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）是中枢神经系统（CNS）最常见的炎症性疾病，影响全球250多万人。MS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通常导致视觉障碍、失禁以及感觉和运动障碍。据估计，这种疾病在女性中的发病率至少是男性的三倍，虽然涉及遗传、激素和免疫反应差异，但这种性别偏见的基础仍然没有得到充分理解。MS被认为是自身免疫性的，髓磷脂特异性CD 4 + Th 1和Th 17细胞是CNS炎症的主要协调者。假设这些细胞最初在外周淋巴器官中被激活，但必须穿过相对不可渗透的血脑屏障（BBB）才能在CNS中重新激活。浸润或驻留在CNS中的其他先天性免疫细胞有助于炎症介导的神经损伤。这些事件中的许多事件最初是通过研究类似的，虽然不完美的啮齿动物模型MS，实验性过敏性/自身免疫性脑脊髓炎（EAE）。肥大细胞是存在于大多数组织中的粒细胞，并且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。携带编码SCF受体ckit的Kit突变的小鼠不能产生肥大细胞，并已用于研究肥大细胞在复发缓解型EAE模型中的作用。我们以前证明，雌性SJLW/Wv小鼠表现出减弱的EAE，一种依赖于肥大细胞的表型。然而，雄性SJLW/Wv小鼠的疾病加重，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ckitW/Wv雄性之间的血清睾酮水平不同，其没有显示出显著差异。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，男性肥大细胞在疾病背景下与女性肥大细胞相比显示出不同的反应;和/或ii）SCF，c-kit的配体，协同发挥神经保护作用 与睾酮，以尽量减少免疫介导的损害，在中枢神经系统。本研究的具体目的是：1）比较野生型与ckitW/Wv雄性小鼠中导致EAE发展的事件（例如外周中的T细胞引发、炎性细胞进入CNS、局部CNS炎性反应），以确定c-kit信号在何处发挥其保护性影响2） 确定肥大细胞或其他c-kit相关因子是否以及如何改变男性疾病易感性。 公共卫生相关性：目前还不清楚为什么男性通常比女性更不易患自身免疫性疾病。我们观察到，Kit基因（c-kitW/Wv）（干细胞因子受体）的突变可以保护女性免受严重疾病的影响， 多发性硬化症的啮齿动物模型，但加重男性的疾病。这些小鼠提供了一个完美的系统来探索c-kit信号传导如何与男性性激素的影响相结合，赋予神经保护作用，并可能为这种毁灭性的CNS疾病提供更好的治疗方法。

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. PUBLIC HEALTH RELEVANCE: It is still not understood why males are generally less susceptible to autoimmune disease than females. We observed that mutations in the Kit gene (c-kitW/Wv), the receptor for stem cell factor, protect females from developing severe disease in a rodent model of multiple sclerosis, but exacerbate disease in males. These mice provide a perfect system to explore the how c-kit signaling, in concert with influences from male sex hormones, confers neuroprotection and may lead to better therapies for this devastating CNS disease.