Antibody Mediated Autoimmunity in Neuromyelitis Optica

视神经脊髓炎中抗体介导的自身免疫

• 批准号: 8190120
• 负责人: HANS-CHRISTIAN VON BUEDINGEN
• 金额: $ 18.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190120
• 关键词: Address; Affect; Animal Model; Antibodies; Antibody Repertoire; Antigen Targeting; Antigenic Specificity; Antigens; Astrocytes; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biological Assay; Biological Markers; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Chinese Hamster Ovary Cell; Complement Activation; Complement-Dependent Cytotoxicity; Demyelinating Diseases; Development; Differential Diagnosis; Disease; Disease model; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Foundations; G-substrate; Goals; Homeostasis; Human; Immunity; Immunofluorescence Immunologic; Immunoglobulin G; Immunoglobulins; Immunoprecipitation; In Vitro; Individual; Inflammatory; Mass Spectrum Analysis; Mediating; Methods; Modeling; Molecular Conformation; Monoclonal Antibodies; Multiple Sclerosis; Neuraxis; Neuromyelitis Optica; Neurons; Oligodendroglia; Optic Nerve; Pathologic Processes; Patients; Plasma; Plasma Cells; Play; Population Heterogeneity; Predisposition; Proteins; Publishing; Recombinant Antibody; Recombinants; Role; Serum; Specificity; Spinal Cord; System; Tissues; Translating; Water; antibody-dependent cell cytotoxicity; aquaporin 4; base; brain tissue; cell type; central nervous system demyelinating disorder; in vitro Model; in vivo; induced pluripotent stem cell; novel; peripheral blood; relating to nervous system; research study; response; tool; water channel

DESCRIPTION (provided by applicant): There is increasing appreciation that B cells and antibodies are important players in the immunopathogenesis of autoimmune demyelinating disorders of the central nervous system (CNS) such as neuromyelitis optica (NMO) and multiple sclerosis (MS). NMO is a severe inflammatory demyelinating disease affecting the optic nerves and spinal cord. Aquaporin-4 (AQP4) has been identified as a target of pathogenic autoantibody responses in NMO. Thus, NMO can be considered a model disease for CNS directed B cell and antibody autoimmunity. AQP4 is a water channel protein, which is expressed in astrocytes of the CNS. Anti- AQP4 antibodies have been proposed to exert neuropathological effects by a number of different mechanisms in NMO, including complement activation, antibody-dependent cell-mediated cytotoxicity, and downregulation of AQP4 and associated proteins. However, the exact epitope specificities of pathogenic anti-AQP4 antibodies remain unknown. It is unclear whether antigens other than AQP4 are also targets of pathologically relevant autoantibodies and no information is available regarding epitope targets of pathogenic autoantibodies in anti- AQP4 seronegative patients. However, there is evidence for extensive B cell-dependent autoimmunity in NMO, which likely translates into a diverse, pathogenic, CNS-directed autoantibody repertoire. We hypothesize that the AQP4-specific antibody repertoire is diverse, both in regards to AQP4 epitope recognition and with respect to pathological effects on CNS tissue. To address this hypothesis, we will first delineate the repertoire of AQP4 epitopes recognized by a.) recombinant monoclonal antibodies (rAbs) generated from CSF plasma cells, and by b.) purified soluble immunoglobulins from serum and CSF from anti- AQP4 seropositive NMO patients. Subsequently, monoclonal anti-AQP4 antibodies representative of individual AQP4-epitopes will be further characterized regarding their potential to damage AQP4 expressing cells. To establish an in vitro experimental system as close to in vivo as possible, we will also study pathological effects of anti-AQP4 antibodies on astrocytes derived from induced pluripotent stem cells (iPSC) from NMO patients. We also hypothesize, that antibody mediated immunity against targets other than AQP4 may play a role in AQP4-seronegative and possibly even AQP4-seropositive NMO patients. To address this hypothesis, we propose to identify targets of AQP4 non-reactive antibodies from AQP4-seronegative and -seropositive NMO patients. To achieve this goal, we will determine the reactivity of AQP4 non-reactive antibodies with iPSC-derived CNS cells (e.g. astrocytes, oligodendrocytes or neurons) and study pathological effects resulting from this autoantibody binding. These studies will elucidate pathologically relevant antibody-antigen interactions and are expected to serve as an important foundation for the development of disease-specific therapies and novel biomarkers. PUBLIC HEALTH RELEVANCE: Project Narrative Neuromyelitis optica (NMO) is an autoimmune demyelinating disorder of the central nervous system (CNS) involving pathogenic antibody responses against aquaporin-4 (AQP4). Our research program will examine the epitopes recognized by pathological anti-AQP4 antibodies; attempt to identify additional as yet unknown target antigens; and characterize the spectrum of pathological autoantibody-effector functions involved in tissue damage in NMO. Such knowledge is expected to provide important starting information for the development of selective therapies and novel biomarkers.

描述（由申请人提供）：人们越来越认识到 B 细胞和抗体在中枢神经系统（CNS）自身免疫性脱髓鞘疾病（例如视神经脊髓炎（NMO）和多发性硬化症（MS））的免疫发病机制中发挥着重要作用。 NMO 是一种严重的炎症性脱髓鞘疾病，影响视神经和脊髓。 Aquaporin-4 (AQP4) 已被确定为 NMO 致病性自身抗体反应的靶标。因此，NMO可以被认为是CNS导向的B细胞和抗体自身免疫的模型疾病。 AQP4 是一种水通道蛋白，在中枢神经系统星形胶质细胞中表达。已提出抗AQP4抗体通过NMO中的多种不同机制发挥神经病理学作用，包括补体激活、抗体依赖性细胞介导的细胞毒性以及AQP4和相关蛋白的下调。然而，致病性抗 AQP4 抗体的确切表位特异性仍然未知。目前尚不清楚 AQP4 以外的抗原是否也是病理相关自身抗体的靶标，并且没有关于抗 AQP4 血清阴性患者中致病性自身抗体的表位靶标的信息。然而，有证据表明 NMO 中存在广泛的 B 细胞依赖性自身免疫，这可能转化为多样化的、致病性的、针对 CNS 的自身抗体库。 我们假设 AQP4 特异性抗体库是多种多样的，无论是在 AQP4 表位识别方面还是在对 CNS 组织的病理作用方面。为了解决这一假设，我们将首先描述 AQP4 表位的全部组成，这些表位被 a.) 从 CSF 浆细胞产生的重组单克隆抗体 (rAb) 和 b.) 从抗 AQP4 血清阳性 NMO 患者的血清和 CSF 中纯化的可溶性免疫球蛋白识别。随后，代表单个 AQP4 表位的单克隆抗 AQP4 抗体将进一步表征其损害 AQP4 表达细胞的潜力。为了建立尽可能接近体内的体外实验系统，我们还将研究抗AQP4抗体对来自NMO患者的诱导多能干细胞（iPSC）的星形胶质细胞的病理作用。 我们还假设，抗体介导的针对 AQP4 以外靶标的免疫可能在 AQP4 血清阴性甚至 AQP4 血清阳性 NMO 患者中发挥作用。为了解决这一假设，我们建议从 AQP4 血清阴性和血清阳性 NMO 患者中鉴定 AQP4 非反应性抗体的靶标。为了实现这一目标，我们将确定 AQP4 非反应性抗体与 iPSC 衍生的 CNS 细胞（例如星形胶质细胞、少突胶质细胞或神经元）的反应性，并研究这种自身抗体结合所产生的病理效应。 这些研究将阐明病理相关的抗体-抗原相互作用，并有望成为开发疾病特异性疗法和新型生物标志物的重要基础。 公共健康相关性：项目叙事视神经脊髓炎 (NMO) 是一种中枢神经系统 (CNS) 自身免疫性脱髓鞘疾病，涉及针对水通道蛋白 4 (AQP4) 的致病性抗体反应。我们的研究计划将检查病理性抗 AQP4 抗体识别的表位；尝试识别其他未知的靶抗原；并表征 NMO 组织损伤中涉及的病理性自身抗体效应器功能的谱。这些知识有望为选择性疗法和新型生物标志物的开发提供重要的起始信息。