1,25‐Dihydroxy‐vitamin D3 regulates NK‐cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses

Abstract

Vitamin D has a pivotal role in regulating immune responses by promoting Th2 immune responses and suppressing Th1 responses. Propensities to a Th1 immune response and increased NK-cell levels and cytotoxicity have been reported in women with recurrent pregnancy losses (RPL). In women with RPL, vitamin D deficiency is prevalent IntroductionVitamin D is a group of secosteroids and has a major role in maintaining skeletal health. Various effects of vitamin D on extra skeletal tissues have been reported as well, during the past decade [1]. Vitamin D deficiency is endemic for both men and women and across different age groups in the US population [2]. Low C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 3188-3199 Clinical immunology 3189vitamin D level has been linked to major common health problems in populations, particularly inflammatory conditions such as cardiovascular disease, cancers, diabetes, autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and others [3]. In addition, vitamin D deficiency is a predisposing factor for various female diseases such as osteoporosis, uterine fibroids, endometriosis, and breast cancer and a risk factor for obstetrical complications such as gestational diabetes and preeclampsia [4,5]. Recently, we have reported that 47.4% of women with recurrent pregnancy losses (RPL) have vitamin D deficiency [6]. In women with RPL, decreased vitamin D level was associated with the increased prevalence of antiphospholipid antibody, antinuclear antigen antibody, anti-ssDNA, and anti-thyroperoxidase antibody. In addition, peripheral blood CD19 + B and CD56 + NK-cell levels and NK cytotoxicity were significantly higher in women with low vitamin D level when compared with those of normal vitamin D level [6]. Normal pregnancy is associated with Th2 shift in T-cell immunity [7]. The comparable shift in NK-cell immunity has been reported during normal pregnancy including a bias to NKr1 that produce IL-10 in peripheral blood, and NK3 cells that produce TGF-β in decidual NK cells [8]. Additionally, decidual innate lymphoid cell 3 (ILC3) may play a role in innate defenses, and vessel and tissue rebuilding, thus contributing to maintenance of pregnancy [9]. Contrarily, a propensity to Th1 immune response and increased NK-cell levels and cytotoxicity have been reported in women with RPL and multiple implantation failures (MIF) after in vitro fertilization and embryo transfer cycles [10]. Women with miscarriages and preeclampsia as well, have NK1 and NKT1 shift that produce high amounts of IFN-γ and little IL-4 in peripheral blood [11]. Therefore, cellular immune-regulation including innate immunity is critical for human reproduction.Women with RPL and MIF have significantly higher NK-cell levels and cytotoxicity, and dysregulated cytokine production patterns as compared to normal controls [10,12]. Activating receptor expression on NK cells was significantly increased, while inhibitory receptor expression was significantly decreased in ...

The Role of Vitamin D in the Immune System as a Pro-survival Molecule

“…130 Vitamin D actually plays a modulatory role in dysregulated NK cells. 131 This scenario suggests that vitamin D plays a fundamental role in controlling DC participation in the crossroad innate/acquired immunity.…”

Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential

“…Also the data on the effect of 1,25(OH) 2 D 3 on NK cells are somewhat contradictory. In an NK cell line, 1,25(OH) 2 D 3 induces the cytolytic killing capacity of NK cells (83), but this effect has not been found in healthy control peripheral blood (84, 85). However, when 1,25(OH) 2 D 3 is added during the in vitro differentiation of NK cells from hematopoietic stem cells, the development of NK cells is impaired and their cytotoxicity and IFNγ production are reduced (84).…”

“…However, when 1,25(OH) 2 D 3 is added during the in vitro differentiation of NK cells from hematopoietic stem cells, the development of NK cells is impaired and their cytotoxicity and IFNγ production are reduced (84). Interestingly, 1,25(OH) 2 D 3 specifically inhibits activation, cytotoxic capacity and pro-inflammatory cytokine production in overactivated NK cells in women with recurrent pregnancy losses (85). This supports a hypothesis in which 1,25(OH) 2 D 3 is not a general inhibitor of the immune response, but rather a regulator of immune homeostasis.…”

Vitamin D, the placenta and early pregnancy: effects on trophoblast function

“…This was supported by ex vivo analyses showing that 1,25(OH) 2 D is able to suppress inflammatory cytokine production by endometrial cells from women with unexplained recurrent spontaneous abortions (Tavakoli et al 2011). More recently, 1,25(OH) 2 D has been shown to potently regulate natural killer cells from women with recurrent miscarriage (Ota et al 2015). Considering these observations, the impact of maternal vitamin D status on pregnancy outcome has been studied in several cohorts.…”