Epstein-Barr Virus and HLA-DPB1-*0301 in young adult Hodgkin's disease: evidence for inherited susceptibility to Epstein-Barr Virus in cases that are EBV(+ve).

Cases of Hodgkin's disease (HD) may be distinguished by whether they do [EBV-positive ((+ve)) cases] or do not [EBV-negative ((-ve)) cases] have evidence of EBV DNA in the Reed-Sternberg cells. Only one study has attempted to distinguish epidemiological risk factors for EBV(+ve) and EBV(-ve) HD, and none have compared inherited susceptibility. The present study involves a population-based case series of HD, diagnosed in patients between 16-24 years of age in the United Kingdom (n = 118), of whom 87% were classified by EBV status (EBV(+ve), 19, EBV(-ve), 84). History of infectious illness, EBV antibody titers, and HLA-DPB1 type have been compared in EBV(+ve) and EBV(-ve) cases. Reported infectious mononucleosis was more frequent in EBV(+ve) cases (odds ratio (OR), 5.10; 95% confidence interval (CI), 1.12-24.4). EBV antibody titers to viral capsid antigen were significantly higher in EBV(+ve) cases (P for trend = 0.02). Higher proportions of EBV(+ve) (43%) than EBV(-ve) (31%) cases typed positive for HLA-DPB1*0301, but this was not statistically significant; the association of infectious mononucleosis with EBV(+ve) cases was stronger in this HLA subgroup (OR, 17.1; 95%CI, 1.06-1177) than in other cases (OR, 1.24; 95% CI, 0.02-15.4). Although these results are based on small numbers of HD cases, they provide suggestive evidence that the etiology of EBV(+ve) HD may involve inherited susceptibility to EBV.

Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents.

A UK population-based case-control study of Hodgkin's disease (HD) in young adults (16-24 years) included 118 cases and 237 controls matched on year of birth, gender and county of residence. The majority (103) of the cases were classified by Epstein-Barr virus (EBV) status (EBV present in Reed-Stenberg cells), with 19 being EBV-positive. Analyses using conditional logistic regression are presented of subject reports of prior infectious disease (infectious mononucleosis (IM), chicken pox, measles, mumps, pertussis and rubella). In these analyses HD cases are compared with matched controls, EBV-positive cases and EBV-negative cases are compared separately with their controls and formal tests of differences of association by EBV status are applied. A prior history of IM was positively associated with HD (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.10-5.33) and with EBV-positive HD (OR = 9.16, 95% CI = 1.07-78.31) and the difference between EBV-positive and EBV-negative HD was statistically significant (P = 0.013). The remaining infectious illnesses (combined) were negatively associated with HD, EBV-positive HD and EBV-negative HD (in the total series, for > or =2 episodes compared with < or =1, OR = 0.45, 95% CI = 0.25-0.83). These results support previous evidence that early exposure to infection protects against HD and that IM increases subsequent risk; the comparisons of EBV-positive and EBV-negative HD are new and generate hypotheses for further study.

Further investigation of the role of HLA-DPB1 in adult Hodgkin's disease (HD) suggests an influence on susceptibility to different HD subtypes.

It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPB1 type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86-2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27-0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02-5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10-0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32-104.36), and resistance with *1101 (RR = 0.08; CI 0.01-0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17-326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84-99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04-25.77), Alanine-55 (RR = 15.17; CI 2.00-115.20) and Valine-84 (RR = 15.94; CI 3.55-71.49). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03-0.60). Certain DPB1 alleles and individual DPbeta1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent.

X linked lymphoproliferative disease in a United Kingdom family.

X linked lymphoproliferative disease (XLP; Duncan's disease) is a rare disorder affecting boys and characterised by a defective immune response to Epstein-Barr virus caused by a mutation in a gene located at chromosome Xq25. Three siblings with XLP in a single UK family are reported and the variation in phenotypic expression of the disease in these siblings described. One of the siblings with life threatening fulminant infectious mononucleosis was successfully treated by chemotherapy, followed by bone marrow transplantation using an unaffected brother as the donor. A healthy baby boy recently born into the family was identified as carrying the defective maternal X chromosome using molecular genetic linkage analysis. This family illustrates the extent of present understanding of this often fatal condition.

Lack of association between childhood common acute lymphoblastic leukaemia and an HLA-C locus dimorphism influencing the specificity of natural killer cells.

Previous serological studies documenting an association between acute lymphoblastic leukaemia (ALL) and HLA-Cw antigens suggested that the HLA-C locus might influence susceptibility to ALL. However, associations with more than one Cw antigen suggest that polymorphic variants shared by more than Cw allele could be involved. Recent studies have shown that the HLA-C locus encodes two ligands (NK1 and NK2) recognized by receptors on natural killer (NK) cells. HLA-Cw alleles encoding these ligands are dimorphic, dependent on whether they encode one or other NK ligand. To determine whether susceptibility to the common (CD10+) form of childhood ALL (c-ALL) is associated with NK1 or NK2, we carried out a molecular analysis of 94 childhood c-ALL patients and 136 infant controls. We found no difference in the frequency of NK1 and NK2 alleles, phenotypes or genotypes between the patients and controls, suggesting that this does not explain the role of the HLA-C locus in susceptibility to childhood c-ALL.

Evidence that an HLA-DQA1-DQB1 haplotype influences susceptibility to childhood common acute lymphoblastic leukaemia in boys provides further support for an infection-related aetiology.

Comparison of DQA1 and DQB1 alleles in 60 children with common acute lymphoblastic leukaemia (c-ALL) and 78 newborn infant control subjects revealed that male but not female patients had a higher frequency of DQA1*0101/*0104 and DQB1*0501 than appropriate control subjects. The results suggest a male-associated susceptibility haplotype in c-ALL and supports an infectious aetiology.

Increased frequency of HLA-DPB1*0301 in Hodgkin's disease suggests that susceptibility is HVR-sequence and subtype-associated.

Hodgkin's disease (HD) is a complex lymphoma-like disease which occurs as four main subtypes, nodular sclerosing (NS), mixed cellularity (MC), lymphocyte predominant (LP) and lymphocyte depleted (LD). Suggestions from epidemiological studies that HD may represent an unusual response to infection imply that the lack of previous response could be due to genetic factors. Following recent reports suggesting that there is an increased frequency of HLA-DPB1*0301 in Hodgkins disease, we have studied DPB1 in two series of patients using molecular typing methods. One series is a retrospective group of 118 patients over the age of 15 years from a single centre, and the other is a multi-centre prospective group of 45 patients between the age of 16 and 24 years. In both series, the percentage of HD patients with DPB1*0301 is greater than in the controls, confirming that this seems to be an HD-susceptibility allele. However, extension of the analysis in relation to HD subtype shows that the increase in *0301 is present in nodular sclerosing (NS), mixed cellularity (MC) and lymphocyte predominant patients (LP) HD patients, but preliminary evidence suggests an increase in *0401, and possibly *0501 in MC- and LP-HD. The DPB1 hypervariable region (HVR) amino-acid motif Asp55, Glu56 (*0301-like, HVR-C) is increased in NS compared with non-NS (ie MC+LP), whereas the frequency of Ala55, Ala56 (*0401-like) is increased in non-NS compared with NS. Conversely, Asp84, Glu85Ala86(*0301-like, HVR-F) motif is more frequent in NS than non-NS patients, but there is no increase in Gly84, Gly855, Pro86 (*0401-like). These findings suggest that genetic susceptibility in HD may reside at the level of HVR-encoded DPB1 peptide-binding residues, rather than with a specific allele, and that this may in some way influence the HD subtype.

Molecular analysis of HLA-DQB1 alleles in childhood common acute lymphoblastic leukaemia.

Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of (human leucocyte antigen) HLA genes, an association between an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA-DQB1 allele frequencies in a cohort of 62 children with c-ALL with 76 newborn controls, using group-specific polymerase chain reaction (PCR) amplification, and single-strand conformation polymorphism (SSCP) analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR): 2.54, uncorrected P=0.038], and a marginal excess with DQB1*0501 (RR: 2.18; P=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined relative risk of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1.

Molecular genetic analysis of a family with a history of Hodgkin's disease and dyschondrosteosis.

We describe a family in which two sisters with the autosomal dominant skeletal dysplasia, Leri-Weill dyschondrosteosis (LWD), developed Hodgkin's disease (HD) in late adolescence. In a preliminary attempt to identify HD susceptibility gene(s), HLA-typing and linkage analysis were carried out in the family. Using HLA molecular typing, both sisters were found to have inherited a variant of the HD-susceptibility allele, DPB1*0301, known as DPB1*2001. Following a previous report of a constitutional chromosome translocation (t(2q;8p)) in a family with LWD, preliminary linkage studies were carried out using chromosome 2q and 8p molecular markers. Regions covered by 7/10 chromosome 2 markers and 4/8 chromosome 8 markers were excluded as the location of a candidate LWD gene. Given the rarity of LWD and HD, their simultaneous occurrence is unlikely to have been due to chance. We suggest that a mutation in the LWD gene itself, or a gene closely linked to it, perhaps acting with increased susceptibility to infection conferred by DPB1*2001, resulted in HD in the two sisters.

Preliminary evidence of an association between HLA-DPB1*0201 and childhood common acute lymphoblastic leukaemia supports an infectious aetiology.

It has been suggested that childhood leukaemia may be the abnormal outcome of a common infection. Rare events caused by common environmental events such as infections are likely to be influenced by host genetic susceptibility. We have therefore investigated whether immunogenetic susceptibility contributes to the risk of childhood common ALL (c-ALL). In this preliminary study, we report that children with c-ALL (n = 63) carry the HLA-DPB1 locus allele *0201 twice and nearly three times more frequently than adult (n = 92; relative risk (RR) = 2.9, P < 0.05) or infant controls (n = 82; RR = 2.1). Moreover, children with c-ALL are 3-4 times more likely than controls to be heterozygous for DPB1*0201/*0301, /*0401 and /*0402 (RRadult controls = 3.9; RRinfant controls = 2.8). These results suggest that HLA-DPB1*0201 either alone or with other DPB1 alleles contributes to the risk of childhood c-ALL, possibly by increasing susceptibility to an infectious agent.