Wu Xiaorong, Tüzün Erdem
Department of Ophthalmology, First Affiliated Hospital, Nanchang University, Nanchang 330006, PR China.
Department of Neuroscience, Institute for Experimental Medical Research, Istanbul University, Istanbul 34390, Turkey.
Med Hypotheses. 2017 Feb;99:26-28. doi: 10.1016/j.mehy.2016.11.021. Epub 2016 Dec 16.
Extraocular muscle weakness occurs in most of the myasthenia gravis (MG) patients and it is often the initial complaint. Approximately 10-20% of MG patients with extraocular muscle weakness display only ocular symptoms and rest of the patients subsequently develop generalized muscle weakness. It is not entirely clear why some MG patients develop only ocular symptoms and why extraocular muscle weakness almost always precedes generalized muscle weakness. These facts are often explained by increased susceptibility of extraocular muscles due to their reduced endplate safety factor and lower complement inhibitor expression. Findings of a recently developed animal model of ocular MG suggest that additional factors might be in play. While immunization of HLA transgenic and wild-type (WT) mice with the native acetylcholine receptor (AChR) pentamer carrying conformational epitopes generates severe generalized muscle weakness, immunization of the same mouse strains with recombinant unfolded AChR subunits containing linear epitopes induces ptosis with or without mild generalized muscle weakness. Notably, immunization of mice with deficient T helper cell-mediated antigen presentation with recombinant AChR subunits or whole native AChR pentamer also induces ocular symptoms, AChR-reactive B cells and AChR antibodies. Based on these findings, we hypothesize that ocular symptoms observed in the earlier stages of MG might be triggered by linear and non-conformational AChR epitopes expressed by thymic cells or invading microorganisms. This initial AChR autoimmunity might be managed by T cell-independent and B cell mediated mechanisms yielding low affinity AChR antibodies. These antibodies are putatively capable of inducing muscle weakness only in extraocular muscles which have increased vulnerability due to their inherent biological properties. After this initial attack, as AChR bearing immune complexes form and the immune system gains access to the native AChR expressed by muscle and thymic myoid cells, a more robust anti-AChR autoimmunity develops giving way to high affinity AChR antibodies, thymic germinal center formation and severe generalized muscle weakness. Accurate characterization of chain if events leading to ocular and generalized symptoms in MG might enable development of novel therapeutics that might prevent the transition from mild ocular symptoms to severe generalized weakness in earlier stages of the disease.
眼外肌无力在大多数重症肌无力（MG）患者中都会出现，且常常是首发症状。约10%-20%有眼外肌无力的MG患者仅表现出眼部症状，其余患者随后会出现全身肌无力。目前尚不完全清楚为何有些MG患者仅出现眼部症状，以及为何眼外肌无力几乎总是先于全身肌无力出现。这些现象通常被解释为眼外肌终板安全系数降低和补体抑制因子表达较低，从而导致其易感性增加。最近建立的眼肌型MG动物模型的研究结果表明，可能还有其他因素在起作用。用携带构象表位的天然乙酰胆碱受体（AChR）五聚体免疫HLA转基因小鼠和野生型（WT）小鼠会导致严重的全身肌无力，而用含有线性表位的重组未折叠AChR亚基免疫相同品系的小鼠则会诱发上睑下垂，伴有或不伴有轻度全身肌无力。值得注意的是，用重组AChR亚基或完整天然AChR五聚体免疫缺乏T辅助细胞介导的抗原呈递的小鼠，也会诱发眼部症状、AChR反应性B细胞和AChR抗体。基于这些发现，我们推测MG早期出现的眼部症状可能是由胸腺细胞或入侵微生物表达的线性和非构象性AChR表位触发的。这种初始的AChR自身免疫可能由T细胞非依赖性和B细胞介导的机制控制，产生低亲和力的AChR抗体。这些抗体可能仅能在因固有生物学特性而更易受损的眼外肌中诱发肌无力。在这一初始攻击之后，随着携带AChR的免疫复合物形成，免疫系统接触到肌肉和胸腺肌样细胞表达的天然AChR，会发展出更强有力的抗AChR自身免疫，进而产生高亲和力的AChR抗体、胸腺生发中心形成以及严重的全身肌无力。准确描述导致MG眼部和全身症状的连锁事件，可能有助于开发新的治疗方法，从而在疾病早期阶段预防从轻度眼部症状转变为严重的全身肌无力。
