, 1699-1700.

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