Department of Neurology–Department of Inflammatory Diseases of the Nervous System and Neurooncology,University of Mu¨nster, Germany.
Neurology. 2012 Feb 14;78(7):458-67; discussion 465. doi: 10.1212/WNL.0b013e3182478d4b. Epub 2012 Feb 1.
Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders.
We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLβ2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients.
Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE.
From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.
随着针对多发性硬化症和其他免疫介导性疾病的单克隆抗体治疗的应用，进行性多灶性脑白质病（PML）的发病率显著上升。
我们报告了 2 例接受依那西普（一种针对αLβ2-白细胞整合素（LFA-1）的中和抗体）治疗的严重银屑病患者，这 2 例患者均患有 PML 且死亡，其治疗时间均≥3 年。其中 1 例患者接受了外周血和 CSF 的系列研究，包括白细胞表型分析、体外迁移分析和 CDR3 谱型分析，对照患者来自患有 PML 的 HIV 感染患者。对 2 例患者的尸检 CNS 组织进行了广泛的病理和组织学分析。
这 2 例患者均出现进行性认知和运动功能障碍，CSF 中检测到 JC 病毒。尽管接受了包括血浆置换（PE）在内的治疗，且出现免疫重建迹象，但这 2 例患者均在发病后 2 个月和 6 个月死于 PML。神经病理学检查证实为 PML。依那西普治疗与体外外周 T 细胞的跨内皮迁移减少有关。在 PE 后 LFA-1 在外周 T 细胞上的表达水平逐渐升高，体外迁移增加。外周血和 CSF T 细胞谱型分析显示 CD8+T 细胞克隆性扩张，但激活减弱，在 PE 后恢复。
根据这些数据，我们提出抑制外周和鞘内 T 细胞的激活以及抑制中枢神经系统效应期迁移均为依那西普相关 PML 的特征。LFA-1 可能是控制 JC 病毒的关键因素。
