Immunity to brain Ma proteins: A remote effect of cancer

对脑 Ma 蛋白的免疫：癌症的远程影响

• 批准号: 7483468
• 负责人: Josep O. Dalmau
• 金额: $ 25.91万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483468
• 关键词: Affect; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Autoantigens; Autoimmune Process; Autoimmune encephalitis; Behavior; Brain; Brain Stem; Breast; Carcinoma in Situ; Categories; Cell membrane; Cell surface; Classification; Clinical; Cognition; Cytotoxic T-Lymphocytes; Data; Dendrites; Detection; Development; Diagnosis; Diagnostic tests; Discipline; Disease; Drug abuse; Dysautonomias; Encephalitis; Epilepsy; Epitope Mapping; Event; Family; Functional disorder; Grant; Hippocampus (Brain); Hu antigen; Hypercapnic respiratory failure; Hypothalamic structure; Immune; Immunity; Immunoglobulin G; Immunologics; Invasive; Life; Limbic Encephalitis; Link; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of testis; Mediating; Memory; Memory impairment; Microscopic; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Nerve Tissue; Neurologic; Neurons; Orchiectomy; Patients; Phenotype; Plasma Exchange; Process; Proteins; Recovery; Seizures; Severities; Sleep Disorders; Staging; Surface Antigens; Symptoms; Synapses; Syndrome; Teratoma; Testicular Neoplasms; Testing; Testis; Testis Brain; Thinking; Thymoma; Ultrasonography; Woman; Work; base; concept; improved; men; mouse model; older patient; outcome forecast; prototype; response; tumor

The initial focus of this grant was paraneoplastic immunity to Ma proteins. We initially identified this disorder in men with testicular tumors and brainstem and limbic encephalitis (LE: memory deficits, seizures, sleep disorders) who developed antibodies to neuronal proteins expressed by the tumors. These antibodies served to isolate the target antigens (Mal-3, a family of brain-testis proteins), assisted in characterizing the disorder (Maencephalitis), and led to the development of diagnostic tests currently used worldwide. As this work proceeded we identified patients with treatment responsive LE who were initially thought to have Ma antibodies on clinical grounds but when tested, had other antibodies. An important discovery has been the identification of a new category of autoimmune encephalitis and the target autoantigens, leading to successful treatment strategies for this and similar disorders. The affected patients are young women who develop prominent psychiatric symptoms, seizures, and central hypoventilation often requiring prolonged ventilatory support. All of these patients had antibodies to cell surface antigens (highly enriched in hippocampus), which we identified as the NR2B (and at a lesser degree NR2A) subunits of the NMDA receptor. Although this encephalitis is more lifethreatening than other paraneoplastic disorders, patients are more responsive to treatment (with frequent full recovery) if properly diagnosed. Extensive preliminary data support the concept that the neurologic and psychiatric symptoms are mediated by the NMDA receptor (NMDAR) antibodies. In addition, we identified other treatment responsive phenotypes (some without a cancer association) that occur with antibodies to other cell surface neuronal antigens (pending characterization). Based on these data we postulate the occurrence of two large and heterogeneous groups of autoimmune LE; one group (prototype: Ma-like proteins) includes disorders related to intracellular antigens; the other group (prototype: NMDA receptor) includes disorders related to cell membrane antigens. While disorders of the first group associate with cancer, brain cytotoxic T-cell infiltrates, and variable response to treatment, the second group of disorders associate less frequently with cancer, appear to be mediated by antibodies, and usually respond to IgG-depleting strategies. The three specific aims of this competing renewal application are to 1) fully define the clinical-immunological phenotypes of LE and repertoire of NR2 (NMDAR) antigens, 2) map the epitope regions of NR2 subunits of the NMDAR and isolate other hippocampal antigens, and 3) determine whether antibodies to NR2 subunits of the NMDAR cause LE in a mouse model.

该赠款的最初重点是对MA蛋白的副塑性免疫。我们最初在 患有睾丸肿瘤，脑干和边缘脑炎的男性（LE：记忆缺陷，癫痫发作，睡眠 疾病）患有肿瘤表达的神经元蛋白的抗体。这些抗体用于 隔离靶抗原（MAL-3，一个脑睾丸蛋白家族），有助于表征该疾病（Macerphalalisis），脑膜炎）， 并导致了当前在全球范围内使用的诊断测试的开发。随着这项工作的进行 我们确定了治疗反应性LE的患者，他们最初被认为具有临床上的MA抗体 理由但经过测试时，还有其他抗体。一个重要的发现是确定新的 自身免疫性脑炎和目标自身抗原的类别，导致成功治疗策略 这和类似的疾病。受影响的患者是年轻女性，他们发展出著名的精神病 症状，癫痫发作和中央次数不足通常需要延长通气支持。所有这些 患者对细胞表面抗原具有抗体（高度富含海马），我们确定为 NR2B（在较小程度的NR2A）亚基中，NMDA受体的亚基。尽管这种脑炎更具生命治疗 比其他副塑性疾病，患者对治疗的反应更敏感（经常全面 恢复）如果正确诊断。广泛的初步数据支持神经和 精神病症状是由NMDA受体（NMDAR）抗体介导的。另外，我们确定了 与其他抗体发生的其他治疗反应型表型（一些没有癌症关联的表型） 细胞表面神经元抗原（待处理表征）。基于这些数据，我们假设两个 自身免疫性的大型和异质群体；一组（原型：类似MA的蛋白质）包括疾病 与细胞内抗原有关；另一组（原型：NMDA受体）包括与细胞有关的疾病 膜抗原。第一组的疾病与癌症相关，脑细胞毒性T细胞浸润和 对治疗的可变反应，第二组疾病与癌症相关的频率较低，似乎是 由抗体介导，通常响应耗尽IgG的策略。这三个特定目标 竞争的续订应用是1）完全定义LE和曲目的临床免疫表型 NR2（NMDAR）抗原，2）绘制NMDAR和分离株的NR2亚基的表位区域 海马抗原和3）确定对NMDAR的NR2亚基的抗体是否导致A中的LE 鼠标模型。