Immunological dysregulation in preeclampsia: Pathogenesis and clinical implications.

Hypertensive disorders of pregnancy (HDP), including gestational hypertension, preeclampsia, and eclampsia, represent significant causes of maternal and perinatal morbidity and mortality. The core pathogenesis of HDP involves an imbalance in the immune microenvironment at the maternal-fetal interface, manifested by aberrant interactions among trophoblast cells, decidual immune cells, and systemic inflammatory responses. Trophoblast dysfunction and inadequate spiral artery remodeling result in placental ischemia and hypoxia, which in turn trigger the release of anti-angiogenic factors (such as sFlt-1 and sEng) and damage-associated molecular patterns (DAMPs), leading to systemic inflammation and endothelial injury. Immune cell dysregulation, including an imbalanced Treg/Th17 ratio, enhanced NK cell cytotoxicity, monocyte expansion and pro-inflammatory activation, pro-inflammatory macrophage polarization, excessive formation of neutrophil extracellular traps (NETs), and the production of autoantibodies by B cells, further exacerbates placental pathology. Moreover, genetic and epigenetic factors, such as HLA-C/KIR mismatch, abnormal DNA methylation, and dysregulated microRNA expression, contribute to the disruption of immune tolerance and placental development. Emerging immunologically based therapeutic strategies, including angiotensin II type 1 receptor autoantibody (AT1-AA) antagonism, B cell depletion, complement cascade inhibition, administration of anti-inflammatory agents, and immunomodulation of specific cell types, have shown promise in preclinical and early clinical studies. Coupled with multi-omic biomarker profiling, these approaches offer potential for early prediction and personalized intervention in preeclampsia. This review highlights the critical role of immune microenvironment imbalance in HDP pathogenesis and underscores the translational potential of immune-targeted therapies in improving pregnancy outcomes. With advances in mechanistic understanding, precision stratification, and integrative immunotherapy are poised to become central themes in future HDP management.