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Peer-reviewedCC BY 4.0Frontiers in Immunology

Combination of iKIR missing ligand hypothesis and HLA-B T/T genotypes as predictive biomarkers for recurrent pregnancy loss: a novel algorithmic approach

  • Raquel Gil Laborda1,2
  • Nabil Subhi-Issa1,2
  • Eduardo de la Fuente Muñoz1,2
  • María Palacios Ortega1,2
  • María Guzman-Fulgencio1
  • Angela Villegas Mendiola1
  • MD Mansilla Ruiz1
  • Lydia Pilar-Suarez3
  • Ignacio Cristóbal García3
  • Rafael González Fernández4
  • Silvia Sánchez-Ramón1
  • Miguel Fernández-Arquero1,2
4 affiliations
  1. 1Department of Clinical Immunology, Hospital Clínico San Carlos, IdISSC
  2. 2Immunology, ORL and Ophthalmology Department, Medical Faculty, Universidad Complutense de Madrid
  3. 3Obstetrics and Gynecology Department, Hospital Clínico San Carlos
  4. 4Department of Clinical Immunology, Hospital Reina Sofia
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{laborda2026combination,
  title = {{Combination of iKIR missing ligand hypothesis and HLA-B T/T genotypes as predictive biomarkers for recurrent pregnancy loss: a novel algorithmic approach}},
  author = {Raquel Gil Laborda and Nabil Subhi-Issa and Eduardo de la Fuente Muñoz and María Palacios Ortega and María Guzman-Fulgencio and Angela Villegas Mendiola and MD Mansilla Ruiz and Lydia Pilar-Suarez and Ignacio Cristóbal García and Rafael González Fernández and Silvia Sánchez-Ramón and Miguel Fernández-Arquero},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1866398},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1866398/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Combination of iKIR missing ligand hypothesis and HLA-B T/T genotypes as predictive biomarkers for recurrent pregnancy loss: a novel algorithmic approach
AU  - Raquel Gil Laborda
AU  - Nabil Subhi-Issa
AU  - Eduardo de la Fuente Muñoz
AU  - María Palacios Ortega
AU  - María Guzman-Fulgencio
AU  - Angela Villegas Mendiola
AU  - MD Mansilla Ruiz
AU  - Lydia Pilar-Suarez
AU  - Ignacio Cristóbal García
AU  - Rafael González Fernández
AU  - Silvia Sánchez-Ramón
AU  - Miguel Fernández-Arquero
PY  - 2026
DA  - 2026/10/08
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1866398
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1866398/full
AB  - 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.
SN  - 1664-3224
ER  -