Mechanisms Regulating Reduced c-Kit-Dependent EAE Susceptibility in Male SJL Mice

描述（由申请人提供）：多发性硬化症（MS）是最常见的中枢神经系统（CNS）炎症性疾病，影响全球超过250万人。多发性硬化症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，它们的中断常常导致视觉障碍、尿失禁以及感觉和运动障碍。据估计，这种疾病在女性中的患病率至少是男性的三倍，虽然遗传、激素和免疫反应的差异已被牵连在内，但这种性别偏见的基础仍未完全了解。MS被认为本质上是自身免疫性的，髓鞘特异性CD4+ Th1和Th17细胞是中枢神经系统炎症的主要策划者。据推测，这些细胞最初在周围淋巴器官被激活，但必须穿过相对不渗透的血脑屏障（BBB）才能在中枢神经系统重新激活。其他浸润或驻留在中枢神经系统的先天免疫细胞有助于炎症介导的神经损伤。许多这些事件最初是通过研究类似的，尽管不完善的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。肥大细胞是存在于大多数组织中的粒细胞，是对女性疾病严重程度发挥重要放大作用的先天细胞之一。编码SCF受体ckit的Kit突变小鼠不能发育肥大细胞，并被用于研究肥大细胞在复发-缓解型EAE模型中的作用。我们之前证明雌性SJLW/Wv小鼠表现出EAE减弱，这是一种依赖于肥大细胞的表型。然而，雄性SJLW/Wv小鼠病情加重，表明肥大细胞或其他c-kit相关缺陷在雄性中是病理性的。这不是由于野生型和野生型/野生型男性血清睾酮水平不同，后者没有显着差异。对这些观察结果至少有两种解释：i)在性激素（如睾酮）的影响下，与雌性肥大细胞相比，雄性肥大细胞在疾病情况下表现出不同的反应；和/或ii) c-kit的配体SCF协同发挥神经保护作用

DESCRIPTION (provided by applicant): Multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS), affects more than 2.5 million people worldwide. MS 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 often leads to visual disturbances, incontinence as well as sensory and motor disturbances. The prevalence of this disease is estimated to be at least three times greater in females than males and while genetic, hormonal and immune response differences have been implicated, the basis for this gender bias is still not fully understood. MS is considered to be autoimmune in nature and myelin-specific CD4+ Th1 and Th17 cells are major orchestrators of the CNS inflammation. It is assumed that these cells are initially activated in peripheral lymphoid organs but must cross the relatively impermeable blood-brain barrier (BBB) to become reactivated in the CNS. Other innate immune cells that infiltrate or reside in the CNS contribute to inflammation-mediated neurological damage. Many of these events have been initially defined by studying the similar, albeit imperfect rodent model of MS, experimental allergic/autoimmune encephalomyelitis (EAE). Mast cells are granulocytes that reside in most tissues and are among the innate cells that exert an important amplifying effect on disease severity in females. Mice bearing mutations in Kit, which encodes the SCF receptor, ckit, fail to develop mast cells and have been used to study the role of mast cells in a relapsing-remitting EAE model. We previously demonstrated that female SJLW/Wv mice exhibit attenuated EAE, a phenotype dependent on mast cells. However, male SJLW/Wv mice have exacerbated disease, indicating either mast cells or other c-kit related defects are pathologic in males. This is not due to disparate serum testosterone levels between wild type and ckitW/Wv males, which show no significant differences. There are at least two explanations for these observations: i) Male mast cells, under the influence of sex hormones such as testosterone, show distinct responses in the context of disease compared to female mast cells; and/or ii) SCF, the ligand for c-kit, exerts a neuroprotective effect in concert with testosterone that acts to minimize immune-mediated damage in the CNS. The specific aims of this study are: 1) Compare the events (e.g. T cell priming in the periphery, inflammatory cell entry to the CNS, local CNS inflammatory responses) that lead to development of EAE in wild type versus ckitW/Wv male mice to determine where c-kit signals exert their protective influence 2) Identify whether and how mast cells or other c-kit related factors alter disease susceptibility in males.