Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing-remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab-treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab-treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab-treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab-treated patients may potentially play a role in PML development.

中文翻译：

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那他珠单抗治疗多发性硬化症后的中枢神经系统炎症：一项回顾性组织病理学和脑脊液队列研究

那他珠单抗是一种针对整合素 α4ß1 和 α4ß7 的 α4 亚基的重组人源化单克隆抗体，已被批准用于治疗活动性复发缓解型 MS。尽管那他珠单抗是一种非常有益的药物，可有效降低持续残疾进展的风险和临床复发率，但有些患者对其没有反应，有些患者患进行性多灶性白质脑病 (PML) 的风险较高。那他珠单抗治疗后的组织病理学影响仍然未知。因此，我们对来自那他珠单抗治疗的患者的 24 个脑标本的 CNS 炎症细胞浸润进行了详细的组织学表征，其中包括 20 个活检和 4 个尸检以及 21 个 MS 对照。为了补充分析，通过流式细胞术对 30 名接受那他珠单抗治疗的患者和 42 名 MS 对照的血液和脑脊液 (CSF) 中的免疫细胞进行量化。病灶内炎性浸润主要由T细胞和巨噬细胞、部分B细胞、浆细胞和树突状细胞组成。与对照组相比，那他珠单抗治疗的患者病变中 T 细胞或巨噬细胞和小胶质细胞的数量没有显着差异。在脑脊液中观察到向具有记忆表型的细胞毒性 T 细胞的转变。那他珠单抗治疗患者的活动性脱髓鞘病变中浆细胞显着增加，但未观察到与临床残疾相关。发现病变内的树突状细胞随着持续治疗时间的延长而减少。我们的研究结果表明，那他珠单抗不能完全阻止免疫细胞进入中枢神经系统，并且与浆细胞的积累有关，其致病和临床意义尚不清楚。由于 B 细胞被认为是 JC 病毒的储存库，因此在接受那他珠单抗治疗的患者的 CNS 中观察到的浆细胞积累和树突状细胞减少可能在 PML 发展中发挥作用。