Mechanisms of autoimmunity in myasthenia gravis

重症肌无力的自身免疫机制

• 批准号: 10384076
• 负责人: Kevin C O'connor
• 金额: $ 50.12万
• 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: 2015-08-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10384076
• 关键词: Acetylcholine; Affect; Age; Age of Onset; Antigen Receptors; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Autoimmunity; B cell repertoire; B cell therapy; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Binding Sites; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Blood; Cells; Characteristics; Cholinergic Receptors; Chronic; Clinical; Clinical Trials; Cloning; Collection; Complement; Complement Inactivators; Data; Disease; Docking; Effectiveness; Epitopes; Event; Frequencies; Gene Expression; Gene Expression Profiling; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Human Pathology; Hyperplasia; IgG autoantibodies; IgG(T); Immune; Immunoglobulin-Secreting Cells; Immunologics; Investigation; Knowledge; Libraries; Lymphocytic Infiltrate; Mediating; Membrane Proteins; Molecular; Monoclonal Antibodies; Morphology; Muscle; Muscle Weakness; Myasthenia Gravis; Neuromuscular Junction; Nicotinic Receptors; Outcome; Pathogenicity; Pathology; Patient Care; Patients; Peripheral; Phenotype; Postsynaptic Membrane; Production; Property; Protein Tyrosine Kinase; Public Health; Recombinants; Role; Severity of illness; Signal Transduction; Specimen; Structure of germinal center of lymph node; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Uses; Thymic Tissue; Thymus Gland; Tissues; Treatment outcome; Woman; Work; anti-CD20; base; care providers; clinical subtypes; clinically relevant; design; disorder subtype; early onset; experience; immunopathology; insight; men; neuromuscular; neuromuscular transmission; novel; novel strategies; pathogenic autoantibodies; patient subsets; prognostic; response; sex; skeletal muscle weakness; tertiary lymphoid organ

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.

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患者患有严重的肌无力和由于减少的肌肉疲劳而增加的肌肉疲劳。 神经肌肉信号MG是由靶向神经肌肉接头成分的自身抗体引起的 (NMJ)在大多数患者中，这是烟碱乙酰胆碱受体（AChR）。这些AChR自身抗体介导 病理学通过三种机制：（i）干扰乙酰胆碱对接，（ii）AChR的内化， 和（iii）经典补体级联的激活导致组织损伤。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），其基于 发病年龄、性别和HLA相关性。 尽管不同亚型的MG患者具有相似的疾病表现，但潜在的 免疫病理学可能是不同的。AChR的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，包括AChR特异性IgG、T细胞和B细胞 （包括AChR自身抗体生产者），组织为三级淋巴器官，类似于germinal 中心.相反，LOMG很少包括胸腺异常。虽然异质性的细节 由于缺乏免疫病理学，因此对差异背后的机制的更深入理解是非常重要的。 这对患者和临床医生都很重要。这是因为预期在一个人身上效果良好的治疗方法 亚型可能不具有用于其它亚型的生物学基础。无应答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，清楚地强调了 我们知识上的差距 因此，在这一更新期，我们将研究不同的免疫机制的细节， EOMG和LOMG MG亚型。我们的研究集中在直接导致疾病的B细胞上 病理学，那些产生AChR自身抗体。使用新的方法，我们将分离这些罕见的乙酰胆碱受体， 从胸腺组织和血液中分离产生自身抗体的B细胞，并确定其库特征。人类 然后从这些B细胞产生重组单克隆抗体（mAb）， 病理机制可以使用一套新的测定来确定，以确定它们影响病理的能力 通过补体介导的组织损伤、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，包括对AChR抗原特异的那些。 这项研究旨在提供详细的见解，既对自身抗原特异性免疫细胞的作用， 自身抗体用于促进EOMG和LOMG病理学的亚群和分子机制 亚型这些明确定义的免疫机制预计将通过以下方式影响治疗结果： 告知用于治疗特定MG疾病亚群的生物治疗剂的应用。