CNS Demyelinating Autoimmunity Targeting Water Channel Complexes

描述(由申请人提供)：水通道是中枢神经系统炎症性自身免疫性脱髓鞘疾病的新靶点。视神经脊髓炎(NMO；又名视神经脊髓炎多发性硬化症[MS])是一种毁灭性的疾病，对非高加索人的影响不成比例。它的特点是反复发作视神经炎和横贯性脊髓炎，导致大多数患者失明和截瘫，经常被误诊为MS。与传统教学相反，NMO并不罕见。这是第一个识别出特定抗原的类似MS的疾病--星形细胞水通道蛋白-4(AQP4)。这一发现代表着历史上对少突胶质细胞和髓鞘的重视发生了巨大转变。针对AQP4的自身抗体(NMO/AQP4-Ig G)是一种经临床验证的血清生物标志物，可区分复发的NMO和MS，后者没有明显的生物标志物，需要不同的治疗方法。我们怀疑，相当大比例的被推定为多发性硬化症的严重残疾(即失明或瘫痪)患者，特别是非裔美国人，存在误诊，并将被证明为NMO/AQP4-IgG血清阳性。尽管NMO/AQP4-Ig G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，在活的靶细胞中，与AQP4相互作用的NMO/AQP4-IgG的独特病理结果所对应的定性和定量生物测定可以预测临床结果。我们累积的临床、治疗和免疫病理观察表明，NMO/AQP4-Ig G检测阴性的NMO患者仍存在抗体介导的疾病。我们的初步数据支持存在针对星形细胞AQP4/营养不良多糖复合体的新成分的替代致病NMO-IGG。我们的目标是：1)确定不同种族患者血清中NMO/AQP4-Ig G的患病率，并储存DNA，以便将来用于遗传相关分析；2)评估免疫化学、功能(补体激活、AQP4下调和偶联谷氨酸转运体下调)和生物传感器NMO/AQP4-Ig G检测(指示抗体浓度和亲和力)的预测和预后价值；3)寻找和验证新的Ig G生物标志物(NMO-Ig G X1、X2、...)。作为明显血清阴性患者NMO的潜在基础。了解AQP4自身免疫的频率、与种族的相关性以及多发性硬化症的误诊频率将影响医疗保健的提供和经济。NMO/AQP4-Ig G(滴度、浓度/亲和力和体外功能效应)与临床或放射学结果的正相关性有望揭示预后抗体谱，作为适当治疗的基础。先进的血清学解释洞察力，加上替代诊断标记物的识别(即，新的NMO-IGGS与营养不良糖链复合体中的AQP4伙伴蛋白反应)可能导致针对个别患者的NMO疗法的制定。 公共卫生相关性：针对中枢神经系统(CNS)中星形细胞水通道(Aquaporin-4)的抗体代表了一种严重的炎症性脱髓鞘中枢神经系统疾病的研究新方向，这种疾病通常会导致失明、被限制在轮椅上和终末性呼吸衰竭。这项研究的目的是1)确定针对水通道蛋白-4或其伙伴蛋白的自身抗体的频率，以及这种情况被误诊和误治为多发性硬化症的频率；2)确定有助于诊断、预测结果和导致新的治疗靶点的实验室测试。

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.