Mechanisms of autoimmunity in myasthenia gravis

重症肌无力的自身免疫机制

基本信息

批准号：
10686316
负责人：
Kevin C O'connor
金额：
$ 48.6万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10686316
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 Dimensions 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 Infiltration 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 Physical activity Postsynaptic Membrane Production Property Protein Tyrosine Kinase Public Health Recombinants Role Selection for Treatments 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 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

项目摘要

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 患者因肌力减弱而出现严重的肌无力和肌肉疲劳性增加。神经肌肉信号传导。 MG 是由针对神经肌肉接头成分的自身抗体引起的（国家医学杂志）；在大多数患者中，这是烟碱乙酰胆碱受体（AChR）。这些 AChR 自身抗体介导通过三种机制调节病理学：(i) 干扰乙酰胆碱对接，(ii) AChR 内化， (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，包括早发性和迟发性 MG（EOMG 和 LOMG），其基于发病年龄、性别和 HLA 关联。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有所不同。 AChR EOMG 和 LOMG 亚型很好地说明了这一点。尤其， EOMG 的特点是胸腺淋巴细胞浸润，其中包括 AChR 特异性 IgG、T 细胞和 B 细胞（包括 AChR 自身抗体产生者）组织为三级淋巴器官，类似于生发细胞中心。相反，LOMG 很少包括胸腺异常。虽然异构的细节缺乏免疫病理学，对差异背后的机制有更深入的了解是高度对于患者和临床医生都很重要。这是因为预期在一种治疗中效果良好亚型可能不具有用于其他亚型的生物学基础。无反应 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，清楚地强调了我们的知识差距。因此，在这个更新时期，我们将研究潜在的不同免疫机制的细节。 EOMG 和 LOMG MG 亚型。我们的研究重点关注直接导致疾病的 B 细胞病理学，产生AChR自身抗体的病理学。使用新方法，我们将分离这些罕见的 AChR 从胸腺组织和血液中产生 B 细胞的自身抗体，并确定其所有特征。人类然后，这些 B 细胞将产生重组单克隆抗体 (mAb)，以便分子可以使用一套新的测定来定义病理机制，以确定其影响病理的能力通过补体定向的组织损伤、阻断或调节。最后，我们将定义表型产生自身抗体的 B 细胞亚群和 T 辅助细胞亚群，包括对 AChR 抗原具有特异性的细胞亚群。这项研究旨在详细了解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 病理学的子集和分子机制亚型。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 疾病子集的生物疗法的应用。