Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica

视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘

• 批准号: 8601080
• 负责人: Jeffrey L Bennett
• 金额: $ 37.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601080
• 关键词: Address; Affect; Antibodies; Antibody Formation; Antibody Repertoire; Antigen Targeting; Antigens; Area; Astrocytes; Autoantibodies; Autoimmune Responses; Automobile Driving; Binding; Biological Assay; Biological Models; Blindness; Blood - brain barrier anatomy; Brain; Brain Injuries; Cell Line; Cell-Mediated Cytolysis; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Complement; Complement Activation; Conditioned Culture Media; Demyelinating Diseases; Demyelinations; Development; Diagnosis; Disease; Disease model; Early Diagnosis; Epitopes; Equipment and supply inventories; Event; Fluorescence-Activated Cell Sorting; Foot Process; Frequencies; Human; Humoral Immunities; Immune response; Immune system; Immunoglobulin G; In Vitro; Individual; Inflammatory; Injection of therapeutic agent; Injury; Lesion; Leukocytes; Libraries; Link; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Mus; Myelin; Nature; Neuraxis; Neuroglia; Neurologic; Neuromyelitis Optica; Neuronal Injury; Neurotransmitters; Oligodendroglia; Optic Nerve; Paralysed; Pathogenesis; Pathology; Patient Care; Patients; Pattern; Physicians; Plasma Cells; Plasmablast; Population; Reagent; Recombinant Antibody; Recombinants; Relapse; Relative (related person); Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Series; Serum; Severities; Severity of illness; Sorting - Cell Movement; Specificity; Spinal Cord; Staging; System; Technology; Tissues; Transgenic Animals; advanced disease; antibody-dependent cell cytotoxicity; aquaporin 4; central nervous system demyelinating disorder; central nervous system injury; cytokine; disability; excitotoxicity; high risk; human monoclonal antibodies; immunopathology; in vivo; in vivo Model; inhibitor/antagonist; innovation; kainate; novel; public health relevance; research study; response; skills; water channel; young adult

DESCRIPTION (provided by applicant): Neuromyelitis optica (NMO) is a severe human demyelinating disorder with predilection for the optic nerve and spinal cord. Approximately 70% of affected individuals demonstrate a serum autoantibody response, NMO-IgG, against the aquaporin-4 (AQP4) water channel. NMO-IgG binding to AQP4 in astrocytes in the central nervous system (CNS) is thought to initiate a series of inflammatory events, including complement- and cell-mediated astrocyte damage, leukocyte recruitment, cytokine release, and myelin damage. Using single- cell FACS and recombinant antibody technology, we have faithfully reconstructed the intrathecal humoral immune response in NMO and demonstrated that AQP4 autoantibodies are sufficient to initiate astrocyte injury and disease pathology. To further the care of patients with human demyelinating disease, we will use our novel resources and innovative approach to address fundamental gaps in our understanding of NMO pathogenesis: 1) Are there alternative targets of the immune response in NMO? 2) Does the nature of the AQP4 immune response correlate with disease severity? 3) What are the mechanisms driving astrocyte injury and myelin damage In NMO pathology? First, to identify novel targets of the autoimmune response in NMO, we will examine non-AQP4 specific NMO recombinant antibodies (rAbs) for binding to human and murine tissue, glial cell lines and primary glial cultures. A compendium of candidate rAbs will be generated from our existing antibody repertoires as well as new cases of AQP4 seronegative disease. Second, to investigate the association between NMO-IgG specificity and clinical disease activity, we will evaluate the relationship between two distinct patterns of AQP4 epitope specificity and the frequency and severity of clinical activity. We hypothesize that the spectrum of AQP4 epitope specificity in NMO-IgG will influence antibody effector function and CNS injury. And third, we will define the mechanisms underlying AQP4-mediated astrocyte injury and myelin damage using a combination of disease models, transgenic animals, and NMO CSF rAbs. Specifically, we will use mixed glial cultures, ex vivo spinal cord explants, and intracerebral injections to evaluate th effect of complement activation, antibody-dependent cell mediated cytotoxicity, excitotoxicity, cytokine release, and astrocyte metabolism on AQP4 antibody-mediated CNS injury. The detailed characterization of the humoral immune response in NMO will aid in the diagnosis and treatment of NMO, the identification of novel target antigens in human demyelinating disease, and the elucidation of the mechanisms causing glial and neuronal injury in CNS inflammatory disease.

描述（由申请人提供）：视神经脊髓炎（NMO）是一种严重的人类脱髓鞘疾病，多发生于视神经和脊髓。大约70%的受影响个体表现出针对水通道蛋白-4 （AQP4）水通道的血清自身抗体NMO-IgG反应。中枢神经系统（CNS）星形胶质细胞中NMO-IgG与AQP4结合被认为可引发一系列炎症事件，包括补体和细胞介导的星形胶质细胞损伤、白细胞募集、细胞因子释放和髓磷脂损伤。利用单细胞FACS和重组抗体技术，我们忠实地重建了NMO鞘内体液免疫反应，并证明AQP4自身抗体足以启动星形胶质细胞损伤和疾病病理。为了进一步治疗人类脱髓鞘病患者，我们将利用我们的新资源和创新方法来解决我们对NMO发病机制的理解的根本空白：1)NMO中是否存在其他免疫应答靶点？2) AQP4免疫反应的性质是否与疾病严重程度相关？3) NMO病理中星形胶质细胞损伤和髓鞘损伤的机制是什么？首先，为了确定NMO自身免疫反应的新靶点，我们将检测非aqp4特异性NMO重组抗体（rAbs）与人和小鼠组织、胶质细胞系和原代胶质培养物的结合。将从我们现有的抗体库以及AQP4血清阴性疾病的新病例中生成候选rAbs纲要。其次，为了研究NMO-IgG特异性与临床疾病活动性之间的关系，我们将评估AQP4表位特异性的两种不同模式与临床活动的频率和严重程度之间的关系。我们推测NMO-IgG中AQP4表位特异性的谱会影响抗体效应功能和中枢神经系统损伤。第三，我们会