NATURE REVIEWS | NEUROLOGY
doi:10.1038/nrneurol.2016.44
Published online 22 Apr 2016
（中英）重症肌無力的
自身抗體特性及其對治療的啟示（一）
Abstract 摘要
Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that target the neuromuscular junction, leading to muscle weakness and fatigability. Currently available treatments for the disease include symptomatic pharmacological treatment, immunomodulatory drugs, plasma exchange, thymectomy and supportive therapies. Different autoantibody patterns and clinical manifestations characterize different subgroups of the disease: early-onset MG, late-onset MG, thymoma MG, muscle-specific kinase MG, low-density lipoprotein receptor-related protein 4 MG, seronegative MG, and ocular MG. These subtypes differ in terms of clinical characteristics, disease pathogenesis, prognosis and response to therapies. Patients would, therefore, benefit from treatment that is tailored to their disease subgroup, as well as other possible disease biomarkers, such as antibodies against cytoplasmic muscle proteins. Here, we discuss the different MG subtypes, the sensitivity and specificity of the various antibodies involved in MG for distinguishing between these subtypes, and the value of antibody assays in guiding optimal therapy. An understanding of these elements should be useful in determining how to adapt existing therapies to the requirements of each patient.
重症肌無力是一種由自身抗體引起的自身免疫性疾病，其以神經肌肉接頭為靶點，導致肌無力和肌疲勞。近來對此疾病的治療方法包括藥物對症治療、免疫調節劑、血漿置換、胸腺切除術及支持療法等。通過不同的自身抗體和臨床表現可以將此疾病分為不同亞型：早髮型MG、遲髮型MG、胸腺瘤型MG、肌特異性激酶型MG、低密度脂蛋白受體相關蛋白4的MG、血清陰性型MG、眼肌型MG。這些亞型以臨床特徵，發病機制，預後，及其對治療的反應而分類。因此，依據不同病人各自疾病亞型及其他可能的疾病生物學標記如抗細胞質肌蛋白抗體，實施對應的治療方案，病人可能獲益更多。這裡，我們討論不同的MG亞型，MG相關抗體的對應檢測方法的敏感度和特異度，以及這些抗體檢測結果用於指導最佳治療方案的價值。理解這些因素有助於判定如何在現有治療方案中選擇對每個MG病人最合理的治療。
Key points 要 點
The characteristic muscle weakness in myasthenia gravis (MG) is caused by antibodies directed against the neuromuscular junction
MG is divided into subgroups on the basis of specific antibodies, other biomarkers, and clinical characteristics, such as age of onset, presence of thymoma, and involvement of ocular muscles
The most common antibodies detected in MG are antibodies against acetylcholine receptors (AChRs), muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4)
Additional antibodies of interest in MG are directed against agrin, titin, KV1.4, ryanodine receptors, collagen Q, and cortactin
Therapy should be tailored to the individual patient and guided by MG subgroup, and can include symptomatic drug therapy, immunosuppressive drug therapy, thymectomy and/or supportive therapy
The aim of treatment should be normal or near-normal function, which in most patients requires long-term immunosuppressive treatment with a drug combination that is individualized for the patient for optimal effectiveness
重症肌無力（MG）的肌無力症狀是因為抗體直接對抗神經肌肉接點作用所致。
基於抗體特異性，其他生物學標記以及如發病年齡、胸腺瘤、眼部肌肉是否受累等臨床特點，MG可以被分為不同亞組。
MG常見的抗體包括AChR抗體、MuSK抗體和LRP4抗體。
其他MG相關的抗體包括聚集蛋白抗體、肌聯蛋白抗體、KV1.4抗體、Ryanodine受體抗體、膠原蛋白Q抗體以及皮動蛋白抗體。
針對MG的治療方案應該立足於個體化並且依據MG亞組，包括針對症狀的藥物療法、免疫抑制藥物療法、胸腺切除術及視情況使用的支持療法。
治療的目的是使功能恢復正常或者接近正常，大多數病人需要個體化長期藥物聯合的免疫抑制治療以達到最優療效。
Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies targeting the neuromuscular junction. In MG, these antibodies bind to the postsynaptic muscle end-plate and attack and destroy postsynaptic molecules. This process leads to impaired signal transduction and, consequently, muscle weakness and fatigability —— the hallmark symptoms of MG1–4. The weakness can be focal or generalized, and usually affects ocular, bulbar and proximal extremity muscles. Respiratory muscle weakness develops only rarely, but can be life-threatening. Weakness is typically symmetrical, except in affected external eye muscles, in which the weakness is usually asymmetrical1–4.
重症肌無力系作用於自身神經肌肉接頭的抗體所引起的一種自身免疫性疾病。抗體結合於突觸後肌終板上，攻擊和損害突觸後分子。這一過程會損害（乙醯膽鹼）信號傳導並最終導致肌無力和肌疲勞——這是重症肌無力的標誌性特徵1–4。上述肌無力可累及局部或全身骨骼肌，並常常影響眼部，延髓節段支配區及肢體近端的肌肉。呼吸肌無力很少見，但若出現常可威脅生命。這種肌無力的分布通常很對稱，但眼部受累的肌無力除外，因後者往往是非對稱性的。
In most populations, the prevalence of MG is 150–300 per 1,000,000 individuals, with an annual incidence of more than 10 in 1,000,000 people5,6. Both prevalence and incidence increase with age. With modern treatment, MG should not increase mortality7. Therapeutic options in MG include symptomatic pharmacological treatment, immunomodulatory pharmacological treatment, plasma exchange, thymectomy and supportive treatment4,8. The treatment should be tailored to the individual patient depending on their MG subgroup, which can be defined on the basis of biomarkers and clinical characteristics. Immunosuppressive therapy can lead to rapid improvement even when the disease is in a chronic phase, as the synthesis of postsynaptic molecules is continuously increased in MG to counteract the destruction of molecules by autoantibodies. However, well-controlled therapeutic studies in MG are rare, and have not taken into account variability between MG subgroups. Recommendations for clinical management, therefore, rely partly on consented guidelines and expert reviews.
重症肌無力的患病率是150-300/1,000,000，年發病率大於10/1,000,0005,6。其患病率和發病率都隨著年齡增加而增加。隨著現代治療方法的應用，MG的死亡率沒有再增加7。MG治療方法的選擇包括藥物對症治療、免疫調節藥物治療、血漿置換、胸腺切除術及支持療法4，8。這些治療方法的選擇依據為患者的MG亞型，而這些亞型分類又是以不同的生物學標記和臨床特徵為基礎的。免疫抑制療法可能會使疾病迅速好轉----即使疾病處於慢性期。這是由於在MG中，突觸後分子的生成是持續增加的，而增加量與自身抗體導致的分子破壞量相抵消。然而很少能夠看到隨機對照性MG的治療研究證據，而且現有研究往往未考慮到MG亞型之間的療效差異。因此MG臨床治療的推薦意見在一定程度上依賴於臨床共識和專家綜述意見。
Autoantibodies against proteins in the postsynaptic membrane are the most important biomarkers in guiding diagnosis of MG (BOX 1) and helping to define which MG subtype a patient has. Moreover, an improved understanding of the autoantibody-associated pathophysiology in MG could facilitate therapeutic decision-making. In this Review, we discuss the antibodies involved in MG pathogenesis, sensitivity and specificity of various antibody assays, as well as the value of these assays in guiding optimal therapy.
突觸後膜的自身抗體是診斷MG最為重要的生物學標記（框1），其有助於明確病人到底是哪種亞型的MG。此外，對於MG自身抗體相關病理生理的深入理解有助於臨床治療決策。在這篇綜述中，我們討論了MG的相關抗體，其對應檢測方法的敏感度和特異度，以及這些抗體檢測結果用於指導最佳治療方案的價值。
The sensitivity and specificity of the diagnostic rely on the quality of the investigation. The response (or lack thereof) to pharmacological treatment with anticholinesterase drugs also has diagnostic value.
框1 重症肌無力的鑑別診斷
MG需要同其他神經肌肉疾病相鑑別，比如：
遺傳毒性肌無力症候群
蘭伯特-伊頓症候群（癌性肌無力）
神經性肌強直
吉蘭-巴雷症候群
出現肌肉無力症狀並且抗AChR或者MuSK抗體陽性的病人，不需要其他的檢測便可以明確診斷為MG。沒有檢測出抗體的病人需要進一步做神經電生理的檢測。包括：
診斷的準確性依賴於檢測技術的可靠性。對抗膽鹼酯酶藥物的治療反應同樣具有診斷價值。
Autoantibodies in myasthenia gravis
重症肌無力的自身抗體
MG serves as a prototypical antibody-mediated disease because the physiological function, antigenic targets, and immune responses to autoantibodies at the neuromuscular junction are well understood (FIG. 1a). The major antigen in MG is the acetylcholine receptor (AChR) on the muscle membrane1–4. Some patients without AChR antibodies have autoantibodies against the muscle specific kinase (MuSK), a protein responsible for AChR clustering and maintenance of the neuromuscular junction4,9. A fraction of patients with MG who do not have either AChR or MuSK antibodies have antibodies against low-density lipoprotein receptor-related protein 4 (LRP4), a receptor for neural agrin that relays the signal to MuSK to initiate AChR clustering4,10. Patients without detectable antibodies against any of these three antigens are referred to as seronegative. Some patients with MG also have antibodies against cytoplasmic muscle proteins; although these antibodies are not pathogenic, they can serve as disease markers11–14.
MG是一種典型的抗體介導的自身免疫疾病，這從已明確的神經肌肉接頭的生理功能，MG對應的抗原靶點以及針對自身抗體的免疫應答過程可以看出來（圖1a）。MG的主要抗原是在肌膜上的乙醯膽鹼受體（AChR）1-4。一些沒有AChR抗體的病人卻有抗肌特異性激酶（MuSK）的抗體，後者的主要作用是負責AChR的聚集並且維護神經肌肉接點4,9。一部分既沒有AChR抗體也沒有MuSK抗體的MG病人可以檢測出抗低密度脂蛋白受體相關蛋白4（LRP4）抗體，LRP4是一種中繼MuSK信號引起AChR聚集的神經源性聚集蛋白受體4,10。沒有檢測出任何針對這三種抗體的病人被稱為血清學標誌陰性。一些MG病人同樣伴有抗細胞質肌蛋白抗體；雖然這種抗體不具有致病性，但其可以作為一種疾病的指徵11-14。
圖1 MG中的神經肌肉接點。a神經肌肉接點的正常功能以及MG相關的主要組件。突觸前膜神經末梢的動作電位引起電壓依賴的鈣離子通道的開放，觸發乙醯膽鹼和聚集蛋白向突觸間隙釋放。乙醯膽鹼與AChR結合促進鈉通道的開放，反過來觸發肌肉收縮。聚集蛋白與LRP4和MuSK組成的複合體結合引起AChR的聚集，這個過程對於神經肌肉接點的突觸後形態的維持至關重要。b AChR抗體在MG中主要的致病機制包括神經肌肉接點處補體的激活引起肌膜上攻膜複合體的形成並且破壞了典型的肌纖維膜摺疊（1）；抗原調節導致膜表面的AChR的內化和退化（2）；以及AChR抗體與AChR的配基結合位點結合（3），這種結合可以直接阻滯乙醯膽鹼的結合從而阻滯通道開放。抗MuSK以及抗LRP4抗體已經被證實分別阻滯MuSK和LRP4分子間的相互作用，並且因此破壞神經肌肉接點正常結構完整性和連接功能（4）。已知MG相關的致病抗體用紅色標出。c 通過增加乙醯膽鹼的水平改善信號傳導或者降低自身抗體的濃度（免疫抑制藥物，血漿置換/免疫吸附，B細胞靶向治療；紅色），MG的治療方法可以恢復神經肌肉接點的功能（膽鹼酯酶抑制劑；綠色），緩解（b）中所述的致病機制。Kv1.4，電壓門控鉀通道1.4；RyR，ryanodine受體。
（未完待續）
編輯：李會琪
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