Mast cell actions in chronic progressive versus relapsing remitting EAE

肥大细胞在慢性进展性与复发缓解性 EAE 中的作用

• 批准号: 8256257
• 负责人: Julianne K Hatfield
• 金额: $ 4.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256257
• 关键词: Abnormal coordination; Acute; Affect; Allergic; Animal Disease Models; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Biological Response Modifiers; Bladder; Blood - brain barrier anatomy; Brain; Brain region; C57BL/6 Mouse; CD8B1 gene; Cell Communication; Cell physiology; Cells; Cellular Infiltration; Central Nervous System Diseases; Cervical lymph node group; Chronic; Clinical; Data; Demyelinations; Development; Disease; Disease model; Disease remission; Dura Mater; Etiology; Event; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Generations; Genes; Immune; Immune system; Immunization; Incontinence; Infiltration; Inflammation; Inflammatory; Interruption; Intestines; Investigation; Kinetics; Laboratories; Learning; Lesion; Lymphoid; Mediating; Mediator of activation protein; Meningeal; Meninges; Minor; Modeling; Molecular; Motor; Mouse Strains; Movement; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Nerve Fibers; Neuraxis; Neurologic; Neutrophil Infiltration; Onset of illness; Organ; Patients; Pattern; Peptides; Peripheral; Permeability; Peroxidases; Play; Population; Primary Progressive Multiple Sclerosis; Progressive Disease; Recruitment Activity; Relapse; Relapsing-Remitting Multiple Sclerosis; Rodent; Rodent Model; Role; SJL Mouse; Sensory; Severity of illness; Site; Spinal Cord; Structure; Symptoms; Syndrome; T-Lymphocyte; TNF gene; Testing; Th1 Cells; Tissues; Vascular Permeabilities; Visual; arm; autoreactive T cell; cell type; central nervous system demyelinating disorder; clinically relevant; disability; experience; insight; mast cell; neutrophil; partial recovery; research study; response; trafficking; transmission process; virus genetics

Multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS), affects more than 2.5 million people worldwide. This autoimmune disease is characterized by perivascular inflammation in the CNS, demyelination of nerve fibers as well as axonal damage. The resulting interruption of motor and sensory impulses as they pass through demyelinated regions of the brain or spinal cord leads to visual disturbances, bowel and bladder incontinence, sensory and motor disturbances and lack of coordination. Myelin-specific CD4+ Th1 and Th17 cells are major orchestrators of the CNS inflammation. It is assumed that these cells along with CD8+ T cells are initially activated in peripheral lymphoid organs but must cross the normally relatively impermeable blood-brain barrier (BBB) to become reactivated and initiate inflammation. Many of these events were initially defined by studying the similar, even if imperfect, rodent model of MS, experimental allergic/autoimmune encephalomyelitis (EAE). Susceptible strains of mice develop many of the same neurological deficits and similar CNS histological features after immunization with myelin components. The MOG-induced C57BL/6 model mimics features of primary progressive (PP) disease that presents in ~ 10 % of MS patients. Arguably, the PLP-induced model in SJL mice is more relevant because it presents with a relapsing-remitting (RR) course experienced by ~85% of MS patients. There are significant advantages inherent in studying EAE in C57BL/6 mice including the availability of mice on the C57BL/6 background that contain targeted deletions in many immune system genes. Not surprisingly, the insight gained from these studies of PP-like disease in our laboratory and others has been invaluable. It has been clearly demonstrated that mast cells, an innate cell type that is widely distributed throughout the body, negatively modifies disease course. The primary site of mast cell action is the meninges, where they regulate BBB permeability and cellular accumulation in the CNS which is associated with neutrophil influx. There is also evidence that mast cells affect T cell reactivation in CNS-proximal sites such as the meninges and cervical lymph nodes. We have developed a mast cell deficient mouse on the SJL background that shows mast cell dependent severity of disease. This model will allow the investigation of mast cell actions during relapses that are associated with new waves of blood brain barrier permeability and inflammatory cell influx. We hypothesize that the co-localization of mast cells, T cells and neutrophils within the meninges in early disease results in cross-activation of cells and facilitates BBB breach associated with disease. The specific aims of our study are: Aim 1: To determine the molecular requirements for MC-dependent PMN trafficking to the dura and CNS parenchyma during EAE. Aim 2: To examine PMN/MC/Tcell interactions and activation of resident and infiltrating cells in the meninges during EAE.

多发性硬化症（MS）是中枢神经系统（CNS）最常见的炎症性疾病，影响全球超过250万人。这种自身免疫性疾病的特征在于CNS中的血管周围炎症、神经纤维脱髓鞘以及轴突损伤。当运动和感觉冲动通过脑或脊髓的脱髓鞘区域时，所产生的运动和感觉冲动的中断导致视觉障碍、肠和膀胱失禁、感觉和运动障碍以及缺乏协调。髓鞘特异性的CD 4 + Th 1和Th 17细胞是中枢神经系统炎症的主要协调者。假设这些细胞沿着CD 8 + T细胞最初在外周淋巴器官中被激活，但必须穿过通常相对不可渗透的血脑屏障（BBB）以重新激活并引发炎症。许多这些事件最初是通过研究类似的，即使是不完美的，啮齿动物模型的MS，实验性过敏/自身免疫性脑脊髓炎（EAE）。敏感品系的小鼠在用髓磷脂组分免疫后发展出许多相同的神经缺陷和相似的CNS组织学特征。MOG诱导的C57 BL/6模型模拟了在约10%的MS患者中存在的原发性进行性（PP）疾病的特征。可以说，SJL小鼠中PLP诱导的模型更相关，因为它呈现约85%的MS患者经历的复发-缓解（RR）过程。在C57 BL/6小鼠中研究EAE具有显著的固有优势，包括在许多免疫系统基因中含有靶向缺失的C57 BL/6背景小鼠的可用性。毫不奇怪，从我们实验室和其他实验室的PP样疾病研究中获得的见解是无价的。已经清楚地表明，肥大细胞，一种广泛分布于全身的先天性细胞类型，对疾病进程产生负面影响。肥大细胞作用的主要部位是脑膜，在那里它们调节BBB渗透性和CNS中的细胞积聚，这与中性粒细胞流入有关。也有证据表明，肥大细胞影响CNS近端部位（如脑膜和颈淋巴结）的T细胞再活化。我们在SJL背景下开发了肥大细胞缺陷小鼠，其显示肥大细胞依赖性疾病严重程度。该模型将允许研究复发期间肥大细胞的作用，其与血脑屏障通透性和炎性细胞流入的新波相关。我们推测，在疾病早期脑膜内肥大细胞、T细胞和中性粒细胞的共定位导致细胞的交叉激活，并促进与疾病相关的BBB破坏。我们研究的具体目标是： 目的1：确定EAE时MC依赖的PMN向硬脑膜和CNS实质运输的分子要求。目的2：研究EAE时脑膜内PMN/MC/T细胞的相互作用及驻留细胞和浸润细胞的活化。