Department of Epidemiology Research, Statens Serum Institut, DK-23005, Copenhagen, Denmark.
Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6400-5. doi: 10.1073/pnas.0915054107. Epub 2010 Mar 22.
A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A01 and HLA-A02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A01 and HLA-A02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.
一部分经典霍奇金淋巴瘤（HL）被认为与普遍存在的淋巴嗜性 EBV 感染有关。导致 EBV 相关 HL 的发展的决定性因素仍知之甚少，但可能涉及对病毒感染的免疫控制。因此，HLA Ⅰ类区域的标志物与 EBV 相关 HL 的风险相关。为了进一步研究 EBV 相关 HL 的宿主遗传成分，我们在传染性单核细胞增多症（IM）的背景下同时研究了 HL 中与 HLA-A01 和 HLA-A02 的关联，IM 是 EBV 相关 HL 的危险因素，在包括 278 例 EBV 相关和 656 例 EBV 无关的 HL 病例系列分析中进行了研究。通过逻辑回归，HLA-A01 等位基因[每等位基因的优势比（OR），2.15；95%可信区间（CI），1.60-2.88]与 EBV 相关 HL 的风险增加相关，而 HLA-A02 等位基因[每等位基因的 OR，0.70；95%CI，0.51-0.97]与 EBV 相关 HL 的风险降低相关。这些等位基因特异性关联对应于 HLA-A01 和 HLA-A02 纯合子之间 EBV 相关 HL 的风险差异近 10 倍。IM 病史也与 EBV 相关 HL 的风险相关（OR，3.40；95%CI，1.74-6.66）。在存在 HLA-A*02 的情况下，未观察到 IM 与 EBV 相关 HL 之间的关联，因为该等位基因似乎中和了 IM 对 EBV 相关 HL 风险的影响。我们的研究结果表明，HLA Ⅰ类限制的 EBV 特异性细胞毒性 T 细胞反应和 IM 中 EBV 感染的早期免疫反应事件在 EBV 相关 HL 的发病机制中起关键作用。
