Role of Inflammation in Progressive Multifocal Leukoencephalopathy

炎症在进行性多灶性白质脑病中的作用

• 批准号: 9334313
• 负责人: Igor J Koralnik
• 金额: $ 36.97万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-13 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334313
• 关键词: AIDS-Related Opportunistic Infections; Affect; Anti-Retroviral Agents; Blood flow; Central Nervous System Diseases; Cerebral cortex; Clinical; Clinical Management; Demyelinations; Deterioration; Development; Diagnosis; Diagnostic; Disease; Electrophysiology (science); Encephalopathies; Epileptogenesis; Etiology; Evolution; Frequencies; Goals; HIV; Histologic; Image; Immune; Immune response; Immunologic Markers; Immunologics; Immunology; Individual; Inflammation; Inflammatory; JC Virus; Knowledge; Lesion; Lipids; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Metabolism; Mission; Morbidity - disease rate; National Institute of Neurological Disorders and Stroke; Neuroglia; Neurologic; Neurons; Nitric Oxide; Outcome; Pathogenesis; Pathogenicity; Patients; Perfusion; Phagocytes; Pharmaceutical Preparations; Preventive; Preventive Intervention; Production; Progressive Multifocal Leukoencephalopathy; Protons; Public Health; Radiology Specialty; Research; Role; Seizures; Signal Transduction; Spin Labels; Surrogate Markers; Syndrome; T cell response; Testing; Therapeutic; Therapeutic Intervention; Virus; astrogliosis; central nervous system demyelinating disorder; contrast enhanced; granule cell; gray matter; immunosuppressed; innovation; macrophage; mortality; nervous system disorder; novel; predictive marker; prospective; public health relevance; reconstitution; virology; white matter

DESCRIPTION: There is a fundamental gap in our understanding of the immune reconstitution inflammatory syndrome (IRIS), which occurs frequently in HIV+ patients with progressive multifocal leukoencephalopathy (PML) treated with antiretroviral medications. This poses a difficult diagnostic and therapeutic conundrum, since neurological deterioration associated with inflammation in PML-IRIS cannot be differentiated from the demyelination occurring with the natural evolution of PML. In addition, a growing number of PML patients are developing seizures, thought to originate in the cerebral cortex. How PML, a disease affecting predominantly the CNS white mater triggers seizures is unknown. Our long term goal is to understand the pathogenic mechanisms of PML-IRIS, and the cause of epileptogenesis in PML and its association with IRIS. Our objective is to establish precise criteria to diagnose and track IRIS and predict the development of seizures in PML, which can then be used for preventive and therapeutic purposes. We have shown that the T-cell response to the causative agent of PML, JC virus (JCV), was associated with PML survival. Using proton magnetic resonance spectroscopy (1H-MRS) and arterial spin labeling (ASL) MRI, we have defined differences in the metabolism and perfusion of PML lesions with and without IRIS. Finally, we have identified a novel MRI marker associated with seizures and IRIS. This hyperintense cortical signal (HCS) can be seen on pre- contrast T1-weighted images in cortical gray matter adjacent to PML lesions. We hypothesize that hyperperfusion seen in PML progressors delineates virologically active lesions and is triggered by local production of nitric oxide (NO). We postulate that HCS is caused by an infiltrate of macrophages and astrogliosis in deep layers of the cerebral cortex affected by JCV demyelination, and constitutes the nidus of epileptogenesis in PML. We propose that IRIS is caused by an imbalance between Th1, Th2 and Th17 immune responses. The rationale for the proposed research is that a combination of immunological, neuroradiological and electrophysiological parameters will predict the development of IRIS and seizures in PML, and directly help in the management of these challenging patients. To test these hypotheses, we will pursue the following set of Specific Aims: 1) Characterize immunological and radiological determinants of inflammation and outcome in PML patients with and without IRIS. We will study JCV-specific T-cell responses, MRI, 1H- MRS and perfusion MRI to define further the mechanisms of IRIS and identify surrogate markers of PML progression and survival. 2) Analyze the role of IRIS in PML-associated epileptogenesis. We will determine prospectively the value of HCS and of dense array electroencephalographic findings as predictive markers of IRIS and seizures in PML. 3) Decipher the histopathological substrates of PML progression, epileptogenesis and IRIS. We will characterize histologically the pathogenic mechanisms leading to HCS, hyperperfusion and IRIS. Our multifaceted innovative approach will have direct impact on the management of patients with PML-IRIS and seizures. The knowledge gained will greatly advance the fields of Neuroradiology, Immunology and Epileptology.

产品说明：我们对免疫重建炎症综合征（IRIS）的理解存在根本性差距，IRIS经常发生在接受抗逆转录病毒药物治疗的进行性多灶性白质脑病（PML）的HIV+患者中。这造成了一个难以诊断和治疗的难题，因为与PML-IRIS中炎症相关的神经功能恶化无法与PML自然演变中发生的脱髓鞘区分开来。此外，越来越多的PML患者出现癫痫发作，被认为起源于大脑皮层。PML是一种主要影响CNS白色物质的疾病，其如何触发癫痫发作尚不清楚。我们的长期目标是了解PML-IRIS的发病机制，以及PML中癫痫发生的原因及其与IRIS的关系。我们的目标是建立精确的标准来诊断和跟踪 IRIS并预测PML中癫痫发作的发展，然后可用于预防和治疗目的。我们已经证明，T细胞对PML病原体JC病毒（JCV）的应答与PML存活率相关。使用质子磁共振波谱（1H-MRS）和动脉自旋标记（ASL）MRI，我们已经确定了有和没有IRIS的PML病变的代谢和灌注的差异。最后，我们已经确定了一种新的MRI标记物与癫痫发作和IRIS。这种高信号皮质信号（HCS）可以在增强前T1加权像上在PML病变附近的皮质灰质中看到。我们假设，在PML进展者中观察到的过度灌注描绘了病毒学活性病变，并由局部一氧化氮（NO）的产生触发。我们推测HCS是由JCV脱髓鞘影响的大脑皮层深层巨噬细胞浸润和星形胶质细胞增生引起的，并构成PML癫痫发生的病灶。我们认为IRIS是由Th 1，Th 2和Th 17免疫应答之间的失衡引起的。拟议研究的基本原理是，免疫学、神经放射学和电生理学参数的组合将预测PML中IRIS和癫痫发作的发展，并直接帮助管理这些具有挑战性的患者。为了检验这些假设，我们将追求以下一组特定目标：1）表征有和无IRIS的PML患者的炎症和结局的免疫学和放射学决定因素。我们将研究JCV特异性T细胞反应、MRI、1H-MRS和灌注MRI，以进一步确定IRIS的机制，并确定PML进展和生存的替代标志物。2)分析IRIS在PML相关癫痫发生中的作用。我们将前瞻性地确定HCS和密集阵列脑电图结果作为PML患者IRIS和癫痫发作的预测标志物的价值。3)解读PML进展、癫痫发生和IRIS的组织病理学基础。我们将从组织学上描述导致HCS、高灌注和IRIS的致病机制。我们多方面的创新方法将对PML-IRIS和癫痫患者的管理产生直接影响。所获得的知识将大大推进神经放射学，免疫学和癫痫学领域。