Mast cell actions in chronic progressive versus relapsing remitting 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，影响着全球250多万人。这种自身免疫性疾病的特征是中枢神经系统血管周围炎症，神经纤维脱髓鞘以及轴突损伤。当运动和感觉冲动通过大脑或脊髓的脱髓鞘区域时，其结果是中断，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。髓磷脂特异性CD4+ Th1和Th17细胞是中枢神经系统炎症的主要协调者。据推测，这些细胞和CD8+ T细胞最初在外周淋巴器官被激活，但必须穿过通常相对不渗透的血脑屏障（BBB）才能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，即使不完善的MS啮齿动物模型，实验性过敏性/自身免疫性脑脊髓炎（EAE）来定义的。易感小鼠在髓磷脂成分免疫后出现许多相同的神经功能缺陷和相似的中枢神经系统组织学特征。mog诱导的C57BL/6模型模拟了约10%的MS患者出现的原发性进行性（PP）疾病的特征。可以说，plp诱导的SJL小鼠模型更相关，因为它呈现出约85%的MS患者经历的复发缓解（RR）过程。在C57BL/6小鼠中研究EAE具有显著的先天优势，包括具有C57BL/6背景的小鼠在许多免疫系统基因中含有靶向缺失。毫不奇怪，从我们实验室和其他实验室对pp样疾病的研究中获得的见解是非常宝贵的。肥大细胞是一种广泛分布于全身的先天细胞类型，已被清楚地证明，肥大细胞对疾病进程具有负面影响。肥大细胞的主要作用部位是脑膜，在这里它们调节血脑屏障的通透性和中枢神经系统中与中性粒细胞内流相关的细胞积聚。也有证据表明肥大细胞影响中枢神经系统近端部位（如脑膜和颈部淋巴结）的T细胞活化。我们在SJL背景下开发了肥大细胞缺陷小鼠，显示了肥大细胞依赖性疾病的严重程度。该模型将允许研究与新一波血脑屏障通透性和炎症细胞流入相关的复发期间肥大细胞的作用。我们假设肥大细胞、T细胞和中性粒细胞在疾病早期脑膜内的共定位导致细胞的交叉激活，并促进与疾病相关的血脑屏障破坏。我们研究的具体目的是：

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.