Mechanisms of autoantibody production in myasthenia gravis

重症肌无力自身抗体产生机制

• 批准号: 9026120
• 负责人: Kevin C O'connor
• 金额: $ 10.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-04 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026120
• 关键词: Address; Adverse effects; Affect; Aftercare; Antibodies; Antibody Repertoire; Antigen Presentation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell repertoire; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Cellular Immunity; Characteristics; Cholinergic Receptors; Chronic; Clinical; Clinical Trials; Collection; Controlled Clinical Trials; Coupled; Data; Defect; Disease; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Exhibits; Feeds; Frequencies; Functional disorder; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Immune; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunotherapy; Inflammatory; Interferon Type II; Interleukin-10; Interleukin-17; Investigation; Life; Link; Maps; Mature B-Lymphocyte; Measures; Mediating; Mediator of activation protein; Memory; Memory B-Lymphocyte; Methods; Mission; Modeling; Monitor; Myasthenia Gravis; National Institute of Neurological Disorders and Stroke; Neuromuscular Junction; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Placebo Control; Play; Population; Process; Production; Randomized; Recombinants; Refractory; Role; Services; Specimen; Staining method; Stains; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Effect; Translational Research; United States National Institutes of Health; Work; autoreactive B cell; autoreactive T cell; base; central tolerance; cytokine; design; effective therapy; experience; human disease; immunopathology; improved; ineffective therapies; innovation; insight; nervous system disorder; neuromuscular transmission; new technology; next generation; next generation sequencing; novel; peripheral tolerance; programs; prospective; public health relevance; rituximab; targeted treatment

 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.

 描述（由适用提供）：肌无力重症（MG）是神经肌肉传播的自身免疫性疾病。 Mg病理归因于乙酰胆碱受体（ACHR）自身抗体的存在，该自身抗体的靶向ACHR在神经肌肉连接处。许多患者在医学上保持难治性或对当前疗法产生抗衰果的影响。因此，需要另一个用于MG管理的代理。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在MG患者中通过利妥昔单抗治疗的益处。 Ninds-Neuronext正在进行多中心随机，双盲，安慰剂控制的II期临床试验，评估利妥昔单抗对MG的治疗作用。我们已经专门与该试验合作，以便我们首先可以提高对B细胞部署在MG和第二的作用机理的理解，以便可以解决有关人自身免疫性的基本问题。在我们工作之前，期间和治疗后的样本都在收集我们的工作中。这项研究提供了研究药物和疾病机制的独特机会，因为与许多其他使用利妥昔单抗的自身免疫性疾病不同，MG提供了直接参与该疾病免疫病理学的抗原特异性成分的投资。我们的机械研究将检验以下假设：临床益处的基本机制涉及T细胞依赖性的自动反应性记忆B细胞的储层，该储量提供了抗体分泌细胞的群体，并且对于MG自身抗体的产生至关重要。利妥昔单抗消除了记忆B细胞的这种储藏。然后重塑了新形成的B细胞室，以使自身抗体的产生减少。为了检验这一假设，我们已经开发了/应用刺客来测量B细胞耐受性缺陷，描述这项工作将进一步了解我们对MG免疫病理学的理解，它代表了对B细胞介导的自身免疫性疾病治疗的免疫机制的更完整理解的第一步。该提案与人类疾病直接相关，并且与NIH的使命有明确的一致性和相关性。也就是说，这项翻译的研究重点是用人类衍生的细胞研究人类疾病。此外，研究MG的重要性通过其服务作为抗体介导的疾病的模型而放大。创新的新技术（例如下一代测序和抗原特异性T细胞测定法）将应用于回答基本问题。该研究旨在阐明MG主要免疫学成分的致病作用，即B和T细胞的贡献，包括基本自身免疫机制的投资，即B细胞耐受性和T细胞病原表型。通过研究MG细胞介导的免疫学，我们将进一步定义启动和传播这种疾病的事件，以提供对自身免疫性疾病机制的基本见解。