Characteristics of Hodgkin's Lymphoma after Infectious Mononucleosis

Hjalgrim, Henrik; Askling, Johan; Rostgaard, Klaus; Hamilton-Dutoit, Stephen; Frisch, Mørten; Zhang, Jinsong; Madsen, Mette; Rosdahl, N; Konradsen, Helle Bossen; Storm, Hans H.; Melbye, Mads

doi:10.1056/nejmoa023141

Cited by 372 publications

(276 citation statements)

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“…Contradicting the delayed-exposure hypothesis in our data for young adults are the risk of EBV-positive HL with lower birth order and the lack of association with self-reported IM, a clinically evident expression of infection delayed past childhood. For IM, the null finding resembles that of Sleckman et al 11 for EBV-positive early-stage HL but differs markedly from the case-control results of Alexander et al, 14 who found self-reported IM to be strongly associated with HL irrespective of EBV status, and from the cohort results of Hjalgrim et al, 15 who demonstrated a similar, 3-fold elevated risk of EBVpositive HL but no increase for EBV-negative HL in serologically confirmed IM patients.…”

Section: Discussioncontrasting

confidence: 62%

“…The inconsistencies of our findings with the delayed-exposure etiologic model for HL and with other published findings [11][12][13][14][15] have several possible explanations. (i) The proportion of HL tumors that are EBV-positive has been shown to vary markedly with the composition of the patient population.…”

Section: Discussioncontrasting

confidence: 54%

“…30,40,41 If such a mechanism impacts control of other etiologically relevant infections, risk patterns could differ between our data and data from populations including males. 15 the association of IM with EBV-positive HL was not adjusted for confounders, meaning that IM could be correlated with an important but unmeasured exposure. 14 Other etiologic viruses have been sought for HL, but none has been found to date.…”

Section: Discussionmentioning

confidence: 99%

“…13 Among the 4 studies considering prior IM and risk of EBV-positive HL, one found no association 11 and 3 found a strong increase in risk. [13][14][15] To help resolve inconsistencies in the epidemiologic data regarding childhood infection and risk of EBV-defined HL, we analyzed interview information and tumor EBV status from a population-based case-control study of HL in Greater San Francisco Bay area women. Our purpose in these analyses was to evaluate whether determinants of childhood exposure to other children and self-reported history of several common infections (including IM) predicted development of EBV-positive or EBV-negative HL.…”

mentioning

confidence: 99%

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Exposure to childhood infections and risk of Epstein‐Barr virus–defined Hodgkin's lymphoma in women

Glaser

Keegan

Clarke

et al. 2005

Intl Journal of Cancer

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The role of Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) etiology remains unresolved as EBV is detected in only some HL tumors and few studies have tried to reconcile its presence with factors suggesting viral etiology (e.g., childhood social class, infection history). In a population-based case-control study of San Francisco Bay area women, we analyzed interview data by tumor EBV status. Among 211 young adult cases, EBV-positive HL (11%) was associated with a single vs. shared bedroom at age 11 (OR ¼ 4.0, 95% CI 1.1-14.4); risk was decreased for common childhood infections (OR ¼ 0.3, 95% CI 0.1-1.0), including measles before age 10, but not with prior infectious mononucleosis (IM), which is delayed EBV infection. No study factors affected risk of young adult EBV-negative HL. Among 57 older adult cases, EBV-positive HL (23%) was unrelated to study factors; EBV-negative HL was associated with a single bedroom at age 11 (OR ¼ 3.6, 95% CI 1.5-9.1) and IM in family members (OR ¼ 3.1, 95% CI 1.1-9.0). Thus, delayed exposure to infection may increase risk of EBV-positive HL in young adults, but risk patterns differ in younger and older women for both EBV-positive and -negative HL. Late EBV infection does not appear relevant to risk, suggesting that other pathogens impact HL etiology in affluent female populations. Inconsistency of findings with prior studies may reflect failure of study risk factors to proxy meaningful exposures, risk differences by gender, or selection or misclassification bias. Null findings for EBV-negative HL indicate that etiologic models should be reconsidered for this common form. ' 2005 Wiley-Liss, Inc.Key words: Hodgkin's lymphoma; Epstein-Barr virus; etiology; risk factor; infectious mononucleosis Infections have long been suspected in the etiology of HL, particularly for young adult cases. Initial clues came from its heterogeneous clinical behavior and histologic appearance, which suggest both a chronic infection and a malignancy. 1,2 Subsequently, epidemiologic studies showed that young adult HL cases tended to have childhood characteristics such as early birth order and small family size that are consistent with delayed exposure to other children, suggesting that timing of childhood infections was etiologically important. 3,4 EBV, a ubiquitous herpesvirus, was of early interest as a possible causative infectious agent because HL patients were more likely than controls to report prior IM (the clinical manifestation of primary infection with EBV delayed until adolescence) and to have elevated antibody titers to EBV before as well as after HL diagnosis. 5,6 Involvement by EBV was further supported when molecular studies identified EBV genes and gene products within malignant cells of affected HL tumors and in a form suggesting that infection preceded malignant transformation. 7 Nevertheless, the role of EBV in HL etiology remains unresolved as present methods detect evidence of EBV in the tumor cells of only a proportion of HL patients, and this evidence is least common in young adul...

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Section: Discussioncontrasting

confidence: 62%

Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Exposure to childhood infections and risk of Epstein‐Barr virus–defined Hodgkin's lymphoma in women

Glaser

Keegan

Clarke

et al. 2005

Intl Journal of Cancer

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“…Population‐based studies have demonstrated a positive association between infectious mononucleosis and cHL 60. However, this does not necessarily implicate EBV in the aetiology of cHL.…”

Section: Discussionmentioning

confidence: 95%

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

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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.

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Multiple Sclerosis After Infectious Mononucleosis

Nielsen¹,

Rostgaard²,

Nielsen³

et al. 2007

Arch Neurol

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143

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Characteristics of Hodgkin's Lymphoma after Infectious Mononucleosis

Abstract: A causal association between infectious mononucleosis-related EBV infection and the EBV-positive subgroup of Hodgkin's lymphomas is likely in young adults.

Cited by 372 publications

References 13 publications

Exposure to childhood infections and risk of Epstein‐Barr virus–defined Hodgkin's lymphoma in women

Exposure to childhood infections and risk of Epstein‐Barr virus–defined Hodgkin's lymphoma in women

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

Multiple Sclerosis After Infectious Mononucleosis

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