重症肌无力症状持续或缓解后复发的机制及其标志物探查

Myasthenia gravis (MG) is one of the most common autoimmune neurological diseases affecting the neuromuscular junction. Although there are many therapeutic methods leading to marked symptomatic improvement in majority of MG patients, there are many cases who still experience fluctuating muscle weakness and fatigability to some degree, or develop myasthenic crisis even after a clinical remission. Thus, it is very imperative for clinicians to develop more effective methods to better control the symptoms and to obtain a more satisfactory life and work quality. It is well known that viral, bacterial, or fungal infection or occult infection constitutes the most common predisposing factor for symptomatic exacerbation or myasthenic crisis, but unfortunately the kinds of infecting germs and the detailed mechanisms causing exacerbation of MG symptoms are not known yet. Based on the reports and our studies, we suppose that the heterogneity of immunological pathogenesis may be the crucial reason for the differences in treatment effectiveness in individual MG patients. More importantly, the long-living antigen-specific autoreactive T cells in the peripheral immune system are being hypothesized to be the key pathogenic step in maintaining the dysfunctional immunity, which could be triggered by recurrent reactivating autoreactive T cells. Infecting pathogens (peptides) are hypothesized to activate the autoreative T cells to proliferate and secrete cytokines through molecular mimicry or imbalanced cytokines. Thymectomy is a commonly used clinical method to delete the origin of the autoreactive T cells, but cohorts of studies demonstrated that the numbers and proportion of circulating pathogenic T cells in the peripheral lymphocytes in MG patients are not significantly affected after thymectomy. In order to test our hypotheses that the thymus-originated autoreactive T cells will early immigrate to the peripheral immune system to dwell and those T cells will be re-activated by many ways such as infecting peptides to further trigger down-stream autoimmunity, we plan to compare the pattern of seral cytokines, the biological behavior of the circulating autoreactive T cells, the immunological features of the thymus, and the potential role of infecting antigens in re-activating autoreactive T cells, in MG patients with different clinical types and in the healthy controls. In addition, the autoreactive T cells will be passively transferred to severe combined immunodeficient mice to generate experimental autoimmune myasthenia gravis model, to further demonstrate the pathogenic characters of the T cells. The expected results are to confirm that the behavior of the antigen-specific autoreactive T cells could be a reliable marker for MG activity and for monitoring effectiveness of immunotherapy.

重症肌无力（MG）是神经系统较常见的自身免疫性疾病，虽大部分患者对治疗有较好反应，但仍有许多患者的症状持续存在或反复发作而严重影响患者生活质量甚至发生肌无力危象而危及生命，解决这一难题是临床科研工作者的首要任务。临床证据表明细菌、病毒或其他微生物感染往往是症状加重、复发或诱发危象的重要原因，但其机制不明。我们认为MG个体的免疫异质性可能是导致疗效差异的主要原因，自身反应性T细胞在外周淋巴器官中长期存在并被反复激活是MG免疫异常维持的机制。还认为感染通过释放细胞因子或分子模拟等机制重新活化自身反应性T细胞而导致症状复发或恶化。尽管胸腺切除在一定程度上减少了自身反应性T细胞的数量或来源，但仍难清除循环性致病性T细胞。本项目拟通过比较研究不同临床类型MG患者及对照者血清、外周循环T淋巴细的生物学行为、胸腺的免疫学特征和感染的作用等，来验证自身反应性T细胞的长期存在和反复活化是MG经久不愈的机制。

我们建立了MG患者的组织库和信息库，在评价不同MG患者亚分类的临床和免疫学特征的同时，通过比较研究不同临床类型的MG患者和对照组血清、外周循环T淋巴细胞的生物学行为、胸腺的免疫学特征和感染的作用等，以及建立了SCID小鼠T细胞被动转移EAMG模型，初步验证了自身反应性T细胞的长期存在和反复活化是导致MG症状持续或缓解后复发的重要原因。尽管临床认为感染是导致MG症状复发或恶化的重要原因之一，但本项目目前尚未发现与MG感染直接相关病原体，即任何病原体感染均可能通过活化致病性T细胞而触发免疫反应导致症状复发。在寻找MG疾病活动度的客观指标中，我们发现活化的自身反应性T淋巴细胞、AChR-ab水平及多种细胞因子浓度均与MG病情严重程度有关。通过以上研究内容及已获取的结果，我们证实了活化的自身反应性T细胞是MG个体免疫异质性的重要因素，也是临床MG病情变化及患者疗效差异的重要监测指标，在MG症状持续或缓解后复发中起着重要作用。通过控制感染、抑制T细胞增殖活化、降低一些细胞因子浓度及胸腺切除等均是治疗MG的有效手段。