Personalized reproductive immunology: the impact of KIR/HLA genotypes on implantation and maternal–fetal health

Reproductive immunology is redefining how we understand fertility by shifting focus from isolated embryonic or endometrial factors to the dynamic immunological dialogue between mother and fetus. At the heart of this dialogue lies the interaction between maternal Killer Immunoglobulin-like Receptors (KIR) and fetal Human Leukocyte Antigen (HLA), particularly HLA-C, a molecular crossroads where genetics and immunity converge. These interactions fundamentally shape uterine natural killer (uNK) cell behavior, guiding trophoblast invasion, spiral artery remodeling, and ultimately the success of implantation and early placentation. When KIR/HLA recognition is suboptimal - as in women with KIR AA haplotypes carrying HLA-C2 fetuses - the system may become overly inhibitory, potentially restricting trophoblast invasion and contributing to recurrent implantation failure, pregnancy complications, or unexplained reproductive outcomes.Despite growing evidence, many questions remain about how specific immunogenetic combinations influence implantation, placental development, and clinical outcomes such as pregnancy loss, preeclampsia, and fetal growth restriction. Advances in single-cell technologies, spatial profiling, and systems immunology have begun to elucidate these mechanisms, yet the translation of such insights into routine reproductive care is still emerging. This gap highlights a pressing need to understand not only what these interactions are, but how they can be harnessed to inform personalized reproductive medicine.This Research Topic aims to connect foundational immunological discoveries with future clinical practice by synthesizing knowledge on KIR/HLA immunogenetics and their implications for fertility in both natural conception and assisted reproductive technologies (ART). Key objectives include clarifying how maternal KIR haplotypes and fetal HLA-C variants shape uNK cell responses and trophoblast invasion; exploring whether immunogenetic compatibility should be considered in embryo or donor selection; and evaluating the potential of KIR/HLA testing to illuminate cases of unexplained implantation failure or ART non-response. Particular emphasis will be placed on assessing the readiness of immunogenetic markers for clinical translation, refining predictive models, and envisioning how immunomodulatory strategies might restore balance in cases of excessive immune inhibition.The scope of this Research Topic encompasses mechanistic, translational, and clinically oriented studies relevant to the maternal–fetal interface, ART, and pregnancy outcomes. We welcome contributions addressing, but not limited to, the following themes:- Mechanistic insights into KIR/HLA interactions and their regulation of uNK cell function, implantation, and placental development- Clinical associations between specific KIR/HLA combinations and outcomes such as implantation failure, miscarriage, preeclampsia, and fetal growth restriction- Immunogenetic compatibility in oocyte donation, embryo selection, and personalized ART strategies- Best practices for genotyping, diagnostic workflows, and standardized clinical reporting- Evaluation of immunomodulatory therapies aimed at restoring immune balance in cases of inhibitory KIR/HLA interactions Topic editors: Mauro Cozzolino, Diana Alecsandru Source: https://www.frontiersin.org/research-topics/76688/personalized-reproductive-immunology-the-impact-of-kirhla-genotypes-on-implantation-and-maternal-fetal-health