CNS Demyelinating Autoimmunity Targeting Water Channel Complexes

针对水通道复合物的中枢神经系统脱髓鞘自身免疫

• 批准号: 7879779
• 负责人: Sean Joseph Pittock
• 金额: $ 34.5万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879779
• 关键词: Accounting; Acute Disseminated Encephalomyelitis; Address; Affect; Affinity; African American; African Caribbean; American Indians; Antibodies; Antibody Affinity; Antigens; Arts; Asians; Astrocytes; Autoantibodies; Autoimmune Process; Autoimmunity; Binding; Biological Assay; Biological Markers; Biosensor; Blindness; Caucasians; Caucasoid Race; Cells; Central Nervous System Diseases; Clinic; Clinical; Clinical Research; Complement; Complement Activation; Complex; Coupled; DNA; Data; Databases; Demyelinating Diseases; Diagnosis; Diagnostic; Disabled Persons; Disease; Down-Regulation; Drug Formulations; Dystroglycan; Economics; Educational process of instructing; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Foundations; Frequencies; Funding; Future; Genetic; Glutamate Transporter; Hispanic Americans; Immunofluorescence Immunologic; Immunoglobulin G; Immunoprecipitation; In Vitro; Individual; Inflammatory; Investigation; Kinetics; Knowledge; Laboratories; Lead; Life; MDCK cell; Measures; Mediating; Medicine; Multiple Sclerosis; Myelin; Names; Neuraxis; Neurologist; Neurology; Neuromyelitis Optica; Neurons; Oligodendroglia; Optic Nerve; Optic Neuritis; Optics; Outcome; Paraplegia; Pathologic; Pathology; Patients; Physicians; Prevalence; Proteins; Qualifying; Recovery; Recurrence; Relapse; Reporting; Research; Research Ethics Committees; Research Infrastructure; Research Personnel; Respiratory Failure; Scientist; Sensitivity and Specificity; Serological; Seroprevalences; Serum; Services; Severities; Severity of illness; Specificity; Spinal; Spinal Cord; Study Subject; Surface Plasmon Resonance; System; Testing; Therapeutic; Transverse Myelitis; Variant; Wheelchairs; aquaporin 4; base; blind; central nervous system demyelinating disorder; clinical phenotype; cohort; disability; disease diagnosis; ethnic minority population; health care delivery; improved; insight; interest; neuroimmunology; new therapeutic target; novel; prognostic; public health relevance; quality assurance; repository; treatment strategy; water channel

DESCRIPTION (provided by applicant): Water channels are a newly recognized target for CNS inflammatory autoimmune demyelinating diseases. Neuromyelitis optica (NMO; aka optic spinal multiple sclerosis [MS]) is a devastating disease that disproportionally affects non-Caucasians. It is characterized by recurrent episodes of optic neuritis and transverse myelitis, resulting in blindness and paraplegia in most patients, and it is frequently misdiagnosed as MS. Contrary to traditional teaching, NMO is not rare. It is the first MS-like disease for which a specific antigen has been identified--the astrocytic water channel aquaporin-4 (AQP4). This discovery represents a seismic shift from historic emphasis on the oligodendrocytes and myelin. An autoantibody specific for AQP4 (NMO/AQP4-IgG) is a clinically validated serum biomarker that distinguishes relapsing NMO from MS, which has no distinguishing biomarker and calls for different therapies. We suspect that a significant proportion of patients who are severely disabled (i.e., blind or paraparetic) from presumed MS, particularly African Americans, carry a misdiagnosis and will prove to be NMO/AQP4-IgG seropositive. Despite the high sensitivity and specificity of NMO/AQP4-IgG for NMO, the relationship of serum level to disease severity has not been established. We anticipate that qualitative and quantitative bioassays corresponding to distinctive pathologic outcomes of NMO/AQP4-IgG interacting with AQP4 in living target cells may predict clinical outcome. Our cumulative clinical, therapeutic and immunopathologic observations suggest that NMO patients who test negative for NMO/AQP4-IgG nevertheless have an antibody-mediated disorder. Our preliminary data support the existence of alternative pathogenic NMO-IgGs targeting novel components of the astrocytic AQP4/dystroglycan complex. We aim to 1) determine the prevalence of NMO/AQP4-IgG in serum of ethnically diverse patient cohorts and store DNA for future use in genetic correlative analyses; 2) assess the predictive and prognostic value of immunochemical, functional (complement activation, AQP4 downregulation and coupled glutamate transporter downregulation) and biosensor NMO/AQP4-IgG assays (indicative of antibody concentration and affinity) and 3) search for and validate novel IgG biomarkers (NMO-IgG X1, X2, ...) as the potential basis of NMO in apparently seronegative patients. Knowledge of the frequency of AQP4 autoimmunity, correlation with ethnicity and frequency of MS misdiagnosis will impact health care delivery and economics. Positive correlations of NMO/AQP4-IgG (titer, concentration/affinity and functional in vitro effects) with clinical or radiologic outcomes are anticipated to reveal prognostic antibody profiles as basis for appropriate therapy. Advanced serological interpretive insights, coupled with identification of alternative diagnostic markers (i.e., new NMO-IgGs reactive with AQP4 partner proteins in the dystroglycan complex) may lead to formulation of individual patient-specific NMO therapies. PUBLIC HEALTH RELEVANCE: Antibodies directed at astrocytic water channels (aquaporin-4) in the central nervous system (CNS) represent a new direction in research of a severe inflammatory demyelinating CNS disorder that often results in blindness, confinement to a wheel chair and terminal respiratory failure. This study aims to 1) determine the frequency of autoantibodies targeting aquaporin-4 or its partner proteins and how often this condition is misdiagnosed and mistreated as multiple sclerosis and 2) identify laboratory tests that aid its diagnosis, predict outcome and lead to new therapeutic targets.

描述（由申请人提供）：水通道是CNS炎症自身免疫性脱髓鞘疾病的新认识的目标。神经霉素炎（NMO；又名视神经多发性硬化症[MS]）是一种毁灭性的疾病，对非高加索人的影响不成比例。它的特征是视神经炎和横向脊髓炎的复发发作，导致大多数患者的失明和截瘫，并且经常被误诊为MS。与传统教学相反，NMO并不罕见。这是已鉴定出特定抗原的第一个类似于MS的疾病 - 星形胶质细胞水道Aquaporin-4（AQP4）。这一发现代表了从对少突胶质细胞和髓磷脂的历史强调的地震转变。针对AQP4（NMO/AQP4-IGG）特异的自身抗体是一种经过临床验证的血清生物标志物，它将复发NMO与MS区分开，MS没有区分生物标志物，并且需要不同的疗法。我们怀疑，在假定的MS，尤其是非裔美国人的严重残疾（即盲人或副疾病）的患者中，很大一部分患者遭受了误诊，并且将被证明是NMO/AQP4-IGG血清阳性。尽管NMO/AQP4-IGG对NMO具有高灵敏度和特异性，但尚未建立血清水平与疾病严重程度的关系。我们预计，在活物靶细胞中与AQP4相互作用的NMO/AQP4-IGG与AQP4相互作用的定性和定量生物测定可能预测临床结果。我们的累积临床，治疗和免疫病理学观察结果表明，NMO对NMO/AQP4-IGG阴性测试的NMO患者仍然患有抗体介导的疾病。我们的初步数据支持针对星形胶质细胞AQP4/Dystroglycan复合物的新成分的替代致病性NMO-IGG。我们的目的是1）确定NMO/AQP4-IGG在种族多样的患者同类血清中的患病率，并将DNA存储在遗传相关分析中； 2）评估免疫化学，功能（补体激活，AQP4下调和耦合的谷氨酸转运蛋白下调）和生物传感器NMO/AQP4-IGG测定法（指示抗体浓度和亲和力）的预测和预后价值NMO在显然是血清神经病患者中。了解AQP4自身免疫性的频率，与种族和MS误诊的频率的相关性将影响医疗保健提供和经济学。 NMO/AQP4-IGG（滴度，浓度/亲和力和在体外效应的功能）与临床或放射性结果的正相关，预计将揭示预后抗体谱图作为适当治疗的基础。先进的血清学解释见解，再加上替代性诊断标记物（即，在多核糖综合体中用AQP4伴侣蛋白反应性的新型NMO-IGGS）可能会导致对个别患者特异性NMO疗法的表述。 公共卫生相关性：中枢神经系统（CNS）中针对星形胶质细胞水通道（Aquaporin-4）的抗体代表了研究严重炎症性脱髓鞘中枢神经系统疾病的新方向，通常会导致盲目性，限制对轮椅和末端呼吸衰竭。这项研究的目的是1）确定靶向Aquaporin-4或其伴侣蛋白的自身抗体的频率，以及该疾病被误诊和虐待作为多发性硬化症的频率； 2）确定实验室测试，以帮助其诊断，预测结果并导致新的治疗靶标。