REVIEW article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1617140
This article is part of the Research TopicComplementRarity – Complement System in Rare Systemic and Renal Diseases: A New Vision of an Old System.View all articles
The complement system in human pregnancy and preeclampsia
Provisionally accepted
- Morehouse School of Medicine, Atlanta, United States
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Human pregnancy is a complex condition that poses significant challenges for women due to the necessity of a uterus for key processes such as fertilization, embryo implantation, fetal development, and childbirth. These processes are governed by immunological factors and accompanied by various physiological changes. For a successful pregnancy, maternal immune reprogramming is crucial because the developing embryo is considered a semi-allograft. Any immunological alteration during pregnancy induces recurrent pregnancy loss and other fetalmaternal health issues, including preeclampsia. However, despite advances in reproductive immunology, the exact immunopathogenesis of preeclampsia remains unclear. The complement system (CS) comprises an evolutionary ancient and critical innate immune component that plays a significant role in maintaining immune homeostasis. The current article discusses the critical role of CS in human pregnancy and how its dysregulation predisposes pregnant women to preeclampsia. The article introduces the concept of the Th1 to Th2 immunological shift as a prerequisite for a successful pregnancy and the evolution of decidualization via transposable elements, which recruit genes responsible for the process in the endometrium. The immune system plays a critical role in decidualization. The second section discusses the CS signaling pathway, its negative regulators, and the roles of the C3a/C3aR and C5a/C5aR1/C5aR2 or C5L2 axis in immune homeostasis. The third section elaborates on the role of CS in the establishment of human pregnancy, such as fertilization, implantation, and fetal development. The fourth section describes maternal CS signaling alteration during successful human pregnancy. The fifth section describes the role of CS signaling in preeclampsia, including its systemic and local (placental) alterations and the responsible mechanisms. The article closes with future perspectives and a summary that describes important complement-based approaches for diagnosing and treating preeclampsia.
Keywords: Human pregnancy, Preeclampsia, CS, Placenta, Immunoregulation, Immune homeostasis
Received: 23 Apr 2025; Accepted: 23 Jul 2025.
Copyright: © 2025 KUMAR and Stewart IV. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: VIJAY KUMAR, Morehouse School of Medicine, Atlanta, United States
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