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第三部分（4-3） 译 者 崔兴华、赵思佳、范秉林、刘玉娇 王力群、拱忠影、薛 萍、邱晓峰 文献审校：张慜 文献提供：林宏
李神经文献翻译中心 出品 责任人：柳宏伟 Pathophysiology Conduction block and nerve pathology Motor conduction block is the characteristic, although not entirely specific, electrophysiological finding in MMN. The pathophysiological mechanisms underlying this feature and other aspects of nerve dysfunction have not been completely elucidated. Results from electrophysiological studies have shown clear signs of dysfunction at the nodes of Ranvier, with hyperpolarization and depolarization, both of which can lead to failure of action potential conduction. In theory, conduction block can result from primary dysfunction of the axon at the nodes of Ranvier or paranodal abnormalities of the myelin sheath. Pathology studies of motor nerves from patients with MMN are scarce, and have shown contradictory results, with signs of demyelination in some studies and primary axonal degeneration in another study.Nerve dysfunction in MMN is, however, probably more widespread than sites of conduction block, suggesting generalized rather than focal dysfunction of the axonal membrane.
A second striking characteristic of MMN compared with other inflammatory demyelinating neuropathies is the high frequency of axonal degeneration. Axon loss, rather than conduction block, is the most important determinant of permanent weakness and disability.Treatment with IVIg may counteract pathogenic pathways that cause axon loss, by reducing axonal dysfunction and promoting reinnervation.
病理生理学
传导阻滞与神经病理
MMN神经电生理检测发现运动传导阻滞，但不具有特异性。其病理生理机制尚未完全阐明。电生理研究发现在郎飞结发生的明显的功能障碍，表现为超极化和去极化，这两者均会影响动作电位传导。理论上说，传导阻滞可以导致在郎飞结或髓鞘异常节点上的轴突障碍。MMN患者的运动神经病理研究中非常少，且已得出相反的结果，如脱髓鞘和轴索变性。然而，MMN神经功能障碍可能远比传导阻滞部位多，可能存在广泛的而不是轴突膜的局灶性功能障碍。
与其他炎性脱髓鞘性神经病相比，MMN的第二个显着的特点是轴索变性。MMN患者持久无力以及残疾的最重要的决定因素是轴突的损失，而不是传导阻滞。静注免疫球蛋白治疗可能是通过减轻轴索功能障碍和促进神经再生来阻止引起轴索脱失的病理途径。 Immunopathology 输入标题输入小
Pathological studies of motor nerves from patients with MMN are scarce. Small perivascular lymphocyte infiltrates have been documented in two patients, which could suggest an inflammatory or immune component of the disease, but were not detected in others. Results from other studies, discussed below, seem to support the concept of an immune-mediated pathogenesis.
GM1-specific antibody titers
Antibodies to glycolipids, including gangliosides, are associated with a wide range of inflammatory neuropathies. GM1 is ubiquitously expressed, but is probably more abundant in motor than in sensory nerves. It is enriched in paranodal myelin, and also expressed in the axolemma at the nodes of Ranvier of peripheral motor nerves. The neurobiological functions of gangliosides are not fully understood, but they are thought to play a part in the maintenance and repair of nervous tissues, stabilization of paranodal junctions, and clustering of ion channels, all of which are essential for rapid propagation of action potentials.
The relative abundance of GM1 in motor nerves offers an explanation for the association of GM1-specific IgG antibodies with pure motor axonal forms of Guillain–Barré syndrome (GBS). The pathogenic potential of GM1 IgM antibodies in MMN is less clear. On one hand, low titers of GM1-specific IgM antibodies have been detected in a small percentage of patients with MND, leading some researchers to doubt the specificity—and, therefore, the pathogenicity—of these antibodies in MMN. Moreover, initial in vivo and in vitro studies on the pathogenic properties of GM1-specific IgM antibodies yielded conflicting results. On the other hand, more-recent studies have shown that high titers of anti-GM1 IgM are considerably more common in MMN than in MND and other neuropathies. The antibodies can activate the classic comple-ment pathway, and complement-activating capacity correlates with antibody titers. Patients with MMN who were seropositive for GM1-specific IgM antibodies had significantly more weakness, disability and axon loss than patients without these antibodies. Moreover, higher antibody titers correlated with more-severe weakness. These studies indicate that GM1-specific IgM serum antibodies from patients with MMN may share pathogenic characteristics with GM1-specific IgG serum antibodies from patients with GBS.
免疫病理学
MMN患者运动神经病理学研究极少，曾报道两例患者出现小血管周围淋巴细胞浸润，意味着有炎症或免疫机制参与该病，但其他患者并没发现这种情况。其他研究结果似乎支持免疫介导疾病的观点。
GM-1特异性抗体滴度 包括神经节苷脂在内的糖脂抗体与许多炎性神经病变相关。GM1在神经系统广泛表达，但在运动神经较感觉神经更为丰富。其在髓鞘节旁区密集，同时在周围运动神经郎飞结轴膜也有表达。目前神经节苷脂的神经生物学功能尚不清楚，有研究认为其在神经组织功能维护、修复、结旁接头处的稳定以及离子通道聚集中均发挥作用，而这些功能在动作电位快速传播中起重要作用。
GM1在运动神经相对丰富可以解释GM1特异IgG抗体与纯运动轴索型GBS有关。而GM1 IgM抗体在MMN的发病机制尚不清楚。一方面，少数MND患者检测到了低滴度的GM1特异性IgM抗体，这导致一些研究者质疑这些抗体在MMN发病中的特异性甚至致病性。而且，在体及体外关于GM1特异性IgM抗体致病性的研究结果并不一致。另一方面，更多近期研究表明，与MND以及其它神经病相比，高滴度的抗GM1 IgM抗体在MMN中更常见。这些抗体能激活经典的补体通路，而补体激活能力与抗体滴度相关。相对于抗体阴性患者来说，血清GM1特异性IgM抗体阳性MMN患者的肌无力、残疾、轴索脱失更严重，而且抗体滴度越高肌无力症状越严重。这些研究表明，MMN患者GM1特异IgM血清抗体与GBS患者的GM1特异性IgG血清抗体具有相同致病特点。 Antibody-mediated pathology Antibody-mediated pathology Specific animal models of MMN are not available. However, data from experimental models of GBS have revealed various effects of GM1-specific antibodies on the func-tion of peripheral nerves that might be relevant for MMN pathogenesis. First, binding of anti-GM1 antibodies to GM1 at paranodal junctions may alter the paranodal anatomy, and cause mislocalization or disruption of sodium and potassium channel clusters. Second, anti-bodies may activate the classic complement pathway and formation of the membrane attack complex, a porin that compromises membrane integrity, leading to disruption of sodium channel clusters (Figure 1).
抗体介导病理学
目前MMN没有特异性的动物模型。然而，GBS动物模型提示GM1特异性抗体对周围神经的影响，可能与MMN的发病机制有关。首先，抗GM1抗体与结旁连接处GM1结合可能改变节旁的解剖结构，并导致钾和钠离子通道错位或破坏。其次，抗体可能激活经典补体通路并导致膜攻击复合体形成，损害膜蛋白的完整性，导致钠通道簇破坏（图1）。 图1 多灶性运动神经病可能的病理机制。a. 郎飞节点正常条件下能确保电信号的跳跃式传导。神经节苷脂，如GM1，在维持副结区的紧密连接、钾离子通道固定及钠离子通道聚集中发挥作用。 b.50％的多灶性运动神经病患者体内产生特定GM1-IgM抗体。这些抗体可以结合在郎飞结点并激活补体，从而破坏施万细胞膜的结合点，使离子通道簇移动或破坏中断。补体因子，包括膜攻击复合物，它们的沉积可能会损害膜的完整性并导致轴突损伤。缩写：MMN（多灶性运动神经病）。 These experimental findings may reflect the pathogenic mechanisms that ultimately cause conduction block and axonal damage, and offer clues as to how immunological and electro-physiological characteristics of MMN may be linked. Antibody-inhibiting and complement-inhibiting drugs counteracted the pathogenic effects of ganglioside-specific antibodies in experimental models of antibody-mediated polyneuropathy. Indeed, the efficacy of IVIg in MMN may be explained by its capacity to inhibit anti-GM1 IgM-mediated complement deposition and to induce a systemic reduction of classic pathway function.
GM1 IgM antibodies are part of the repertoire of the innate immune system, which probably explains the lack of specificity of low titers of anti-GM1 IgM antibodies for MMN. GM1-specific B?cell activation would explain increased titers, but the underlying mechanism remains to be clarified.
Anti-GM1 antibodies in GBS are associated with infections by microorganisms—most commonly Campylobacter jejuni—that express ganglioside-like structures on their surface a few days or weeks before disease onset. Infection with C. jejuni can cause activation of GM1-specific B cells and increased anti-GM1 antibody titers——a process known as ‘molecular mimicry’. Results from small-scale serological studies have failed to document a similar association with MMN.
Monoclonal IgM gammopathy of undetermined significance is also associated with increased titers of GM1-specific IgM, suggesting that intrinsic B?cell clone changes may underlie MMN. Indeed, the frequency of IgM monoclonal gammopathy seems to be higher in patients with MMN than in healthy age-matched controls (6% versus 2%; L. Vlam, S. Piepers, N. A. Sutedja, E. A. Cats, W.?L. van der Pol and L. H. van den Berg, unpublished work). Taken together, infections with C. jejuni and premalignant B?cell changes do not seem to explain increased anti-GM1 IgM titers in most MMN cases, suggesting other unknown mechanisms of B?cell activation in MMN.
MMN patients with and without anti-GM1 IgM antibodies show similar clinical features. This finding could indicate that the serum of ‘seronegative’ patients contains antibodies against as yet unidentified antigens that have a similar function or anatomical distribution to GM1. Some candidate antigens have been identified. Serum reactivity to complexes consisting of multiple gangliosides, as reported in other inflammatory neuropathies, could not be demonstrated in MMN. However, serum IgM from patients with MMN was found to bind to a mixture of lipids containing GM1, galactocerebroside and cholesterol.
This lipid-context-dependent antibody binding to GM1 could partly explain the large proportion of patients with MMN who are seronegative for anti-GM1 antibodies. More recently, disulfated heparin disaccharide was identified as a potential antigen in patients with motor neuropathies. These results need to be further explored to enable us to understand their clinical significance in MMN.
这些试验发现可能反应了传导阻滞和轴突损害的致病机制，并为探究MMN免疫和电生理特性提供线索。在抗体介导的多神经病实验模型中，抑制抗体和抑制补体的药物能阻止神经节苷脂特异性抗体的致病性。事实上，静注人免疫球蛋白治疗MMN可能通过抑制抗GM1 IgM介导的补体沉积以及诱导经典途径功能来发挥作用。
GM1 IgM 抗体是先天免疫系统的一部分，或许可以解释MMN的GM1 IgM 抗体滴度低时缺乏特异性的原因。GM1特异性B细胞活化可解释抗体滴度升高的原因，但其根本机制仍有待澄清。
GBS的抗GM1抗体与微生物感染有关-最常见的是空肠弯曲菌，起病前数天到数周其表面表达神经节苷脂类似结构。空肠弯曲菌感染可导致GM1特异B细胞活化，抗GM1抗体滴度升高，这一过程称为分子模拟。但一些小规模血清学研究未发现与MMN有相关性。
意义不明的单克隆IgM丙种球蛋白症也可升高GM1特异性IgM的滴度，提示内源性B细胞克隆改变可能是MMN的病理基础。实际上，在MMN患者中，IgM单克隆丙种球蛋白症出现频率似乎高于同年龄的健康对照组（6%比2%）。总之，空肠弯曲菌感染和症状出现前的B细胞改变似乎不能解释大多数MMN患者抗GM1 IgM滴度升高的原因，意味着MMN还有其他机制可促使B细胞活化。
抗GM1-IgM抗体阳性的MMN患者和抗GM1-IgM抗体阴性的MMN患者具有相似的临床特点；这一发现意味着GM1-IgM抗体阴性的多灶性运动神经病患者的血清中含有某种抗体，这种抗体针对一种尚未发现的抗原，而这种尚未发现的抗原和GM1具有相似的功能或解剖分布。一些候选抗原已被确定。在其它炎性神经病变中，血清对神经节苷脂组成的免疫复合物具有反应性已有报道，但在MMN尚无报道。有研究发现，MMN患者血清中的IgM结合于GM1、半乳糖和胆固醇的混合物上。这种结合于GM1与脂质上相互依赖的抗体可以部分解释抗神经节苷脂抗体阴性的MMN患者的病因。近来硫酸肝素糖被认为是一种潜在于运动神经病患者体内的抗原。这些结果尚需进一步证实，以使我们了解它们在MMN中的临床意义。 Other features of autoimmunity Other features of autoimmunity
Whether MMN is a classic autoimmune disease remains undetermined. Many autoimmune diseases are associated with specific HLA alleles. The HLA system is crucial for presentation of specific peptide antigens to T lymphocytes, and particular HLA haplotypes can facilitate activation of autoreactive lymphocytes. The frequency of the HLA-DRB1*15 haplotype was increased among Dutch patients with MMN, similar to the association found in multiple sclerosis. However, evidence for involvement of peptides as autoantigens in MMN is lacking, and how the observed HLA association fits into a concept of MMN pathogenesis is currently unclear. An increased incidence of other autoimmune diseases in patients with MMN (E. A. Cats, A. S. Bertens, J. H. Veldink, L. H. van den Berg and W.?L. van der Pol, unpublished work) is a further line of evidence supporting autoimmunity in MMN. Other findings, however, argue against autoimmunity in MMN; in particular, the higher incidence in males than in females, the lack of response to corticosteroids, and the lack of disease association with single nucleotide polymorphisms in genes that predispose to B?cell-mediated autoimmune disease.
其它自身免疫特点
MMN是否是一种典型的自身免疫性疾病尚未确定。许多自身免疫性疾病与特定的HLA 等位基因相关。HLA系统对特定的肽抗原提呈给T淋巴细胞是至关重要的，而且特定的单倍型HLA可促进自反应性淋巴细胞的活化。在荷兰MMN患者中，单倍型HLADRB1* 15出现的频率较高，类似于其与多发性硬化的相关性。然而，肽作为自身抗原参与MMN的证据尚不足， HLA如何参与MMN的发病，机制目前还不清楚。其他自身免疫性疾病合并MMN的患者，发病率上升进一步支持该病的自身免疫机制。然而，有调查结果不支持MMN的自身免疫机制，尤其是：男性发病率高于女性，皮质类固醇治疗效果差，以及鲜有病例因缺乏基因单核苷酸多态性而易患B细胞介导的自身免疫疾病的证据。 未完待续 ， 明天刊出最后部分（4-4） 译 者：王力群、拱忠影、薛萍、邱晓峰、崔兴华、赵思佳、范秉林、刘玉娇 文献审校：张慜；文献提供：林宏； 李神经文献翻译中心 出品 |
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来自： 雨林医风 > 《李神经群临床推理系列》
