The Role of NK‑Cell Dysregulation in Adverse Pregnancy Outcomes Associated with Rheumatic Immune Diseases: Mechanisms and Translational Advances
- 1Department of Rheumatology and Immunology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
Abstract
Rheumatic autoimmune diseases induce sustained systemic inflammatory imbalance and substantially elevate the incidence of adverse pregnancy complications, such as recurrent spontaneous abortion, preeclampsia, preterm delivery, and fetal growth restriction. Decidual natural killer (dNK) cells constitute the major lymphocyte subset at the maternal-fetal interface and maintain the homeostasis of immune tolerance, trophoblast invasion and spiral artery remodeling; peripheral NK (pNK) cells differ greatly from dNK cells in phenotype, cytotoxicity and secretory function under the regulation of local uterine microenvironment. Emerging evidence indicates that dysregulated NK‑cell number, subset distribution, receptor signalling and cytokine release may perturb the decidual immune‑vascular microenvironment and contribute to inflammatory placental‑associated pathology, with considerably more robust mechanistic support in antiphospholipid syndrome than in systemic lupus erythematosus, primary Sjögren’s syndrome, rheumatoid arthritis, and systemic sclerosis. Solid preclinical and clinical evidence confirms that excessive NK cell activation participates in placental injury in antiphospholipid syndrome, whereas the direct inflammatory pathogenic cascades underlying gestational complications remain insufficiently clarified for other rheumatic disorders. This work elucidates the physiological heterogeneity of pNK and dNK cells, delineates six core inflammatory axes driving NK-mediated placental injury, characterizes disease-specific aberrant inflammatory phenotypes of NK cells, summarizes translational advances in NK-targeted anti-inflammatory strategies, and identifies existing research bottlenecks. We also put forward prospective research schemes based on single-cell multi-omics and large-scale clinical cohorts to reveal NK-centered inflammatory pathology, which offers theoretical support for immune inflammation regulation in childbearing-age women with rheumatic autoimmune diseases.
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BibTeX
@article{zhu2026role,
title = {{The Role of NK‑Cell Dysregulation in Adverse Pregnancy Outcomes Associated with Rheumatic Immune Diseases: Mechanisms and Translational Advances}},
author = {Lingxiao Zhu and Li Hua and Hongwei Du},
journal = {International Journal of Women's Health},
year = {2026},
month = oct,
doi = {10.2147/ijwh.s641811},
url = {https://doi.org/10.2147/ijwh.s641811},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - The Role of NK‑Cell Dysregulation in Adverse Pregnancy Outcomes Associated with Rheumatic Immune Diseases: Mechanisms and Translational Advances
AU - Lingxiao Zhu
AU - Li Hua
AU - Hongwei Du
PY - 2026
DA - 2026/10/26
JO - International Journal of Women's Health
DO - 10.2147/ijwh.s641811
UR - https://doi.org/10.2147/ijwh.s641811
AB - Rheumatic autoimmune diseases induce sustained systemic inflammatory imbalance and substantially elevate the incidence of adverse pregnancy complications, such as recurrent spontaneous abortion, preeclampsia, preterm delivery, and fetal growth restriction. Decidual natural killer (dNK) cells constitute the major lymphocyte subset at the maternal-fetal interface and maintain the homeostasis of immune tolerance, trophoblast invasion and spiral artery remodeling; peripheral NK (pNK) cells differ greatly from dNK cells in phenotype, cytotoxicity and secretory function under the regulation of local uterine microenvironment. Emerging evidence indicates that dysregulated NK‑cell number, subset distribution, receptor signalling and cytokine release may perturb the decidual immune‑vascular microenvironment and contribute to inflammatory placental‑associated pathology, with considerably more robust mechanistic support in antiphospholipid syndrome than in systemic lupus erythematosus, primary Sjögren’s syndrome, rheumatoid arthritis, and systemic sclerosis. Solid preclinical and clinical evidence confirms that excessive NK cell activation participates in placental injury in antiphospholipid syndrome, whereas the direct inflammatory pathogenic cascades underlying gestational complications remain insufficiently clarified for other rheumatic disorders. This work elucidates the physiological heterogeneity of pNK and dNK cells, delineates six core inflammatory axes driving NK-mediated placental injury, characterizes disease-specific aberrant inflammatory phenotypes of NK cells, summarizes translational advances in NK-targeted anti-inflammatory strategies, and identifies existing research bottlenecks. We also put forward prospective research schemes based on single-cell multi-omics and large-scale clinical cohorts to reveal NK-centered inflammatory pathology, which offers theoretical support for immune inflammation regulation in childbearing-age women with rheumatic autoimmune diseases.
SN - 1179-1411
ER -