Mechanisms of Immune Escape in Central Nervous System Infection With Neurotropic JC Virus Variant
Mechanisms of Immune Escape in Central Nervous System Infection With Neurotropic JC Virus Variant
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DOI：
10.1002/ana.24574
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发表时间：
2016-03-01
影响因子：
11.2
通讯作者：
Martin, Roland
中科院分区：
文献类型：
--
作者：
Jelcic, Ivan;Jelcic, Ilijas;Martin, Roland
目的：JC多瘤病毒（JCV）中枢神经系统（CNS）的症状性感染通常是免疫功能低下的结果，表现为进行性多灶性脑白质病（PML）或颗粒细胞神经病变（GCN）。在免疫重建后，这些病例中的一些可能表现出长期持续的JCV和延迟的临床改善，尽管有炎症。方法：我们随访了4例多发性硬化症患者，他们发生了natalizumab相关的PML或GCN，与中枢神经系统的JC病毒载量和jjc特异性t细胞反应有关。所有患者均出现免疫重建炎症综合征（IRIS），但有2例患者在IRIS后JCV持续21个月，并伴有延迟的临床改善。结果：1例患者在免疫重建期间，JCV的持续存在与缺乏JCV vp1特异性t细胞反应相关。对另一名神经持续性JCV患者脑浸润的详细分析显示，CD8(+) T细胞强烈浸润，CD4(dim) CD8（+）表型的活化CD8（+）效应T细胞克隆扩增，两者都对JCV大T抗原保守表位具有良好的特异性。然而，清除JCV并不有效，因为主要衣壳蛋白VP1的突变导致CD4(+) t细胞对鉴定的JCV变异的反应减少，随后导致IRIS后CD8(+) t细胞反应下降。解释：我们的研究结果表明，CD4(+) T细胞对嗜神经型JCV变异的有效识别对于支持CD8(+) T细胞对抗中枢神经系统的JCV感染至关重要。
Objective: Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long-term persistence of JCV and delayed clinical improvement despite inflammation.Methods: We followed 4 patients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted >21 months after IRIS accompanied by delayed clinical improvement.Results: Persistence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8(+) T cells and clonal expansion of activated CD8(+) effector T cells with a CD4(dim) CD8(+) phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4(+) T-cell responses against the identified JCV variant and subsequently resulted in a decline of CD8(+) T-cell responses after IRIS.Interpretation: Our findings suggest that efficient CD4(+) T-cell recognition of neurotropic JCV variants is crucial to support CD8(+) T cells in combating JCV infection of the CNS.