The impact of NKG2A and NKG2D receptors and HLA-E and MICA ligands polymorphisms on post-transplant complications after paediatric allogeneic HSCT: a single-centre experience

Abstract

Introduction: Natural Killer cells are the first subpopulation of lymphocytes that reconstitute after allogeneic haematopoietic stem cell transplantation (HSCT). Their activity is regulated by various receptor-ligand interactions, including stimulation of the activating NKG2D receptor by the MICA molecule, and inhibitory NKG2A receptor interacting with the HLA-E. In this study the research effort focused on the effect of selected NKG2A and NKG2D receptors and their ligands (HLA-E and MICA molecules) polymorphisms that may affect the pathomechanisms of post-transplant complications after HSCT in children. Methods: One hundred donor-recipient pairs from a single paediatric transplantation centre were investigated. Altogether six single nucleotide substitutions (NKG2A rs7301582; NKG2D rs1049174, rs1154831; HLA-E rs1264457; MICA rs1051792, rs1063635) were genotyped, and the influence of polymorphisms was analysed on acute and chronic graft-versus-host disease (GvHD), cytomegalovirus (CMV) infection incidence, disease relapse and survival. Results: The distribution of the evaluated polymorphisms did not differ between patients and their donors. The results showed a significant influence of HLA-E rs1264457 polymorphism in patients' HLA-E*01:01 allele, which was associated with increased risk of CMV infection (p = 0.050), especially in children positive for CMV IgG before transplantation (p = 0.001). Furthermore, the effect of HLA-E*01:01 allele on CMV infections was more evident in children above the age of 7 years (p = 0.031). Strong tendencies (0.05 < p < 0.10) towards association with the risk of acute GvHD were also observed for the NKG2A or MICA polymorphisms of the recipients. In addition, NKG2D rs1154831 AA and MICA rs1063635 GG might play a protective role as they were not present in any recipient who died after transplantation. Conclusion: In summary, there is emerging evidence that genotyping results of NKG2 receptors and their ligands, may have prognostic value for the outcome of paediatric allogeneic HSCT, but more extensive studies performed on larger groups of donors and transplant recipients are required to confirm these observations.

Keywords: HLA-E; HSC; MICA; NK cell receptors; NK cells; paediatric HSCT patients.

FIGURE 1

Schematic representation of analysed receptor–ligand pairs and single-nucleotide polymorphisms studied in paediatric patients and their donors. (A) SNP localisation. (B,D) Linkage disequilibrium between HLA-E and MICA ligand SNPs. (C,E) LD between NKG2D and NKG2A receptor SNPs. The results for recipients are shown in the upper panel, while for donors, they are shown in the lower panel. LD values as R-squared.

FIGURE 2

Relationships of MICA and NKG2A polymorphisms with the risk for aGvHD development. (A) MICA rs1051792 G allele was less frequent among recipients who developed more severe aGvHD grades II–IV. (B) Recipients who did not develop aGvHD carried the NKG2A rs7301582 T allele less frequently.

FIGURE 3

Associations between CMV infection and various clinical and genetic factors in transplant recipients. (A) HLA-E*01:01 (rs1264457 T) allele prevails in patients with CMV infection. (B) Recipients with the HLA-E*01:01 (rs1264457T) allele with positive CMV IgG status before transplantation developed CMV infection more often. (C) Incidence of CMV infection is higher in older children (above the median age of 7 years). (D) Children above 7 years of age, carrying the HLA-E*01:01 (rs1264457 T) allele, had an increased risk for CMV infection.

FIGURE 4

Survival curves for paediatric HSCT recipients with respect to NKG2D and MICA variants. No fatal outcomes were seen in recipients carrying MICA rs1063635 GG (A), being homozygous for NKG2D rs1154831 A (B), or carrying both MICA rs1063635 GG and NKG2D rs1154831 AA genotypes (C).