Aguilar Ruth, Casabonne Delphine, O'Callaghan-Gordo Cristina, Vidal Marta, Campo Joseph J, Mutalima Nora, Angov Evelina, Dutta Sheetij, Gaur Deepak, Chitnis Chetan E, Chauhan Virander, Michel Angelika, de Sanjosé Silvia, Waterboer Tim, Kogevinas Manolis, Newton Rob, Dobaño Carlota
ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
Front Immunol. 2017 Oct 26;8:1284. doi: 10.3389/fimmu.2017.01284. eCollection 2017.
Epstein-Barr virus (EBV) is a necessary cause of endemic Burkitt lymphoma (eBL), while the role of in eBL remains uncertain. This study aimed to generate new hypotheses on the interplay between both infections in the development of eBL by investigating the IgG and IgM profiles against several EBV and antigens. Serum samples collected in a childhood study in Malawi (2005-2006) from 442 HIV-seronegative children (271 eBL cases and 171 controls) between 1.4 and 15 years old were tested by quantitative suspension array technology against a newly developed multiplex panel combining 4 EBV antigens [Z Epstein-Barr replication activator protein (ZEBRA), early antigen-diffuse component (EA-D), EBV nuclear antigen 1, and viral capsid antigen p18 subunit (VCA-p18)] and 15 antigens selected for their immunogenicity, role in malaria pathogenesis, and presence in different parasite stages. Principal component analyses, multivariate logistic models, and elastic-net regressions were used. As expected, elevated levels of EBV IgG (especially against the lytic antigens ZEBRA, EA-D, and VCA-p18) were strongly associated with eBL [high vs low tertile odds ratio (OR) = 8.67, 95% confidence interval (CI) = 4.81-15.64]. Higher IgG responses to the merozoite surface protein 3 were observed in children with eBL compared with controls (OR = 1.29, 95% CI = 1.02-1.64), showing an additive interaction with EBV IgGs (OR = 10.6, 95% CI = 5.1-22.2, = 0.05). Using elastic-net regression models, eBL serological profile was further characterized by lower IgM levels against preerythrocytic-stage antigen CelTOS and EBV lytic antigen VCA-p18 compared with controls. In a secondary analysis, abdominal Burkitt lymphoma had lower IgM to EBV and higher IgG to EA-D levels than cases with head involvement. Overall, this exploratory study confirmed the strong role of EBV in eBL and identified differential IgG and IgM patterns to erythrocytic vs preerythrocytic antigens that suggest a more persistent/chronic malaria exposure and a weaker IgM immune response in children with eBL compared with controls. Future studies should continue exploring how the malaria infection status and the immune response to interact with EBV infection in the development of eBL.
爱泼斯坦-巴尔病毒（EBV）是地方性伯基特淋巴瘤（eBL）的必要病因，而[某种病原体，原文未明确写出]在eBL中的作用仍不确定。本研究旨在通过调查针对几种EBV和[该病原体]抗原的IgG和IgM谱，就这两种感染在eBL发生发展过程中的相互作用提出新的假设。在马拉维一项针对儿童的研究（2005 - 2006年）中，收集了442名1.4至15岁HIV血清学阴性儿童（271例eBL病例和171名对照）的血清样本，采用定量悬浮阵列技术，针对一个新开发的多重检测板进行检测，该检测板组合了4种EBV抗原[Z爱泼斯坦-巴尔病毒复制激活蛋白（ZEBRA）、早期抗原弥散成分（EA-D）、EBV核抗原1和病毒衣壳抗原p18亚基（VCA-p18）]以及15种因其免疫原性、在疟疾发病机制中的作用以及在不同寄生虫阶段的存在情况而选择的[该病原体]抗原。使用了主成分分析、多变量逻辑模型和弹性网回归分析。正如预期的那样，EBV IgG水平升高（尤其是针对裂解抗原ZEBRA、EA-D和VCA-p18）与eBL密切相关[高四分位数与低四分位数比值比（OR） = 8.67，95%置信区间（CI） = 4.81 - 15.64]。与对照组相比，eBL患儿对裂殖子表面蛋白3的IgG反应更高（OR = 1.29，95% CI = 1.02 - 1.64），显示出与EBV IgGs存在相加相互作用（OR = 10.6，95% CI = 5.1 - 22.2，P = 0.05）。使用弹性网回归模型，与对照组相比，eBL的血清学特征进一步表现为针对[该病原体]红细胞前期抗原CelTOS和EBV裂解抗原VCA-p18的IgM水平较低。在一项二次分析中，腹部伯基特淋巴瘤患者针对EBV的IgM水平低于头部受累病例，而针对EA-D的IgG水平则更高。总体而言，这项探索性研究证实了EBV在eBL中的重要作用，并确定了针对红细胞期与红细胞前期[该病原体]抗原的IgG和IgM模式差异，这表明与对照组相比，eBL患儿的疟疾暴露更持久/慢性，且IgM免疫反应较弱。未来的研究应继续探索疟疾感染状况以及对[该病原体]的免疫反应如何与EBV感染在eBL的发生发展过程中相互作用。
