Natural Killer Cells in Obstetric Antiphospholipid Syndrome

Natural Killer Cells in Obstetric Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombotic events or obstetric complications resulting from the persistent presence of antiphospholipid antibodies (aPLs). These antibodies include lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein I (anti-β2GPI) antibodies. The primary target antigen in APS is β2GPI, which binds to cell membranes and activates membrane receptors and downstream signaling pathways. This activation can lead to the stimulation of natural killer (NK) cells, contributing to obstetric complications such as recurrent pregnancy loss (RPL) and preeclampsia.

NK cells play a critical role in maintaining immune tolerance during pregnancy, allowing the embryo to evade the maternal immune system. Uterine NK (uNK) cells, in particular, are involved in trophoblast invasion and spiral artery remodeling, secreting cytokines that regulate immune balance at the maternal-fetal interface. Disruptions in the number and function of NK cells, as well as imbalances between NK cells and other immune cells, can lead to pathological pregnancies. This review explores the relationship between NK cells and obstetric APS, focusing on the mechanisms underlying NK cell dysfunction and their role in adverse pregnancy outcomes.

Origin and Function of Uterine NK Cells

uNK cells originate through three potential pathways. The first pathway involves the transformation of peripheral blood NK (pNK) cells into an uNK-like phenotype under the influence of local decidual microenvironments, such as galactolectin 9 and T cell immunoglobulin and mucin domain 3 signaling. The second pathway involves the migration of CD16+ pNK cells into uterine tissue, where factors like transforming growth factor-beta (TGF-β) alter their phenotype. The third pathway involves the differentiation of CD34+ CD122+ CD127+ hematopoietic progenitors into uNK cells when co-cultured with decidual stromal cells in the presence of interleukin-15 (IL-15).

NK cells are equipped with two types of receptors: activating killer receptors (AKRs) and inhibiting killer receptors (IKRs). Structurally, these receptors are classified into killer cell immunoglobulin-like receptors (KIRs), killer cell lectin-like receptors (KLRs), and natural cytotoxic receptors (NCRs). KIRs such as KIR2DL1, KIR2DL2, and KIR2DL3 are IKRs that bind to HLA-C to regulate the cytotoxicity of decidual NK cells. KIR2DS1, an AKR, also interacts with HLA-C and activates downstream signaling through the adaptor protein DAP12. The immune receptor tyrosine-based activator (ITAM) in DAP12 triggers NK cell activation and the production of pro-inflammatory cytokines.

NKG2, a member of the KLR family, includes NKG2D, an AKR that activates NK cells, and NKG2A, an IKR that inhibits excessive NK cell activation. NCRs, such as NKp46, NKp44, and NKp30, are AKR-type receptors that mediate the toxic effects of uNK cells. During pregnancy, the balance between AKRs and IKRs in uNK cells is crucial for optimal cytokine and growth factor production, such as vascular endothelial-derived growth factor (VEGF), which enhances maternal immune tolerance to embryonic cells. An imbalance in uNK cell regulation can lead to the production of harmful cytokines, resulting in pregnancy complications like abortion.

Role of uNK Cells in Pregnancy

uNK cells play a pivotal role in trophoblast invasion and spiral artery remodeling during early pregnancy. TGF-β and interleukin-10 (IL-10) secreted by uNK cells promote trophoblast invasion, protect the fetus from maternal immune attack, and enhance angiogenesis. The absence of invasive extravascular trophoblasts in early spiral arteries suggests that uNK cells are essential for the reconstruction of these arteries. uNK cells transform spiral arteries into highly dilated vessels, ensuring low-pressure blood flow to the placenta and developing fetus. Additionally, CD49a+ Eomes+ uNK cells produce growth factors that support embryonic development before the placenta is fully established.

NK Cells in Pathological Pregnancy

The normal development of a fetus depends on the appropriate number and percentage of pNK and uNK cells during pregnancy. Studies on pNK cells in RPL patients have yielded conflicting results. While some studies found no significant difference in pNK cell numbers, others reported higher absolute numbers and percentages of pNK cells in RPL patients compared to healthy controls. These discrepancies may arise from differences in experimental methods and the timing of pregnancy assessments. Increased numbers and percentages of uNK cells have been linked to preeclampsia and fetal growth restriction, suggesting that maintaining NK cell levels within a specific range is essential for normal embryonic development.

In APS patients, the imbalance between NK cells and other immune cells, along with the cytokines they secrete, can lead to maternal rejection of the fetus. Anti-β2GPI antibodies inhibit trophoblast autophagy, induce excessive inflammasome activation, and increase the secretion of pro-inflammatory cytokines like IL-1β, triggering an inflammatory response at the maternal-fetal interface. This mechanism may underlie APS-induced RPL. Additionally, β2GPI polarizes helper T (Th) cells into Th17 cells and activates uNK cells to produce interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which mediate cytotoxic activity against target cells. This activity can damage placental endothelial cells and lead to the formation of placental microthrombi. Excessive TNF-α also induces the proliferation of uNK cells and promotes their differentiation into cytotoxic lymphofactor-cytotoxic killer cells, contributing to APS-related RPL.

NK Cells and Anti-Trophoblast Activity

Under specific conditions, NK cells can adopt anti-trophoblast characteristics. For example, uNK cells abnormally activated by inflammation caused by bacterial endotoxins in mice target embryonic tissue and induce fetal absorption. The remodeling of uterine arteries and placental damage induced by uNK cells can be reversed by inhibiting uNK cells using NK cell antibodies, such as those targeting NKp46. Low-dose rapamycin has been shown to increase the number of uNK cells and decrease the expression levels of NKG2D, NKp30, and NKp46 through autophagy in mouse models of abortion, promoting embryo absorption. These findings suggest that abnormal NK cell numbers and functions are closely related to pathological pregnancy.

Therapeutic Interventions

Abnormal NK cell numbers and functions in APS patients can lead to miscarriage, but appropriate interventions may improve pregnancy outcomes. Studies have shown that uNK cells are elevated in women with pathological pregnancies. Prednisone has been shown to reduce uNK cell numbers but does not improve pregnancy outcomes. Intravenous immunoglobulin (IVIG) therapy has been found to increase the live birth rate in patients with recurrent abortions. IVIG treatment reduces the percentage and cytotoxicity of NK cells in RPL patients and increases the expression levels of inhibitory receptors like KIR2DL1, KIR2DL2, and KIR2DL3 while decreasing the expression levels of NKG2A and KIR2DS1. These changes promote a favorable immune environment for pregnancy.

Conclusion

Successful pregnancy requires a complex interplay of factors, with NK cells and cytokines playing a central role in maintaining immune balance at the maternal-fetal interface. Changes in the number and function of uNK cells, as well as their proportional imbalance with other immune cells, are key contributors to APS-related RPL. While the specific signaling pathways and cytokines involved in NK cell immune regulation remain unclear, further research is needed to develop effective immune or targeted therapies for APS patients.

doi.org/10.1097/CM9.0000000000001908

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