Once people with multiple sclerosis enter the progressive clinical phenotype of their disease, they often develop a syndrome resembling chronic myelopathy dominated by deteriorating spastic paraparesis, bladder, sexual and bowel dysfunction and lower limb sensory loss (10). Nevertheless, MS pathology in the spinal cord is significantly less well studied than in the brain, perhaps in part, due to the more laborious dissection involved (6). However, there has been renewed interest in the MS spinal cord, not least through efforts using magnetic resonance imaging to improve visualization and quantitation of subtle changes in the spinal cord thereby providing better short‐term predictors of clinical change (4, 14). In this edition of Brain Pathology, Reali and co‐workers explore the role of meningeal B cells in the spinal cord (13). The authors selected three spinal cord samples from each of 22 progressive MS cases, half of which were found to have follicle‐like clusters (FLC⁺) in the meninges of the brain, whilst the other half did not (FLC⁻). They then investigated the composition of the inflammatory infiltrate in the meninges and the perivascular and parenchymal grey and white matter of the spinal cord. Similar to earlier studies by the same group exploring the potential role of meningeal inflammation in the brain for cortical demyelination and neuronal loss (8, 9), significant association was detected between the degree of inflammation and spinal cord pathology characterised by a greater degree of lymphocyte infiltration of the spinal leptomeninges, perivascular spaces and parenchyma, microglial activation, demyelination and axonal loss. Thus, spinal cord involvement could easily contribute to the deterioration in lower limb function noted in people with FLC in the brains (8). Of particular interest is their finding of a correlation between parenchymal spinal cord damage and the density of B cell, but not T cell, infiltrates in the cord meninges suggesting a prominent role of B cells in the pathogenesis of progressive MS. The observation that a topographic association between meningeal inflammation and parenchymal damage cannot only be detected in the forebrain (ie, in the subpial cortex), but also in the spinal cord (ie, in the subpial white matter and the underlying grey matter), supports a rather direct pathogenetic role of this meningeal infiltrate with TNF, IL6, IFNγ, CXCL13 and Semaphorin A (3) all suggested candidate mediators, more than 100 years after the close relationship between the subarachnoid space and MS lesions in the subpial parenchyma led Otto Marburg to hypothesize a toxic ‘soluble ‘factor’. Reali and coworkers' paper is timely: Despite the undisputed relevance of downstream mechanisms, such as oxidative stress, metabolic failure and excitotoxicity (5), the importance of B cells in progressive MS has been underpinned through successful phase III trials of immunotherapies with major impact on B cell subsets, including ocrelizumab (11) and siponimod (7). Against the backdrop of these clinical observations, and studies on the etiology of MS, Reali et al.’s quantitative immune phenotyping combined with standard neuropathology support the notion that B cells play a major role in MS pathogenesis (1). Another interesting feature of the work by Reali and colleagues is the significant microglia and macrophage activation in both FLC⁺ and FLC^‐ cases, compared to controls (13). Whilst the lack of a difference between the two MS groups may be due to a limited sample size, one may speculate that a proportion of the tissue damage facilitated by the sequestered immune response in progressive MS is driven by microglial/ macrophage activity that is, at least in part, independent from a myelin antigen‐specific, adaptive immune response (12). And whilst some success of treating progressive MS can be attributed to peripheral B cell depletion and modulation (1), clearing the central nervous system of FLC using CNS‐penetrant and active immunotherapeutics will be the essential human experiment to demonstrate the causal importance of these B cells. The tools are perhaps on hand to achieve this goal (2). Reali et al.’s work provides yet more support that such studies are now worth undertaking.

一旦患有多发性硬化症的人进入其疾病的进行性临床表型，他们通常会出现类似于慢性脊髓病的综合征，主要表现为痉挛性下肢轻瘫、膀胱、性和肠道功能障碍以及下肢感觉丧失 ( 10 )。然而，与大脑相比，脊髓中的 MS 病理学研究明显较少，这可能部分是由于所涉及的解剖更费力 ( 6 )。然而，人们对 MS 脊髓重新产生了兴趣，尤其是通过使用磁共振成像来改善脊髓细微变化的可视化和量化，从而提供更好的临床变化的短期预测指标 ( 4, 14)）。在本期《脑病理学》中，Reali 及其同事探索了脑膜 B 细胞在脊髓中的作用 ( 13 )。作者从 22 个进行性多发性硬化症病例中的每一个中选择了三个脊髓样本，其中一半被发现在大脑的脑膜中有毛囊样簇 (FLC ⁺ )，而另一半没有 (FLC ^- )。然后，他们研究了脑膜和脊髓血管周围和实质灰质和白质中炎症浸润的成分。类似于同一小组的早期研究，探索大脑中脑膜炎症对皮质脱髓鞘和神经元丢失的潜在作用 ( 8, 9)，在炎症程度和脊髓病理学之间检测到显着关联，其特征在于脊髓软脑膜、血管周围间隙和实质、小胶质细胞激活、脱髓鞘和轴突损失的更大程度的淋巴细胞浸润。因此，脊髓受累很容易导致大脑中 FLC 患者下肢功能的恶化（8）。特别令人感兴趣的是，他们发现实质脊髓损伤与 B 细胞（而非 T 细胞）密度之间存在相关性，这表明 B 细胞在进行性 MS 的发病机制中起着重要作用。脑膜炎症和实质损伤之间的地形关联不仅可以在前脑（即软膜下皮层）中检测到，而且在脊髓（即软膜下白质和下面的灰质中）也能检测到这一观察结果，支持这种脑膜浸润与 TNF、IL6、IFNγ、CXCL13 和信号素 A 具有相当直接的致病作用（3）所有建议的候选介质，在蛛网膜下腔与软膜下实质中的 MS 病变之间的密切关系导致 Otto Marburg 假设一种有毒的“可溶性“因子”之后 100 多年。Reali 和同事的论文是及时的：尽管下游机制无可争议地具有相关性，例如氧化应激、代谢衰竭和兴奋性毒性 ( 5 )，但 B 细胞在进展性 MS 中的重要性已经通过具有重大影响的免疫疗法的成功 III 期试验得到了支持B 细胞亚群，包括 ocrelizumab ( 11 ) 和辛波莫德 ( 7)）。在这些临床观察和 MS 病因学研究的背景下，Reali 等人的定量免疫表型结合标准神经病理学支持 B 细胞在 MS 发病机制中起主要作用的观点 ( 1 )。通过REALI和他的同事工作的另一个有趣的特点是在两种FLC的显著小胶质细胞和巨噬细胞活化⁺和FLC ^-的情况下，与对照组相比（13）。虽然两个 MS 组之间缺乏差异可能是由于样本量有限，但可以推测，进展性 MS 中隔离免疫反应促进的组织损伤的一部分是由小胶质细胞/巨噬细胞活动驱动的，即在至少部分地，独立于髓鞘抗原特异性、适应性免疫反应 ( 12 )。虽然治疗进展性 MS 的一些成功可归因于外周 B 细胞耗竭和调节 ( 1 )，但使用 CNS 渗透剂和主动免疫疗法清除 FLC 的中枢神经系统将是证明这些 B细胞因果重要性的基本人体实验细胞。工具也许可以实现这一目标（2）。Reali 等人的工作提供了更多的支持，这些研究现在值得进行。