CNS Demyelinating Autoimmunity Targeting Water Channel Complexes

描述（由申请人提供）：水渠是新发现的中枢神经系统炎症性自身免疫性脱髓鞘疾病的靶点。视神经脊髓炎（NMO，又称视神经脊髓多发性硬化症[MS]）是一种严重的疾病，主要发生在非白种人身上。其特点是视神经炎和横脊髓炎反复发作，多数患者失明和截瘫，常被误诊为多发性硬化症。与传统教学相反，NMO并不罕见。这是第一个被鉴定出特异性抗原——星形细胞水通道水通道蛋白-4 （AQP4）的ms样疾病。这一发现代表了历史上对少突胶质细胞和髓磷脂的重视的巨大转变。针对AQP4的自身抗体（NMO/AQP4- igg）是一种临床验证的血清生物标志物，可区分复发性NMO和MS，后者没有可区分的生物标志物，需要不同的治疗方法。我们怀疑，有相当比例的严重残疾（即失明或瘫痪）的患者，特别是非洲裔美国人，患有误诊，并将被证明是NMO/AQP4-IgG血清阳性。尽管NMO/AQP4-IgG对NMO有很高的敏感性和特异性，但血清水平与疾病严重程度的关系尚未建立。我们预计，NMO/AQP4- igg与活靶细胞中AQP4相互作用的不同病理结果对应的定性和定量生物测定可以预测临床结果。我们的累积临床、治疗和免疫病理学观察表明，NMO/AQP4-IgG检测为阴性的NMO患者仍然存在抗体介导的疾病。我们的初步数据支持存在替代致病性nmo - igg靶向星形细胞AQP4/糖醛酸异常复合物的新组分。我们的目标是：1)确定不同种族患者群体血清中NMO/AQP4-IgG的流行程度，并储存DNA以供将来进行遗传相关分析；2)评估免疫化学、功能（补体激活、AQP4下调和谷氨酸转运蛋白偶联下调）和生物传感器NMO/AQP4-IgG测定（指示抗体浓度和亲和力）的预测和预后价值；3)寻找并验证新的IgG生物标志物（NMO-IgG X1, X2，…）作为明显血清阴性患者NMO的潜在基础。AQP4自身免疫的频率，与种族和MS误诊频率的相关性将影响卫生保健服务和经济。预计NMO/AQP4-IgG（滴度、浓度/亲和力和体外功能效应）与临床或放射学结果呈正相关，从而揭示预后抗体谱，作为适当治疗的基础。先进的血清学解释见解，加上替代诊断标记物的鉴定（即，新的NMO- iggs与异常糖聚糖复合物中的AQP4伴侣蛋白反应）可能导致制定个体患者特异性NMO治疗。

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.