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.

描述：我们对免疫结构炎症综合征（IRIS）的理解存在根本差距，该疾病（IRIS）经常发生在患有抗逆转录病毒药物治疗的进行性多灶性白细胞厌氧菌（PML）的患者中。这构成了困难的诊断和治疗难题，因为与PML-IRIS中炎症相关的神经系统恶化不能与PML的自然演化发生的脱髓鞘区分开。此外，越来越多的PML患者正在发育癫痫发作，这些癫痫发作起源于大脑皮层。 PML是一种主要影响CNS的疾病，CNS白色母校触发癫痫发作尚不清楚。我们的长期目标是了解PML-IRI的致病机制，以及PML中癫痫发生及其与IRIS的关联的原因。我们的目标是建立精确的标准以诊断和跟踪 虹膜并预测PML中癫痫发作的发展，然后可以用于预防和治疗目的。我们已经表明，T细胞对PML JC病毒（JCV）致病剂的T细胞反应与PML存活有关。使用质子磁共振光谱（1H-MRS）和动脉自旋标记（ASL）MRI，我们确定了具有和没有虹膜的PML病变的代谢和灌注的差异。最后，我们确定了与癫痫发作和虹膜相关的新型MRI标记。在与PML病变相邻的皮质灰质中，可以看到这种高强度皮质信号（HCS）。我们假设在PML Progressors中看到的高灌注会描绘出病毒活性病变，并由一氧化氮（NO）局部产生触发。我们假设HCS是由巨噬细胞和星形胶质细胞增多的浸润引起的，该深层皮质的深层受JCV脱髓鞘影响，构成PML中癫痫发生的Nidus。我们建议虹膜是由Th1，Th2和Th17免疫反应之间的不平衡引起的。拟议的研究的基本原理是免疫，神经放射学和电生理参数的结合将预测PML中虹膜和癫痫发作的发展，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的：1）在有和没有虹膜的PML患者中，炎症和结果的免疫学和放射学决定因素表征。我们将研究JCV特异性的T细胞反应，MRI，1H- MRS和灌注MRI，以进一步定义虹膜的机制，并确定PML进展和存活的替代标记。 2）分析虹膜在与PML相关的癫痫发生中的作用。我们将前瞻性地确定HCS和密集阵列脑电图发现的价值，作为PML中虹膜和癫痫发作的预测标记。 3）解密PML进展，癫痫发生和虹膜的组织病理学底物。我们将在组织学上表征导致HC，高灌注和虹膜的致病机制。我们多方面的创新方法将直接影响PML-IRI和癫痫发作患者的管理。获得的知识将大大推动神经放射学，免疫学和癫痫学的领域。