HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

Hjalgrim, Henrik; Rostgaard, Klaus; Johnson, Paul C. D.; Lake, Annette; Shield, Lesley; Little, Ann‐Margaret; Ekström-Smedby, Karin; Adami, Hans‐Olov; Glimelius, Bengt; Hamilton-Dutoit, Stephen; Kane, Eleanor; Taylor, G. Malcolm; McConnachie, Alex; Ryder, Lars P.; Sundström, Christer; Andersen, Paal Skytt; Chang, Ellen T.; Alexander, Freda E.; Melbye, Mads; Jarrett, Ruth F.

doi:10.1073/pnas.0915054107

Cited by 101 publications

(93 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of the four-digit level HLA typing showed that the most common suballele, A*0201, was driving the protective effect. 29 Limitations of this study include misclassification of reported IM in the questionnaire. There is a risk for misclassification as not all IM cases are caused by EBV, and primary cytomegalovirus infections can give similar symptoms.…”

Section: Epstein-barr Virus and Multiple Sclerosis Vs Hla E Sundqvistmentioning

confidence: 93%

Epstein-Barr virus and multiple sclerosis: interaction with HLA

et al. 2011

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM)and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. IM showed association with MS, odds ratio (OR) ¼ 1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR ¼ 1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR ¼ 3.60 (2.75-4.72 95%CI), and also interacted with both DRB1*15 and absence of A*02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection.

show abstract

Section: Epstein-barr Virus and Multiple Sclerosis Vs Hla E Sundqvistmentioning

confidence: 93%

Epstein-Barr virus and multiple sclerosis: interaction with HLA

et al. 2011

View full text Add to dashboard Cite

show abstract

“…With these studies as a basis, there are many further questions to address. How might EBV infection, particularly a history of IM, predispose both to an autoimmune disease, multiple sclerosis [95] and to Hodgkin Lymphoma [96]? Might an inflammatory environment, particularly that induced by a high EBV load in IM, allow rogue T cell priming, leading in one case to cross-reactive auto-immune recognition of neuronal cells and in the other to wrongly polarized T cells that nurture rather than deter lymphoma growth?…”

Section: Conclusion and Future Challengesmentioning

confidence: 99%

Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory

Rickinson

Long

Palendira

et al. 2014

Trends in Immunology

107

104

View full text Add to dashboard Cite

Epstein-Barr virus (EBV), a human herpesvirus with potent B cell growth transforming ability, induces multiple cellular immune responses in the infected host. How these host responses work together to prevent virus pathogenicity, and how immune imbalance predisposes to disease, remain poorly understood. Here, we describe three ongoing lines of enquiry that are shedding new light on these issues. These focus on: (i) patients with infectious mononucleosis or its fatal equivalent, X-linked lymphoproliferative disease; (ii) EBV infection in a range of new, genetically defined, primary immune deficiency states; and (iii) experimental infection in two complementary animal models, the rhesus macaque and the human haemopoietic stem cell reconstituted mouse.

show abstract

“…However, the impact of HLA class I on EBV latency antigen‐specific CD8 + T cell immunity has not been determined systematically. Interestingly, large epidemiological and genomewide association studies have consistently reported differential HLA class I susceptibility to EBV + cHL (Supporting information, Table S1) 14, 15, 16, 17. In western European populations, HLA‐A*01 and HLA‐B*37 are associated with increased susceptibility to EBV + cHL, while HLA‐A*02 is associated with protection 15, 16, 17.…”

Section: Introductionmentioning

confidence: 99%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryIn 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02– versus HLA‐A*02+ EBV+cHL patients, suggesting that LMP2A‐specific CD8+ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8+ T cell responses was elevated in HLA‐A*02+ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8+ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8+ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8+ T cell hierarchies.

show abstract

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

Cited by 101 publications

References 42 publications

Epstein-Barr virus and multiple sclerosis: interaction with HLA

Epstein-Barr virus and multiple sclerosis: interaction with HLA

Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Contact Info

Product

Resources

About