Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis.
Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis.
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DOI：
10.1371/journal.ppat.1003220
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Battistini L
中科院分区：
文献类型：
--
作者：
Angelini DF;Serafini B;Piras E;Severa M;Coccia EM;Rosicarelli B;Ruggieri S;Gasperini C;Buttari F;Centonze D;Mechelli R;Salvetti M;Borsellino G;Aloisi F;Battistini L
人们早就知道，多发性硬化症（MS）与eb病毒（EBV）血清阳性率升高和对EBV的高免疫反应性有关，传染性单核细胞增多症增加了MS的风险。这一证据导致假设EBV感染在MS发病中起作用，尽管其机制存在争议。本研究旨在评估复发缓解型MS患者（n = 113）和健康供者（n = 43）中CD8+ T细胞对EBV潜伏（EBNA-3A, LMP-2A）和溶解（BZLF-1, BMLF-1）抗原的反应的发生率和程度，并研究EBV特异性CD8+ T细胞反应是否与疾病活动性相关，通过临床评估和钆增强磁共振成像来定义。使用HLA I类五聚体，在未治疗的非活动性MS患者中检测到裂解抗原特异性CD8+ T细胞应答少于活动性MS患者和HD患者，而在活动性MS患者和非活动性MS患者中检测到EBV裂解抗原和潜伏抗原特异性CD8+ T细胞的频率分别更高。相比之下，CD8+ T细胞对巨细胞病毒的反应在HD和MS患者之间没有差异，无论疾病阶段如何。在接受干扰素-β和natalizumab治疗的患者中，观察到EBV特异性CD8+ T细胞反应的患病率存在显着差异，这两种获批用于复发缓解型MS的药物纵向研究显示，在未接受治疗的MS患者的活动性疾病期间，EBV溶解抗原特异性CD8+ T细胞扩增，而在无复发的natalizumab治疗的患者中则没有。死后MS脑样本的分析显示EBV裂解蛋白BZLF-1的表达以及细胞毒性CD8+ T细胞与EBV裂解感染的浆细胞在炎症性白质病变和脑膜中的相互作用。因此，我们提出，在非活动性MS期间无法控制EBV感染可能为脑内病毒再激活和疾病复发奠定了基础。人们普遍认为多发性硬化症（MS）与eb病毒（EBV）感染有关，但机制联系仍存在争议。EBV是一种广泛存在于人群中的b淋巴细胞性疱疹病毒，通常作为一种持续的、无症状的感染被免疫监测控制。然而，EBV可引起传染性单核细胞增多症，与许多人类恶性肿瘤有关，并与一些常见的自身免疫性疾病有关。虽然EBV感染本身不能解释多发性硬化症的发生，但有人认为，在易感个体中，调节对病毒免疫反应的机制的改变可能有助于多发性硬化症的发病。在这里，我们表明，与健康供者和活跃的MS患者相比，非活动性疾病的MS患者对EBV的CD8+ T细胞反应较低，而后者具有更高频率的EBV裂解抗原特异性CD8+ T细胞。干扰素-β和natalizumab治疗，两种治疗复发缓解型MS的方法，与EBV特异性CD8+ T细胞反应的显著变化相关。我们还证明，在MS活动期间，在血液中扩增的CD8+ T细胞识别的EBV裂解抗原之一在MS炎症脑中表达。我们的研究结果支持一种MS发病机制模型，其中EBV感染和中枢神经系统的再激活刺激了免疫病理反应，并表明旨在恢复宿主-EBV平衡的抗病毒或免疫调节疗法可能对MS患者有益。
It has long been known that multiple sclerosis (MS) is associated with an increased Epstein-Barr virus (EBV) seroprevalence and high immune reactivity to EBV and that infectious mononucleosis increases MS risk. This evidence led to postulate that EBV infection plays a role in MS etiopathogenesis, although the mechanisms are debated. This study was designed to assess the prevalence and magnitude of CD8+ T-cell responses to EBV latent (EBNA-3A, LMP-2A) and lytic (BZLF-1, BMLF-1) antigens in relapsing-remitting MS patients (n = 113) and healthy donors (HD) (n = 43) and to investigate whether the EBV-specific CD8+ T cell response correlates with disease activity, as defined by clinical evaluation and gadolinium-enhanced magnetic resonance imaging. Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse. There is general consensus that multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection but the mechanistic links are still debated. EBV is a B-lymphotropic herpesvirus widespread in the human population and normally contained as a persistent, asymptomatic infection by immune surveillance. However, EBV can cause infectious mononucleosis, is associated with numerous human malignancies, and is implicated in some common autoimmune diseases. While EBV infection alone cannot explain MS development, it has been postulated that in susceptible individuals alterations in the mechanisms regulating the immune response to the virus may contribute to MS pathogenesis. Here, we show that MS patients with inactive disease exhibit a lower CD8+ T-cell response to EBV when compared to healthy donors and active MS patients while the latter have a higher frequency of CD8+ T cells specific for EBV lytic antigens. Therapy with interferon-β and natalizumab, two treatments for relapsing-remitting MS, was associated with marked changes in the EBV specific CD8+ T cell response. We also demonstrate that one of the EBV lytic antigens recognized by CD8+ T cells expanding in the blood during active MS is expressed in the inflamed MS brain. Our results support a model of MS pathogenesis in which EBV infection and reactivation in the CNS stimulates an immunopathological response and suggest that antiviral or immunomodulatory therapies aimed at restoring the host-EBV balance could be beneficial to MS patients.
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