Mechanisms of autoantibody production in myasthenia gravis

 描述（由申请人提供）：重症肌无力（MG）是一种神经肌肉传递的自身免疫性疾病。MG病理学归因于乙酰胆碱受体（AChR）自身抗体的存在，其靶向神经肌肉接头处的AChR。许多患者仍然是医学难治性的或对目前的治疗有不可耐受的不良反应;因此，需要另一种药物来管理MG。最近的几项研究，包括我们小组的一项研究，已经证明了MG患者通过利妥昔单抗治疗消除B细胞的益处。NINDS-NeuroNEXT正在进行一项多中心、随机、双盲、安慰剂对照的II期临床试验，评估利妥昔单抗对MG的治疗效果。我们与这项试验独家合作，这样我们可以首先提高对MG中B细胞耗竭作用机制的理解，其次，可以解决有关人类自身免疫的基本问题。我们正在收集治疗前、治疗中和治疗后的标本。这项研究提供了一个独特的机会，研究药物和疾病的机制，因为不像许多其他自身免疫性疾病，其中利妥昔单抗已被使用，MG提供了抗原特异性成分，直接参与疾病的免疫病理学的调查。我们的机制研究将检验这一假设，即临床获益的潜在机制涉及T细胞依赖性自身反应性记忆B细胞库，这些细胞提供抗体分泌细胞群，对MG自身抗体产生至关重要。利妥昔单抗消除了记忆B细胞的储存库;然后重新塑造新形成的B细胞区室，从而减少自身抗体的产生。为了检验这一假设，我们开发/应用了测定B细胞耐受性缺陷的方法，描述了产生MG自身抗体的B细胞区室和B细胞亚群的库，并表征了抗原特异性T细胞。这项工作将进一步我们的MG免疫病理学的理解，它代表了第一步获得更完整的理解的免疫机制的基础上治疗B细胞介导的自身免疫性疾病与利妥昔单抗。该提案与人类疾病直接相关，并且与NIH的使命明确一致和相关。也就是说，这项转化研究的重点是用人源性细胞研究人类疾病。此外，研究MG的重要性被其作为抗体介导的疾病的模型的服务放大。创新的新技术，如下一代测序和抗原特异性T细胞检测将被应用于回答基本问题。该研究旨在阐明MG中主要免疫组分的致病作用，即B和T细胞的贡献，包括基本自身免疫机制的研究，即B细胞耐受性和T细胞致病表型。通过研究MG细胞介导的免疫学，我们将进一步确定启动和传播这种疾病的事件，这将为了解自身免疫性疾病的机制提供基本的见解。

 DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission. MG pathology is attributed to the presence of acetylcholine receptor (AChR) autoantibodies, which target the AChR at the neuromuscular junction. Many patients remain medically refractory or have intolerable adverse effects to current therapies; thus, another agent for the management of MG is needed. Several recent studies, including one performed by our group, have demonstrated the benefits of B cell depletion via rituximab treatment in MG patients. The NINDS-NeuroNEXT is conducting a multicenter randomized, double blind, placebo controlled Phase II clinical trial evaluating the therapeutic effect of rituximab for MG. We have exclusively partnered with this trial so that we can first, improve the understanding of the mechanism of action of B cell depletion in MG and second, so that fundamental questions regarding human autoimmunity can be addressed. Specimens prior to, during and after treatment are under collection for our work. This study presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that directly participate in the immunopathology of the disease. Our mechanistic studies will test the hypothesis that the mechanism underlying clinical benefit involves a reservoir of T cell-dependent, autoreactive memory B cells that supply a population of antibody secreting cells and is critical to MG autoantibody production. Rituximab eliminates this reservoir of memory B cells; then the newly formed B cell compartment is reshaped such that autoantibody production is diminished. To test this hypothesis, we have developed/applied assays to measure B cell tolerance defects, describe the repertoire of the B cell compartments and the B cell subsets that produce MG autoantibodies and characterize the antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying the treatment of B cell-mediated autoimmune diseases with rituximab. This proposal is directly relevant to the human disease and is in clear alignment and relevance to the mission of the NIH. That is, this translational research focuses on studying the human disease with human-derived cells. Furthermore, the importance of studying MG is magnified by its service as a model for antibody-mediated disease. Innovative, novel technology such as next generation sequencing and antigen-specific T cell assays will be applied to answer fundamental questions. The study is designed to elucidate the pathogenic role of major immunological components in MG, that is the contribution of B and T cells, including an investigation of fundamental autoimmune mechanisms, namely B cell tolerance and T cell pathogenic phenotypes. Through studying MG cell-mediated immunology we will further define the events that both initiate and propagate this disease that will provide fundamental insight into the mechanisms of autoimmune disease.