Autoimmune Encephalitis - Ataxia and Psychiatric Disease: Identifying and Characterizing Novel Antibody Targets

自身免疫性脑炎 - 共济失调和精神疾病：识别和表征新抗体靶点

• 批准号: 10558638
• 负责人: JOSEPH L. DERISI
• 金额: $ 76.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-16 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558638
• 关键词: Affect; Amino Acids; Animal Disease Models; Animal Model; Antibodies; Antibody titer measurement; Antigens; Ataxia; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune encephalitis; Bacteriophages; Biological Assay; Biological Markers; Biological Products; Brain; Cell Separation; Cells; Cerebellum; Cerebrospinal Fluid; Classification; Clinical; Collection; Communities; Complex; Cytoplasm; Dangerousness; Data; Databases; Defect; Development; Diagnostic; Disease; Encephalitis; Epitopes; Fc Receptor; Functional disorder; Goals; Human; Image; Immunosuppressive Agents; In Vitro; Inflammatory; Injections; Knockout Mice; Libraries; Maintenance; Malignant Neoplasms; Memory; Mental disorders; Molecular; Monoclonal Antibodies; Moods; Mus; N-Methyl-D-Aspartate Receptors; Natural regeneration; Neurologist; Neuropil; Nuclear; Paraneoplastic Syndromes; Pathogenesis; Patients; Pattern; Peptides; Personality; Persons; Phage Display; Phage ImmunoPrecipitation Sequencing; Plasma Cells; Production; Protein Isoforms; Proteins; Proteome; Psychoses; Recombinants; Regional Anatomy; Sampling; Scientist; Seizures; Seminoma; Signs and Symptoms; Specificity; Stains; Steroids; Structure; Synaptic Transmission; Syndrome; Testing; Tissue Stains; Tissues; animal model development; biobank; clinically actionable; cohort; density; improved; in vivo; innovation; insight; men; multiple sclerosis patient; neural; neuroinflammation; neuromechanism; novel; pathogenic autoantibodies; screening

Inflammatory and infectious causes of encephalitis affect 20,000 people a year in the US. More than 50% of patients have inflammatory disorders requiring prolonged treatment with expensive and dangerous biological or immunosuppressive agents. The most common identifiable causes of these syndromes are paraneoplastic, post-infectious or associated with other underlying autoimmune diseases; however, the majority of patients are still classified as idiopathic. In the last 1-2 decades many of these syndromes have been shown to be associated with anti-neural autoantibodies that either cause the pathophysiology or serve as critical biomarkers. The most widely cited examples of these are anti-Hu antibodies, which are highly correlated with an underlying cancer, and anti-NMDA receptor antibodies, which cause psychosis, seizures and memory disturbances. Over the past 5 years, a unique interdisciplinary team of neurologists and basic scientists at UCSF was formed to develop and deploy an integrated approach to rapidly identify anti-neural antibodies associated with encephalitis, with the explicit intent to discover and validate clinically actionable biomarkers in addition to uncovering the fundamental mechanisms of disease pathogenesis underlying these syndromes. The centerpiece of these efforts is a patient cohort being collected at UCSF called the NID (Neuroinflammatory Disease) cohort, consisting of patients with suspected infectious or inflammatory encephalitis. This cohort is now >1,200 patients referred by clinicians at UCSF and from other centers around the world. Already, this cohort has yielded a new paraneoplastic autoimmune syndrome with important implications for men with seminoma. More importantly, we have reason to believe this to be just the tip of the iceberg. Our preliminary data indicates that at least 20% of these patients have associated high titer antibodies in their CSF reactive to neural antigens in mouse brain. Here, we propose to pursue the hypothesis that a plurality of undiscovered autoimmune targets underlie a significant fraction of idiopathic encephalitis cases. Using our unique clinical and molecular approach and our world class patient collection, we will investigate this hypothesis through the following specific aims: Aim 1: To stratify and characterize the UCSF 1,200 patient NID cohort for the presence of anti-neural antibodies in CSF. Aim 2: High-throughput phage display screen to identify and validate auto antigens. Aim 3: Produce recombinant human antibodies from patients with autoantibody syndromes and develop animal models to test autoantibody pathogenicity.

在美国，脑炎的炎症和感染性病因每年影响2万人。超过50% 的患者患有炎症性疾病，需要使用昂贵且危险的生物制剂进行长期治疗。 或免疫抑制剂。这些综合征最常见的可识别原因是副肿瘤， 感染后或与其他潜在的自身免疫性疾病相关;然而，大多数患者 仍被归类为特发性在过去的1- 20年中，许多这些综合征已被证明与 与抗神经自身抗体，要么导致病理生理学或作为关键的生物标志物。最 其中被广泛引用的例子是抗Hu抗体，其与潜在的癌症高度相关， 以及抗NMDA受体抗体，这些抗体会导致精神病、癫痫和记忆障碍。 在过去的5年里，一个独特的跨学科团队的神经学家和基础科学家在加州大学旧金山分校是 形成开发和部署一个综合的方法，以快速识别抗神经抗体相关的 脑炎，明确的意图是发现和验证临床上可操作的生物标志物， 揭示了这些综合征的基本发病机制。的 这些努力的核心是在加州大学旧金山分校收集的一个名为NID（神经炎性 疾病）队列，由疑似感染性或炎性脑炎患者组成。本队列 现在有超过1，200名患者由UCSF和世界各地其他中心的临床医生转诊。已经，这 一个队列产生了一种新的副肿瘤性自身免疫综合征，对患有 子宫肌瘤更重要的是，我们有理由相信这只是冰山一角。我们的初步 数据表明，这些患者中至少20%在其CSF中具有与以下反应的相关高滴度抗体： 小鼠脑中的神经抗原。在这里，我们建议继续假设， 未发现的自身免疫靶点是特发性脑炎病例的重要部分。使用 我们独特的临床和分子方法以及我们世界一流的患者收集，我们将对此进行研究。 目的1：针对CSF中抗神经抗体的存在，对UCSF 1，200例NID患者队列进行分层和表征。目的2：高通量噬菌体展示筛选自身抗原。目的3：从自身抗体综合征患者中制备重组人源抗体，并建立自身抗体致病性的动物模型。