HLA Allele E*01:01 Is Associated with a Reduced Risk of EBV-Related Classical Hodgkin Lymphoma Independently of HLA-A*01/*02

Martín, Paloma; Krsnik, Isabel; Navarro, Belén; Provencio, Mariano; Garcı́a, Juan F.; Bellas, Carmen; Vilches, Carlos; Gómez‐Lozano, Natalia

doi:10.1371/journal.pone.0135512

Cited by 9 publications

(8 citation statements)

References 51 publications

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“…These results have been supported by another work [75]. At last, genotypes with at least one copy of HLA-E R are associated with lower risk of EBV-related classical Hodgkin’s lymphoma [76].…”

Section: Hla-e Dimorphism and Cancersupporting

confidence: 64%

Dimorphism of HLA-E and Its Disease Association

Kanevskiy

Erokhina

Kobyzeva

et al. 2019

IJMS

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HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.

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Section: Hla-e Dimorphism and Cancersupporting

confidence: 64%

Dimorphism of HLA-E and Its Disease Association

Kanevskiy

Erokhina

Kobyzeva

et al. 2019

IJMS

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“…Interestingly, a recently published study identified the HLA-E*0101 variant as a protective factor for EBV-related classic Hodgkin lymphoma. 30 This not only supports our findings but also suggests that the LMP-1 peptide-mediated upregulation of HLA-E may play a role in EBV-associated lymphoproliferative diseases in general. In combination with our data, this highlights the need for further assessment of the potential of LMP-1 variant and HLA-E analysis to identify patients generally at risk for EBV-associated lymphoproliferative diseases.…”

Section: Discussionsupporting

confidence: 90%

HLA-E–restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD

Vietzen

Furlano

Cornelissen

et al. 2023

Blood

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Primary Epstein-Barr virus (EBV) infections may cause infectious mononucleosis (IM), while EBV-reactivations in solid-organ (SOT) and hematopoietic stem cell transplant (HSCT) recipients are associated with post-transplantation lymphoproliferative disorders (PTLD). It is still unclear, why only a minority of primary EBV-infected individuals develop IM, and why only some patients progress to EBV+PTLD post-transplantation. We now investigated, whether non-classical HLA-E-restricted immune responses have a significant impact on the development of EBV-diseases in the individual host. Based on a large study cohort of 1404 patients and controls as well as on functional natural killer (NK) and CD8+ T cell analyses, we could demonstrate that the highly expressed HLA-E*0103/0103 genotype is protective against IM, due to the induction of potent EBV BZLF1-specific HLA-E-restricted CD8+ T cell responses, which efficiently prevent the in vitro viral dissemination. Furthermore, we provide evidence that the risk of symptomatic EBV-reactivations in immunocompetent individuals as well as in immunocompromised transplant recipients depends on variations in the inhibitory NKG2A/LMP-1/HLA-E axis. We show that EBV-strains encoding for the specific LMP-1 peptide variants GDPHLPTL or GGDPPLPTL, presented by HLA-E, elicit strong inhibitory NKG2A+ NK and CD8+ T cell responses. The presence of EBV-strains encoding for both peptides was highly associated with symptomatic EBV-reactivations. The further progression to EBV+PTLD was highly associated with the presence of both peptide-encoding EBV-strains and the expression of HLA-E*0103/0103 in the host. Thus, HLA-E-restricted immune responses and the NKG2A/LMP-1/HLA-E axis are novel predictive markers for EBV+PTLD in transplant recipients and should be considered for future EBV vaccine design.

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“…Several studies reported a higher prevalence of the HLA-E*01:03 allele or the HLA-E*01:03/01:03 genotype in infectious diseases [ 38 ] and several cancer types including nasopharyngeal carcinoma, serous ovarian cancer, and acute leukemia [ 9 , 39 , 40 ]. Interestingly, the HLA-E*01:01 allele seems to be underrepresented in classical Hodgkin lymphomas, especially among Epstein Barr virus (EBV)-positive cases compared to healthy controls [ 41 ]. We observed a slightly higher prevalence of the HLA-E*01:01 genotype in aggressive B-NHL.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants of the NKG2C/HLA-E Receptor–Ligand Axis Are Determinants of Progression-Free Survival and Therapy Outcome in Aggressive B-Cell Lymphoma

Wagner

Hüttmann

Nückel³

et al. 2020

Cancers

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Aggressive B-cell lymphomas account for the majority of non-Hodgkin lymphomas (B-NHL). NK cells govern the responses to anti-CD20 monoclonal antibodies and have emerged as attractive targets for immunotherapy in subtypes of B-NHL. NKG2C and its cognate ligand HLA-E represent key molecules for fine-tuning of NK cell-mediated immune responses. Here, we investigated the impact of genetic variants of NKG2C and HLA-E on clinical outcomes of 441 B-NHL patients. Homozygous deletion of NKG2C (NKG2C−/−) was three-fold increased in patients compared to 192 healthy controls. Among studied patients, NKG2C−/− was more abundant in International Prognostic Index (IPI) high-risk patients compared to patients with a lower IPI (p = 0.013). Strikingly, NKG2C−/− was associated with a significantly reduced 2-year PFS (progression-free survival) (p = 0.0062) and represented an independent risk factor for 2-year PFS in multivariate analysis (p = 0.005). For HLA-E, the cognate ligand of NKG2C, the HLA-E*01:01 allele frequency was increased in B-NHL patients compared to controls (p = 0.033) and was associated with complete remission in univariate (p = 0.034) and multivariate (p = 0.018) analysis. Our data suggest that NKG2C and HLA-E genotyping is a promising tool for both defining risk groups of aggressive B-NHL and predicting response to immune therapeutic approaches.

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HLA Allele E01:01 Is Associated with a Reduced Risk of EBV-Related Classical Hodgkin Lymphoma Independently of HLA-A01/*02

Cited by 9 publications

References 51 publications

Dimorphism of HLA-E and Its Disease Association

Dimorphism of HLA-E and Its Disease Association

HLA-E–restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD

Genetic Variants of the NKG2C/HLA-E Receptor–Ligand Axis Are Determinants of Progression-Free Survival and Therapy Outcome in Aggressive B-Cell Lymphoma

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