Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome
Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome
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DOI：
10.1093/brain/awr206
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发表时间：
2011-09-01
期刊：
影响因子：
14.5
通讯作者：
Martin, Roland
中科院分区：
文献类型：
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作者：
Aly, Lilian;Yousef, Sara;Martin, Roland
进行性多灶性白质脑病和进行性多灶性白质脑病-免疫重建炎性综合征是由JC多瘤病毒感染中枢神经系统引起的。两者都是多发性硬化症和其他自身免疫性疾病单克隆抗体治疗的并发症。进行性多灶性白质脑病-免疫重建炎性综合征可使进行性多灶性白质脑病的诊断变得模糊，并导致严重的临床残疾和可能的死亡。与进行性多灶性白质脑病不同，在进行性多灶性白质脑病中，在没有免疫应答的情况下，JC病毒导致少突胶质细胞溶解而导致脱髓鞘，进行性多灶性白质脑病-免疫重建炎性综合征中的组织破坏是由脑内强烈的免疫应答引起的。进行性多灶性脑白质病-免疫重建炎症综合征中涉及的细胞和介质至今知之甚少。我们检查了2例多发性硬化症患者，他们在那他珠单抗治疗下发生了进行性多灶性白质脑病，后来又发生了进行性多灶性白质脑病-免疫重建炎症综合征。由于最初脑脊液中JC病毒脱氧核糖核酸检测呈阴性，因此对1例患者进行了诊断性脑活检。组织学检查显示脑炎症，其特征为显著的T细胞浸润（CD 4（+）> CD 8（+）T细胞），但也有B/浆细胞和单核细胞。尽管JC病毒载量非常低，但两名患者均显示出高鞘内抗JC病毒抗体。研究了脑浸润性CD 4（+）T细胞的抗原特异性和功能。CD 4（+）T细胞对几种JC病毒蛋白的肽具有高度特异性，特别是主要衣壳蛋白VP 1。T细胞表型显示CD 4（+）Th 1和双功能Th 1 -2细胞。后者分泌大量的干扰素-γ和白细胞介素-4，解释了强烈的脑炎症、浆细胞的存在和鞘内抗VP 1抗体的分泌。脑浸润JC病毒特异性CD 4（+）T细胞的功能表型通过检查脑源性JC病毒特异性CD 4（+）T细胞克隆来确认和扩展。我们的数据为进行性多灶性白质脑病-免疫重建炎性综合征的发病机制提供了新的见解，并表明JC病毒特异性CD 4（+）T细胞在从大脑中消除JC病毒方面发挥重要作用，但也在引起大规模炎症中发挥重要作用，通常具有致命的结果。
Progressive multi-focal leucoencephalopathy and progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are caused by infection of the central nervous system with the JC polyoma virus. Both are complications of monoclonal antibody therapy in multiple sclerosis and other autoimmune diseases. Progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome can obscure the diagnosis of progressive multi-focal leucoencephalopathy and lead to severe clinical disability and possibly death. Different from progressive multi-focal leucoencephalopathy, in which demyelination results from oligodendrocyte lysis by JC virus in the absence of an immune response, tissue destruction in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome is caused by a vigorous immune response within the brain. The cells and mediators that are involved in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome are as yet poorly understood. We examined two patients with multiple sclerosis, who developed progressive multi-focal leucoencephalopathy and later progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome under natalizumab therapy. Due to initially negative JC viral deoxyribonucleic acid testing in the cerebrospinal fluid, a diagnostic brain biopsy was performed in one patient. Histopathology revealed brain inflammation characterized by a prominent T cell infiltrate (CD4(+) > CD8(+) T cells), but also B/plasma cells and monocytes. Despite very low JC viral load, both patients showed high intrathecal anti-JC virus antibodies. Brain-infiltrating CD4(+) T cells were studied regarding antigen specificity and function. CD4(+) T cells were highly specific for peptides from several JC virus proteins, particularly the major capsid protein VP1. T cell phenotyping revealed CD4(+) Th1 and bifunctional Th1-2 cells. The latter secrete large amounts of interferon-gamma and interleukin-4 explaining the strong brain inflammation, presence of plasma cells and secretion of intrathecal anti-VP1 antibodies. The functional phenotype of brain-infiltrating JC virus-specific CD4(+) T cells was confirmed and extended by examining brain-derived JC virus-specific CD4(+) T cell clones. Our data provide novel insight into the pathogenesis of progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome and indicate that JC virus-specific CD4(+) T cells play an important role in both eliminating JC virus from the brain, but also in causing the massive inflammation with often fatal outcome.