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

雄性 SJL 小鼠 c-Kit 依赖性 EAE 易感性降低的调节机制

• 批准号: 8431165
• 负责人: Melissa A Brown
• 金额: $ 23.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431165
• 关键词: Abnormal coordination; Adoptive Transfer; Affect; Age; Allergic; Animal Model; Attenuated; Autoimmune Diseases; Autoimmune Process; Bladder; Blood - brain barrier anatomy; Brain region; CD8B1 gene; Cells; Central Nervous System Diseases; Defect; Demyelinations; Development; Disease; Disease Progression; Disease susceptibility; Environment; Event; Exhibits; Experimental Autoimmune Encephalomyelitis; Female; Gender; Genes; Genetic; Gonadal Steroid Hormones; Hormonal; Hormones; Immune; Immune response; Immunization; Incontinence; Inflammation; Inflammatory; Inflammatory Response; Interruption; Intestines; Investigation; Laboratories; Lead; Link; Lymphoid; Mediating; Mediator of activation protein; Meninges; Modeling; Molecular; Motor; Mouse Strains; Multiple Sclerosis; Mus; Mutant Strains Mice; Mutation; Myelin; Nature; Nerve Fibers; Nervous System Trauma; Neuraxis; Neurologic; Organ; Pathologic; Patients; Peripheral; Phenotype; Play; Population; Predisposition; Pregnancy; Prevalence; Process; Proto-Oncogene Protein c-kit; Recruitment Activity; Relapse; Rodent Model; Role; SJL Mouse; Sensory; Serum; Severity of illness; Sex Bias; Signal Transduction; Site; Spinal Cord; Stem Cell Factor; System; T-Lymphocyte; Testosterone; Time; Tissues; Visual; base; cell type; granulocyte; human disease; late disease onset; male; mast cell; mastocytosis; mutant; neuroprotection; protective effect; reconstitution; response; sex; trafficking

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.

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，影响了全球超过250万人。 MS的特征是中枢神经系统中血管周围炎症，神经纤维的脱髓鞘以及轴突损伤。当电动机穿过大脑或脊髓的脱髓鞘区域时，导致的电动机和感觉冲动会导致视觉障碍，尿失禁以及感觉和运动障碍。估计这种疾病的患病率在女性中至少是男性的三倍，尽管遗传，荷尔蒙和免疫反应差异已涉及，但这种性别偏见的基础仍未完全理解。 MS本质上被认为是自身免疫性的，髓磷脂特异性CD4+ TH1和Th17细胞是中枢神经系统炎症的主要编排。假定这些细胞最初是在周围淋巴器官中激活的，但必须越过相对不可渗透的血脑屏障（BBB）才能在中枢神经系统中重新激活。其他浸润或居住在中枢神经系统中的先天免疫细胞会导致炎症介导的神经系统损害。这些事件中的许多事件最初是通过研究MS，实验性过敏/自身免疫性脑脊髓炎（EAE）的类似啮齿动物模型来定义的。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的重要放大作用的先天细胞之一。编码SCF受体CKIT的套件中轴承突变的小鼠无法发展肥大细胞，并且已被用来研究肥大细胞在复发的EAE模型中的作用。我们先前证明了雌性SJLW/WV小鼠表现为eae，这是一种取决于肥大细胞的表型。然而，雄性SJLW/WV小鼠患有恶化的疾病，表明肥大细胞或其他与C-KIT相关的缺陷是男性的病理学。这不是由于野生型和CKITW/WV雄性之间的不同血清睾丸激素水平，这没有显着差异。这些观察结果至少有两个解释：i）与雌性肥大细胞相比，在睾丸激素等性激素（例如睾丸激素）的影响下，雄性肥大细胞在疾病的背景下显示出不同的反应；和/或ii）SCF，C-KIT的配体在音乐会中发挥神经保护作用 睾丸激素起作用可最大程度地减少中枢神经系统中的免疫介导的损伤。这项研究的具体目的是：1）比较事件（例如，在周围的T细胞启动，炎症细胞进入中枢神经系统，局部CNS炎症反应），从而导致野生型与CKITW/WV雄性小鼠的EAE发育，以确定C-KIT信号在哪里c-kit信号产生保护性影响2） 确定肥大细胞或其他C-KIT相关因素是否改变了男性疾病的易感性。 公共卫生相关性：仍然不了解男性通常不易自身免疫性疾病而不是女性。我们观察到，干细胞因子受体的试剂盒基因（C-KITW/WV）中的突变保护女性免于在A中患上严重疾病 多发性硬化症的啮齿动物模型，但在男性中加剧了疾病。这些小鼠提供了一个完美的系统，可以探索C-Kit信号与男性性激素的影响赋予神经保护作用，并可能为这种毁灭性的CNS疾病提供更好的疗法。