Immunomodulatory role of vitamin D in the pathogenesis of preeclampsia

Abstract

Worldwide, preeclampsia is a significant health risk to both pregnant women and their unborn children. Despite scientific advances, the exact pathogenesis of preeclampsia is not yet fully understood. Meanwhile, the incidence of preeclampsia is expected to increase. A series of potential etiologies for preeclampsia has been identified, including endothelial dysfunction, immunological dysregulation and trophoblastic invasion. In this literature review, we have critically reviewed existing literature regarding the research findings that link the role of vitamin D to the pathogenesis and immunoregulation of preeclampsia. The relationship of vitamin D with the suspected etiologies of preeclampsia underscores its clinical potential in the diagnosis and treatment of preeclampsia.

Keywords: cathelicidin; endothelial dysfunction; immunomodulation; preeclampsia; vitamin D.

Figure 1

A summary of preeclampsia epidemiology. Worldwide up to 8% of all pregnancies are complicated by preeclampsia. In the United States 3.5% of pregnancies are complicated by preeclampsia. In 2014 the World Health Organization (WHO) published a paper entitled: Global causes of maternal death: a WHO systematic analysis, and some of their findings are summarized here. This figure summarizes the most common causes of maternal death. Preeclampsia is included in the “hypertension” category.

Figure 2

A proposed algorithm for diagnosing preeclampsia based on the 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension Pregnancy.

Figure 3

Soluble Fms-like Tyrosine Kinase 1 (sFlt-1)-mediated Vascular Endothelial Dysfunction: Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread endothelial cell dysfunction. Preeclamptic mothers have an increased level of circulating anti-angiogenic cytokines such as sFlt-1. sFlt-1 acts by competitively binding to placental growth factor and vascular endothelial growth factor, inhibiting their ability to promote vascular invasion and endothelial proliferation. This dysfunction results in hypertension and proteinuria, both of which are hallmarks of preeclampsia.

Figure 4

Cellular effects of the active form of vitamin D (1,25(OH)₂D₃) acts as an immune modulator. The 1,25(OH)₂D₃ modulates immune cells including: dendritic cells, CD4+ T-cells, CD8+ T-cells, T-regulatory cells (T-Regs), TH-17 cells, monocytes and macrophages. In dendritic cells 1,25(OH)₂D₃ inhibits differentiation, maturation, and immunostimulatory effects. The 1,25(OH)₂D₃ also decreases dendritic cell expression of MHC class II, CD40, CD80, CD86. The activation of vitamin D receptors (VDR) also causes dendritic cells to decrease synthesis of IL-12 and increases IL-10 production, which acts to stimulate TH2 expression and inhibit TH1 expression. In both CD4+ and CD8+ T-lymphocytes, 1,25(OH)₂D₃ binding to the VDR causes a five-fold increase in VDR expression. In vitro, 1,25(OH)₂D₃ inhibits the expression of IL-2, IFN-γ, and TNF-α. A decrease in the expression of these cytokines decreases TH1 cell proliferation and skews immunity to a Th2 mediated response. The 1,25(OH)₂D₃ also increases IL-4 production by TH2 cell, further inducing TH2 cell proliferation. In addition, 1,25(OH)₂D₃ has a stimulatory effect on FOXP3⁺ T-regulatory cells (T-Regs), causing differentiation and expansion. The 1,25(OH)2D3 has also been shown to inhibit Th17-cells by inhibiting IL-6 and IL-23 cytokine production. The 1,25(OH)₂D₃ decreases the activity of both antigen presenting cells (APC) and T-cells, leading to decreased B-cell proliferation, plasma-cell differentiation, and immunoglobulin secretion. Although most of the effects of 1,25(OH)₂D₃ on the immune system are inhibitory, it stimulates the activity of the innate immune system. The 1,25(OH)₂D₃ has been shown to stimulate monocyte proliferation in vitro, and it caused an increase in the production of IL-1 and cathelicidin (a bactericidal peptide) by monocytes and macrophages.