在艾滋病相关非霍奇金淋巴瘤诊断之前，B细胞Toll样受体2（TLR2）表达失调且调节性B细胞频率升高。
Dysregulated B-cell TLR2 expression and elevated regulatory B-cell frequency precede the diagnosis of AIDS-related non-Hodgkin lymphoma.
作者信息
Siewe Basile, Pham Joey T, Cohen Mardge, Hessol Nancy A, Levine Alexandra, Martinez-Maza Otoniel, Landay Alan
机构信息
aRush University Medical Center bDepartments of Medicine, Stroger Hospital and Rush University, Chicago, Illinois cDepartment of Clinical Pharmacy, University of California San Francisco, San Francisco dCity of Hope National Medical Center, Duarte eUCLA AIDS Institute, University of California, California, USA.
出版信息
AIDS. 2015 Aug 24;29(13):1659-64. doi: 10.1097/QAD.0000000000000687.
OBJECTIVES
In antiretroviral therapy (ART)-treated patients, to determine if AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is preceded by: elevated frequency of potentially malignant abnormal activated/germinal center-like B cells, elevated serum prevalence of B-cell stimulatory Toll-like receptor (TLR) ligands resulting from HIV infection-associated microbial translocation, dysregulated B-cell TLR expression/signaling, and perturbations in the frequency of immunoregulatory cells.
DESIGN
A case-control study nested with a cohort study of HIV-infected women.
METHODS
Prediagnostic AIDS-NHL cases (n = 12, collected 1-12 months before diagnosis) and controls (n = 42) from the Women's Interagency HIV Study cohort, were matched for HIV and ART status, age, race, and CD4 lymphocyte count. Serum levels of TLR ligands, the prevalence of malignancy-associated abnormal activated/germinal center-like (CD19CD10CD71CD86AID) B cells, TLR2 expression on B cells, expression of TLR2-modulating micro-RNA, and the frequency of regulatory T and B cells were assessed.
RESULTS
Diagnosis of AIDS-NHL was preceded by a significantly elevated frequency of activated/germinal center-like CD19CD10CD71CD86AID B cells (P = 0.0072), elevated serum prevalence of the TLR2 ligand, and significantly elevated B-cell TLR2 expression (P = 0.0015), positively correlating with the frequency of activated/germinal center-like B cells (rho = 0.7273, P = 0.0144). In cases, a purified subset of activated/germinal center-like B cells exhibited decreased expression of microRNAs that modulate TLR2 signaling, including miR-21, 146a, 146b, and 155. Finally, cases also exhibited significantly elevated frequencies of antitumor immunity inhibitory regulatory B cells (P = 0.0024), but not regulatory T cells.
CONCLUSIONS
Our findings suggest that increased microbial translocation and dysregulated TLR expression/signaling, coupled with an elevated frequency of regulatory B cells, precede the diagnosis of AIDS-NHL in HIV-infected ART-treated patients.
目的
在接受抗逆转录病毒治疗（ART）的患者中，确定艾滋病相关非霍奇金淋巴瘤（AIDS-NHL）是否在以下情况之前出现：潜在恶性异常活化/生发中心样B细胞频率升高、因HIV感染相关微生物易位导致的B细胞刺激Toll样受体（TLR）配体血清流行率升高、B细胞TLR表达/信号失调以及免疫调节细胞频率紊乱。
设计
一项嵌套于HIV感染女性队列研究的病例对照研究。
方法
从女性机构间HIV研究队列中选取诊断前的AIDS-NHL病例（n = 12，在诊断前1 - 12个月收集）和对照（n = 42），根据HIV和ART状态、年龄、种族以及CD4淋巴细胞计数进行匹配。评估血清中TLR配体水平、与恶性肿瘤相关的异常活化/生发中心样（CD19CD10CD71CD86AID）B细胞的流行率、B细胞上TLR2的表达、调节TLR2的微小RNA的表达以及调节性T细胞和B细胞的频率。
结果
AIDS-NHL诊断前，活化/生发中心样CD19CD10CD71CD86AID B细胞频率显著升高（P = 0.0072），TLR2配体的血清流行率升高，B细胞TLR2表达显著升高（P = 0.0015），与活化/生发中心样B细胞频率呈正相关（rho = 0.7273，P = 0.0144）。在病例中，活化/生发中心样B细胞的一个纯化亚群表现出调节TLR2信号的微小RNA表达降低，包括miR-21、146a、146b和155。最后，病例中抗肿瘤免疫抑制调节性B细胞频率也显著升高（P = 0.0024），但调节性T细胞频率未升高。
结论
我们的研究结果表明，在接受ART治疗的HIV感染患者中，微生物易位增加和TLR表达/信号失调，以及调节性B细胞频率升高，先于AIDS-NHL的诊断出现。
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