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Background: Reproductive failures, including recurrent implantation failures (RIF), recurrent pregnancy losses (RPL), and adverse pregnancy outcomes (APO), are increasingly linked to immunological factors at the maternalfetal interface. Killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells play a key role in regulating maternal immune responses to trophoblast HLA-C antigens.
Methods: In this study, we present a novel flow cytometric protocol to phenotypically characterize the expression of three KIR receptors (KIR2DL1, KIR2DL3, KIR2DS1) on peripheral blood NK cells in 144 women with reproductive failure. KIR phenotyping results were compared with PCR-based genotyping in a subset of 62 patients, revealing a 98.4% concordance.
Results: The KIR AA phenotype, defined by the presence of inhibitory receptors and absence of the activating KIR2DS1, was identified in 45% of patients and was significantly associated with RIF. Multivariate logistic regression further demonstrated that both maternal KIR AA phenotype and higher paternal HLA-C2 allele count were independent predictors of RIF (p = 0.013 and p = 0.030, respectively). Exploratory analysis in RPL and APO subgroups revealed nonrandom patterns suggestive of similar immunogenetic influences, although statistical significance was not reached.
Conclusions: These findings support the hypothesis that maternal KIR AA profiles may predispose to poor reproductive outcomes, particularly in the presence of paternal HLA-C2 alleles. Flow cytometric KIR profiling represents a reliable and clinically informative tool that may facilitate personalized immune-based diagnostics and therapeutic decision-making in reproductive medicine.
DOI: 10.7754/Clin.Lab.2025.250730
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