Mechanisms of autoimmunity in myasthenia gravis

项目摘要。重症肌无力(MG)是一种影响神经肌肉传递的自身免疫性疾病。 MG患者患有严重的肌肉无力和肌肉疲劳性增加，原因是肌肉疲劳减少 神经肌肉信号。MG是由针对神经肌肉连接部分的自身抗体引起的 (NMJ)；在大多数患者中，这是烟碱型乙酰胆碱受体(AChR)。这些AChR自身抗体介导 病理通过三种机制：(I)干扰乙酰胆碱对接，(Ii)AChR内化， 以及(Iii)激活经典的补体级联，导致组织损伤。内部存在异质性 AChR疾病亚型，包括早发性和晚发性MG(EOMG和LOMG)，其基础是 发病年龄、性别和人类白细胞抗原相关性。 尽管不同亚型的MG患者有相似的疾病表现，但潜在的 免疫病理学可能是不同的。AChR、EOMG和LOMG亚型很好地说明了这一点。值得注意的是， EOMG的特征是胸腺淋巴细胞浸润，其中包括AChR特异性的免疫球蛋白G、T细胞和B细胞 (包括AChR自身抗体产生者)，组织为第三级淋巴器官，类似生发 中锋。相比之下，LOMG很少包括胸腺异常。而异质的细节 缺乏免疫病理学，但对这些差异背后的机制的深入了解是非常重要的 对病人和临床医生都很重要。这是因为预计在一次治疗中效果很好的治疗方法 亚型可能没有用于其他亚型的生物学基础(S)。无反应的AChR MG患者 最近的一些临床试验，包括B细胞耗竭和补体抑制疗法，清楚地突出了 我们知识上的这个鸿沟。 因此，在这个更新期，我们将研究不同的免疫机制的细节 EOMG和LONG MG亚型。我们的研究主要集中在直接导致疾病的B细胞上 病理学，产生AChR自身抗体的疾病。使用新的方法，我们将分离出这些罕见的AChR 从胸腺组织和血液中产生B细胞的自身抗体，并确定其谱系特征。人类 然后，这些B细胞将产生重组单抗(MAb)，从而使分子 病理机制可以用一套新的分析方法来确定它们影响病理的能力 通过补体导向的组织损伤、阻断或调节。最后，我们将定义 产生自身抗体的B细胞亚群和辅助性T细胞亚群，包括针对AChR抗原的那些。 这项研究旨在为自身抗原特异性免疫细胞的作用提供详细的见解 自身抗体用于促进EOMG和LOMG病理的亚群和分子机制 子类型。这些明确定义的免疫机制有望通过以下途径影响治疗结果 告知用于治疗特定MG疾病亚型的生物疗法的应用。

Project Summary. Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. MG patients suffer from severe muscle weakness and increased muscle fatigability due to diminished neuromuscular signaling. MG is caused by autoantibodies that target components of the neuromuscular junction (NMJ); in most patients this is the nicotinic acetylcholine receptor (AChR). These AChR autoantibodies mediate pathology through three mechanisms: (i) interfering with acetylcholine docking, (ii) internalization of the AChR, and (iii) activation of the classical complement cascade leading to tissue damage. There is heterogeneity within the AChR disease subtype that includes early-onset and late-onset MG (EOMG and LOMG), which is based on age of onset, sex, and HLA-association. Although MG patients with different subtypes share similar disease presentations, the underlying immunopathology may be distinct. This is well Illustrated by the AChR EOMG and LOMG subtypes. Notably, EOMG is characterized by a thymic lymphocytic infiltrate, which includes AChR-specific IgG, T cells, and B cells (including AChR autoantibody-producers) that organize as tertiary lymphoid organs, resembling germinal centers. In contrast, LOMG rarely includes thymic abnormalities. While details of the heterogenous immunopathology are lacking, a deeper understanding of the mechanisms underlying the differences is highly important for both the patient and clinician. This is because treatments that are anticipated to work well in one subtype may not have a biological basis for use in the other subtype(s). Non-responding AChR MG patients in a number of recent clinical trials, including B cell depletion, and complement inhibition therapies, clearly highlight this gap in our knowledge. Thus, in this renewal period we will investigate details of the divergent immunomechanisms underlying the EOMG and LOMG MG subtypes. Our study is sharply focused on the B cells that directly contribute to disease pathology, those which produce AChR autoantibodies. Using new approaches, we will isolate these rare AChR autoantibody producing B cells from thymus tissue and blood and define their repertoire characteristics. Human recombinant monoclonal antibodies (mAb) will then be produced from these B cells so that molecular mechanisms of pathology can be defined using a suite of novel assays to identify their ability to affect pathology through complement-directed tissue damage, blocking, or modulation. Finally, we will define the phenotypes of autoantibody-producing B cell subsets and T helper cell subsets including those specific for the AChR antigen. This study is designed to provide detailed insights into both the role of autoantigen-specific immune cell subsets and molecular mechanisms used by autoantibodies to facilitate the pathology of the EOMG and LOMG subtypes. These clearly defined immunomechanisms are expected to impact treatment outcomes through informing application of biological therapeutics used to treat specific MG disease subsets.