The “killer cell story” in recurrent miscarriage: Association between activated peripheral lymphocytes and uterine natural killer cells

Kuon, Ruben; Vomstein, Kilian; Weber, Maja; Müller, F.; Seitz, Christoph; Wallwiener, Stephanie; Strowitzki, T.; Schleußner, E; Markert, Udo R.; Daniel, Volker; Tóth, Bettina

doi:10.1016/j.jri.2016.11.002

Cited by 61 publications

(41 citation statements)

References 36 publications

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“…We interpret the increased numbers as an indication of an activated immune system in RM patients, showing up-regulation of immunostimulatory as well as immunoregulatory components. The observation of an up-regulated immune system in RM patients is in line with our previous publications, in which we showed that RM patients have increased absolute numbers of activated CD4 1 and CD8 1 T lymphocytes and NK cells expressing CD16 and/or CD56 [24,25]. In the present study, RM patients showed, in addition, increased absolute numbers of NK cell subsets expressing inhibitory CD158a, CD158b, CD158e and/or NKG2A receptors and/or stimulating NKG2D determinants on the cell surface.…”

Section: Discussionsupporting

confidence: 92%

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

Zhu

Aly

Wang

et al. 2018

Clinical and Experimental Immunology

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Patients with recurrent miscarriage (RM) show up-regulated cytotoxic natural killer (NK) cells that are suspected to play a causal role in abortion. In the present study, we investigated counter-regulating inhibitory mechanisms and compared the results in RM patients with those of healthy controls (HC), patients with end-stage renal disease (ESRD) and kidney transplant recipients late post-transplant (TX). NK, NK T and T cell subsets were analysed in the peripheral blood of 31 RM, 14 female ESRD and nine female TX patients as well as 21 female HC using eight-colour fluorescence flow cytometry. Compared with HC, RM patients showed significantly higher absolute numbers of CD56 NK cells co-expressing the phenotype interferon (IFN)-γR , IL-4 , transforming growth factor (TGF)-β , IL-4 human leucocyte antigen D-related (HLA-DR) , TGF-β HLA-DR , IL-4 TGF-β , IL-4 TGF-β , IFN-γ and/or IL-10 IFN-γ (all P ≤ 0·01), more IL-17 CD56 (P = 0·028) NK cells and more CD56 CD16 NK cells co-expressing IFN-γR, IFN-γ, IL-4 and/or TGF-β (all P ≤ 0·01). When the same cell subsets were analysed in ESRD or TX patients, cytokine-producing NK cell subsets were not significantly different from those of HC. RM patients showed significantly higher absolute numbers of CD158a , CD158b , CD158a CD158e (all P < 0·05), NKG2D NKG2A , NKG2D NKG2A , NKG2D and/or NKG2A (all P ≤ 0·01) CD56 NK cells and higher CD158a , CD158b (all P < 0·05), NKG2D and/or NKG2A (all P < 0·01) CD56 CD16 NK cells than HC. In contrast, ESRD patients had normal and TX recipients had lower CD158a and NKG2D NKG2A CD56 NK cells and lower CD158a CD56 CD16 NK cells (all P < 0·05) than HC. RM patients have abnormally high circulating NK cells expressing inhibitory cytokines and inhibitory surface receptors which might contribute to the pathogenesis of RM.

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Section: Discussionsupporting

confidence: 92%

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

Zhu

Aly

Wang

et al. 2018

Clinical and Experimental Immunology

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“…A recent meta‐analysis showed no significant difference of uNK cells between RM patients and controls . In fact, we previously also reported no difference of uNK cells between various subgroups of RM (eg primary vs. secondary RM) . However, compared to healthy controls, this study shows significantly higher levels of uNK cells in a well‐defined cohort of iRM patients.…”

Section: Discussioncontrasting

confidence: 45%

Uterine natural killer cells in patients with idiopathic recurrent miscarriage

Kuon

Weber

Héger

et al. 2017

American J Rep Immunol

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“…Most of the studies support the concept that in uRPL, the pregnancy-promoting functions of uNK are dysregulated in several ways. Indeed, in women with uRPL, higher concentrations of uNK have been detected than in normal fertile controls [92,[126][127][128][129][130][131], even though this finding has not always been consistent [132]. In other studies, despite no differences in the proportion of endometrial NK cells between controls and women with RPL, women with RPL have a significant decrease in the CD16 − CD56 bright NK cell subset, that is normally found in uncomplicated pregnancies [133]; this suggests that uNK cells in women with uRPL are quantitatively and qualitatively different from those normally found.…”

Section: Unksmentioning

confidence: 99%

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Ticconi

Pietropolli

Simone

et al. 2019

IJMS

144

101

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Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal–fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.

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The “killer cell story” in recurrent miscarriage: Association between activated peripheral lymphocytes and uterine natural killer cells

Cited by 61 publications

References 36 publications

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

Uterine natural killer cells in patients with idiopathic recurrent miscarriage

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

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