Related Experiment Video
Updated: Oct 26, 2026
Multiplexed Fluorescent Immunohistochemical Staining of Four Endometrial Immune Cell Types in Recurrent Miscarriage
Published on: August 4, 2021
Combination of iKIR missing ligand hypothesis and HLA-B T/T genotypes as predictive biomarkers for recurrent
Raquel Gil Laborda1,2, Nabil Subhi-Issa1,2, Eduardo de la Fuente Muñoz1,2
1Department of Clinical Immunology, Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
Introduction:
Natural killer (NK) cell alloreactivity at the maternal-fetal interface is regulated by killer cell immunoglobulin-like receptors (KIR) and CD94/NKG2A receptors. A dimorphism at position -21 of the HLA-B leader peptide (-21M/-21T) biases NK education toward NKG2A (when -21M supplies HLA-E-binding peptides) or toward KIR (when -21T fails to do so). We evaluated whether maternal HLA-B leader genotype and inhibitory KIR (iKIR) missing-ligand (ML) status are associated with unexplained recurrent reproductive failure (uRF).
Methods:
Retrospective case-control study comparing recipient HLA-B leader genotype (M+ versus T/T) and iKIR ML across HLA-C groups with outcomes in uRF patients versus healthy controls. 77 women with uRF (43 recurrent pregnancy loss [RPL], 34 recurrent implantation failure [RIF]) and 75 healthy multiparous controls. Maternal KIR, HLA-B and HLA-C genotypes were typed from peripheral blood using Luminex-based SSP/SSO assays.
Results:
The centromeric KIR AA haplotype was enriched in uRF versus controls (difference 24%, p=0.0056). iKIR-ML analysis showed higher frequency of KIR2DL2/3 with absent C1 ligands in uRF (p=0.015). The HLA-B -21 analysis revealed increased T/T homozygosity in uRF (p=0.0031). The combination of KIR2DL2/3 (absent C1) with -21 T/T was more prevalent in RPL (p=0.04).
Discussion:
HLA-B -21 T/T and iKIR ML (absent C1 for KIR2DL2/3) may aid risk stratification in RPL. Findings warrant validation in larger cohorts.
