Mechanisms of autoantibody production in myasthenia gravis

 描述(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的病理归因于乙酰胆碱受体(AChR)自身抗体的存在，该抗体针对神经肌肉接头处的AChR。许多患者仍然对目前的治疗方法难以耐受或有无法忍受的不良反应；因此，需要另一种治疗MG的药物。最近的几项研究，包括我们小组进行的一项研究，已经证明了通过利妥昔单抗治疗重症肌无力患者B细胞耗竭的好处。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，评估利妥昔单抗治疗MG的疗效。我们独家与这项试验合作，第一，我们可以提高对B细胞耗竭在MG中的作用机制的理解，第二，我们可以解决关于人类自身免疫的基本问题。正在为我们的工作收集治疗前、治疗期间和治疗后的标本。这项研究为研究药物和疾病机制提供了一个独特的机会，因为与使用利妥昔单抗的许多其他自身免疫性疾病不同，MG提供了直接参与疾病免疫病理的抗原特异性成分的研究。我们的机制研究将检验这样一种假设，即临床受益的潜在机制涉及T细胞依赖的、自身反应性记忆B细胞的储存库，该B细胞提供一群抗体分泌细胞，并且对MG自身抗体的产生至关重要。利妥昔单抗消除了这种记忆B细胞的储存库；然后重塑新形成的B细胞隔间，从而减少自身抗体的产生。为了验证这一假设，我们开发/应用了检测B细胞耐受性缺陷的方法，描述了产生MG自身抗体的B细胞亚群和B细胞亚群，并表征了抗原特异性T细胞。这项工作将进一步加深我们对MG免疫病理学的理解，并代表着朝着更完整地了解利妥昔单抗治疗B细胞介导的自身免疫性疾病的免疫机制迈出的第一步。这项建议与人类疾病直接相关，并与国家卫生研究院的使命明确一致和相关。也就是说，这项转译研究的重点是利用人类来源的细胞研究人类疾病。此外，研究MG的重要性因其作为抗体介导性疾病的模型而被放大。创新的新技术，如下一代测序和抗原特异性T细胞分析，将被应用于回答基本问题。本研究旨在阐明免疫成分在MG发病中的作用，即B细胞和T细胞的作用，包括对自身免疫的基本机制，即B细胞耐受和T细胞致病表型的研究。通过研究MG细胞介导的免疫学，我们将进一步定义引发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.