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.

病理生理學(xué)

傳導(dǎo)阻滯與神經(jīng)病理

MMN神經(jīng)電生理檢測(cè)發(fā)現(xiàn)運(yùn)動(dòng)傳導(dǎo)阻滯，但不具有特異性。其病理生理機(jī)制尚未完全闡明。電生理研究發(fā)現(xiàn)在郎飛結(jié)發(fā)生的明顯的功能障礙，表現(xiàn)為超極化和去極化，這兩者均會(huì)影響動(dòng)作電位傳導(dǎo)。理論上說(shuō)，傳導(dǎo)阻滯可以導(dǎo)致在郎飛結(jié)或髓鞘異常節(jié)點(diǎn)上的軸突障礙。MMN患者的運(yùn)動(dòng)神經(jīng)病理研究中非常少，且已得出相反的結(jié)果，如脫髓鞘和軸索變性。然而，MMN神經(jīng)功能障礙可能遠(yuǎn)比傳導(dǎo)阻滯部位多，可能存在廣泛的而不是軸突膜的局灶性功能障礙。

與其他炎性脫髓鞘性神經(jīng)病相比，MMN的第二個(gè)顯著的特點(diǎn)是軸索變性。MMN患者持久無(wú)力以及殘疾的最重要的決定因素是軸突的損失，而不是傳導(dǎo)阻滯。靜注免疫球蛋白治療可能是通過(guò)減輕軸索功能障礙和促進(jìn)神經(jīng)再生來(lái)阻止引起軸索脫失的病理途徑。

輸入小

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.

免疫病理學(xué)

MMN患者運(yùn)動(dòng)神經(jīng)病理學(xué)研究極少，曾報(bào)道兩例患者出現(xiàn)小血管周圍淋巴細(xì)胞浸潤(rùn)，意味著有炎癥或免疫機(jī)制參與該病，但其他患者并沒(méi)發(fā)現(xiàn)這種情況。其他研究結(jié)果似乎支持免疫介導(dǎo)疾病的觀點(diǎn)。

GM-1特異性抗體滴度

包括神經(jīng)節(jié)苷脂在內(nèi)的糖脂抗體與許多炎性神經(jīng)病變相關(guān)。GM1在神經(jīng)系統(tǒng)廣泛表達(dá)，但在運(yùn)動(dòng)神經(jīng)較感覺(jué)神經(jīng)更為豐富。其在髓鞘節(jié)旁區(qū)密集，同時(shí)在周圍運(yùn)動(dòng)神經(jīng)郎飛結(jié)軸膜也有表達(dá)。目前神經(jīng)節(jié)苷脂的神經(jīng)生物學(xué)功能尚不清楚，有研究認(rèn)為其在神經(jīng)組織功能維護(hù)、修復(fù)、結(jié)旁接頭處的穩(wěn)定以及離子通道聚集中均發(fā)揮作用，而這些功能在動(dòng)作電位快速傳播中起重要作用。

GM1在運(yùn)動(dòng)神經(jīng)相對(duì)豐富可以解釋GM1特異IgG抗體與純運(yùn)動(dòng)軸索型GBS有關(guān)。而GM1 IgM抗體在MMN的發(fā)病機(jī)制尚不清楚。一方面，少數(shù)MND患者檢測(cè)到了低滴度的GM1特異性IgM抗體，這導(dǎo)致一些研究者質(zhì)疑這些抗體在MMN發(fā)病中的特異性甚至致病性。而且，在體及體外關(guān)于GM1特異性IgM抗體致病性的研究結(jié)果并不一致。另一方面，更多近期研究表明，與MND以及其它神經(jīng)病相比，高滴度的抗GM1 IgM抗體在MMN中更常見(jiàn)。這些抗體能激活經(jīng)典的補(bǔ)體通路，而補(bǔ)體激活能力與抗體滴度相關(guān)。相對(duì)于抗體陰性患者來(lái)說(shuō)，血清GM1特異性IgM抗體陽(yáng)性MMN患者的肌無(wú)力、殘疾、軸索脫失更嚴(yán)重，而且抗體滴度越高肌無(wú)力癥狀越嚴(yán)重。這些研究表明，MMN患者GM1特異IgM血清抗體與GBS患者的GM1特異性IgG血清抗體具有相同致病特點(diǎn)。

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).

抗體介導(dǎo)病理學(xué)

目前MMN沒(méi)有特異性的動(dòng)物模型。然而，GBS動(dòng)物模型提示GM1特異性抗體對(duì)周圍神經(jīng)的影響，可能與MMN的發(fā)病機(jī)制有關(guān)。首先，抗GM1抗體與結(jié)旁連接處GM1結(jié)合可能改變節(jié)旁的解剖結(jié)構(gòu)，并導(dǎo)致鉀和鈉離子通道錯(cuò)位或破壞。其次，抗體可能激活經(jīng)典補(bǔ)體通路并導(dǎo)致膜攻擊復(fù)合體形成，損害膜蛋白的完整性，導(dǎo)致鈉通道簇破壞（圖1）。

圖1 多灶性運(yùn)動(dòng)神經(jīng)病可能的病理機(jī)制。a. 郎飛節(jié)點(diǎn)正常條件下能確保電信號(hào)的跳躍式傳導(dǎo)。神經(jīng)節(jié)苷脂，如GM1，在維持副結(jié)區(qū)的緊密連接、鉀離子通道固定及鈉離子通道聚集中發(fā)揮作用。 b.50％的多灶性運(yùn)動(dòng)神經(jīng)病患者體內(nèi)產(chǎn)生特定GM1-IgM抗體。這些抗體可以結(jié)合在郎飛結(jié)點(diǎn)并激活補(bǔ)體，從而破壞施萬(wàn)細(xì)胞膜的結(jié)合點(diǎn)，使離子通道簇移動(dòng)或破壞中斷。補(bǔ)體因子，包括膜攻擊復(fù)合物，它們的沉積可能會(huì)損害膜的完整性并導(dǎo)致軸突損傷。縮寫(xiě)：MMN（多灶性運(yùn)動(dòng)神經(jīng)?。?。

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.

這些試驗(yàn)發(fā)現(xiàn)可能反應(yīng)了傳導(dǎo)阻滯和軸突損害的致病機(jī)制，并為探究MMN免疫和電生理特性提供線索。在抗體介導(dǎo)的多神經(jīng)病實(shí)驗(yàn)?zāi)Ｐ椭校种瓶贵w和抑制補(bǔ)體的藥物能阻止神經(jīng)節(jié)苷脂特異性抗體的致病性。事實(shí)上，靜注人免疫球蛋白治療MMN可能通過(guò)抑制抗GM1 IgM介導(dǎo)的補(bǔ)體沉積以及誘導(dǎo)經(jīng)典途徑功能來(lái)發(fā)揮作用。

GM1 IgM 抗體是先天免疫系統(tǒng)的一部分，或許可以解釋MMN的GM1 IgM 抗體滴度低時(shí)缺乏特異性的原因。GM1特異性B細(xì)胞活化可解釋抗體滴度升高的原因，但其根本機(jī)制仍有待澄清。

GBS的抗GM1抗體與微生物感染有關(guān)-最常見(jiàn)的是空腸彎曲菌，起病前數(shù)天到數(shù)周其表面表達(dá)神經(jīng)節(jié)苷脂類似結(jié)構(gòu)?？漳c彎曲菌感染可導(dǎo)致GM1特異B細(xì)胞活化，抗GM1抗體滴度升高，這一過(guò)程稱為分子模擬。但一些小規(guī)模血清學(xué)研究未發(fā)現(xiàn)與MMN有相關(guān)性。

意義不明的單克隆IgM丙種球蛋白癥也可升高GM1特異性IgM的滴度，提示內(nèi)源性B細(xì)胞克隆改變可能是MMN的病理基礎(chǔ)。實(shí)際上，在MMN患者中，IgM單克隆丙種球蛋白癥出現(xiàn)頻率似乎高于同年齡的健康對(duì)照組（6%比2%）?？傊漳c彎曲菌感染和癥狀出現(xiàn)前的B細(xì)胞改變似乎不能解釋大多數(shù)MMN患者抗GM1 IgM滴度升高的原因，意味著MMN還有其他機(jī)制可促使B細(xì)胞活化。

抗GM1-IgM抗體陽(yáng)性的MMN患者和抗GM1-IgM抗體陰性的MMN患者具有相似的臨床特點(diǎn)；這一發(fā)現(xiàn)意味著GM1-IgM抗體陰性的多灶性運(yùn)動(dòng)神經(jīng)病患者的血清中含有某種抗體，這種抗體針對(duì)一種尚未發(fā)現(xiàn)的抗原，而這種尚未發(fā)現(xiàn)的抗原和GM1具有相似的功能或解剖分布。一些候選抗原已被確定。在其它炎性神經(jīng)病變中，血清對(duì)神經(jīng)節(jié)苷脂組成的免疫復(fù)合物具有反應(yīng)性已有報(bào)道，但在MMN尚無(wú)報(bào)道。有研究發(fā)現(xiàn)，MMN患者血清中的IgM結(jié)合于GM1、半乳糖和膽固醇的混合物上。這種結(jié)合于GM1與脂質(zhì)上相互依賴的抗體可以部分解釋抗神經(jīng)節(jié)苷脂抗體陰性的MMN患者的病因。近來(lái)硫酸肝素糖被認(rèn)為是一種潛在于運(yùn)動(dòng)神經(jīng)病患者體內(nèi)的抗原。這些結(jié)果尚需進(jìn)一步證實(shí)，以使我們了解它們?cè)贛MN中的臨床意義。

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.

其它自身免疫特點(diǎn)

MMN是否是一種典型的自身免疫性疾病尚未確定。許多自身免疫性疾病與特定的HLA 等位基因相關(guān)。HLA系統(tǒng)對(duì)特定的肽抗原提呈給T淋巴細(xì)胞是至關(guān)重要的，而且特定的單倍型HLA可促進(jìn)自反應(yīng)性淋巴細(xì)胞的活化。在荷蘭MMN患者中，單倍型HLADRB1* 15出現(xiàn)的頻率較高，類似于其與多發(fā)性硬化的相關(guān)性。然而，肽作為自身抗原參與MMN的證據(jù)尚不足， HLA如何參與MMN的發(fā)病，機(jī)制目前還不清楚。其他自身免疫性疾病合并MMN的患者，發(fā)病率上升進(jìn)一步支持該病的自身免疫機(jī)制。然而，有調(diào)查結(jié)果不支持MMN的自身免疫機(jī)制，尤其是：男性發(fā)病率高于女性，皮質(zhì)類固醇治療效果差，以及鮮有病例因缺乏基因單核苷酸多態(tài)性而易患B細(xì)胞介導(dǎo)的自身免疫疾病的證據(jù)。

未完待續(xù) ，

明天刊出最后部分（4-4）