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，影响全球超过 250 万人。 MS 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，由此产生的中断通常会导致视觉障碍、失禁以及感觉和运动障碍。据估计，这种疾病在女性中的患病率至少是男性的三倍，虽然遗传、激素和免疫反应差异已被证实，但这种性别偏见的基础仍不完全清楚。 MS 被认为本质上是自身免疫性的，髓磷脂特异性 CD4+ Th1 和 Th17 细胞是中枢神经系统炎症的主要协调者。据推测，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）才能在中枢神经系统中重新激活。其他浸润或驻留在中枢神经系统的先天免疫细胞会导致炎症介导的神经损伤。其中许多事件最初是通过研究相似但不完美的 MS 啮齿动物模型、实验性过敏/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。 Kit（编码 SCF 受体 ckit）携带突变的小鼠无法发育肥大细胞，并已被用来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 小鼠表现出减弱的 EAE，这是一种依赖肥大细胞的表型。然而，雄性 SJLW/Wv 小鼠的疾病加剧，表明肥大细胞或其他 c-kit 相关缺陷在雄性中是病理性的。这并不是因为野生型和 ckitW/Wv 雄性之间的血清睾酮水平不同，没有显示出显着差异。对于这些观察结果至少有两种解释： i) 与女性肥大细胞相比，男性肥大细胞在睾酮等性激素的影响下，在疾病背景下表现出不同的反应；和/或 ii) SCF（c-kit 的配体）协同发挥神经保护作用 睾酮可最大限度地减少中枢神经系统免疫介导的损伤。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 发生的事件（例如外周 T 细胞启动、炎症细胞进入 CNS、局部 CNS 炎症反应），以确定 c-kit 信号在何处发挥其保护作用 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的疾病易感性。 公共卫生相关性：目前尚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，干细胞因子受体 Kit 基因 (c-kitW/Wv) 的突变可以保护女性免于患上严重疾病。 多发性硬化症的啮齿动物模型，但会加剧雄性的疾病。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中枢神经系统疾病带来更好的治疗方法。