Transcriptomic analysis of vitamin D responses in uterine and peripheral NK cells.

Vitamin D deficiency is prevalent in pregnant women and is associated with adverse pregnancy outcomes, in particular disorders of malplacentation. The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a potent regulator of innate and adaptive immunity, but its immune effects during pregnancy remain poorly understood. During early gestation, the predominant immune cells in maternal decidua are uterine natural killer cells (uNK), but the responsivity of these cells to 1,25(OH)2D3 is unknown despite high levels of 1,25(OH)2D3 in decidua. Transcriptomic responses to 1,25(OH)2D3 were characterised in paired donor uNK and peripheral natural killer cells (pNK) following cytokine (CK) stimulation. RNA-seq analyses indicated 911 genes were differentially expressed in CK-stimulated uNK versus CK-stimulated pNK in the absence of 1,25(OH)2D3, with predominant differentially expressed pathways being associated with glycolysis and transforming growth factor ß (TGFß). RNA-seq also showed that the vitamin D receptor (VDR) and its heterodimer partner retinoid X receptor were differentially expressed in CK-stimulated uNK vs CK-stimulated pNK. Further analyses confirmed increased expression of VDR mRNA and protein, as well as VDR-RXR target in CK-stimulated uNK. RNA-seq analysis showed that in CK-stimulated pNK, 1,25(OH)2D3 induced 38 and suppressed 33 transcripts, whilst in CK-stimulated uNK 1,25(OH)2D3 induced 46 and suppressed 19 genes. However, multiple comparison analysis of transcriptomic data indicated that 1,25(OH)2D3 had no significant overall effect on gene expression in either CK-stimulated pNK or uNK. These data indicate that CK-stimulated uNK are transcriptionally distinct from pNK and, despite expressing abundant VDR, neither pNK nor uNK are sensitive targets for vitamin D.

The immunological basis of villitis of unknown etiology - review.

Villitis of unknown etiology (VUE) represents a common placental inflammatory lesion, primarily, but not exclusively, identifiable T lymphocytes at term. Despite considerable evidence to contest that this simply represents a benign pathological finding, VUE remains a significantly undervalued diagnosis. Given its association with adverse pregnancy outcomes; including fetal growth restriction, preterm birth, and recurrent pregnancy loss, an increased awareness amongst clinician obstetricians is certainly warranted. The underlying immunopathogenesis of VUE remains uncertain. Despite initial theories that this represents an infectious placental lesion of undiagnosed pathogenic source, a more complex sequence of events involving the "breakdown" of maternal-fetal tolerance is emerging. Characterization of a unique inflammatory phenomenon in which both maternal and fetal T lymphocytes and Höfbauer cells interact has captivated particular research interest and has generated analogies to both the problems of allograft rejection and graft-versus-host disease (GvHD). Within the context of VUE, this review evaluates how disruption of the multidimensional immunological mechanisms underlying feto-maternal tolerance may permit abnormal lymphocyte infiltration into placental villi. We shall review the existing evidence for these events in VUE and outline areas of certain future interest.