Role of Sex Chromosome Complement in the CNS during Autoimmune Disease

性染色体补体在自身免疫性疾病期间中枢神经系统中的作用

• 批准号: 8527589
• 负责人: Sienmi Du
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527589
• 关键词: Address; Affect; Autoimmune Diseases; Autoimmune Process; Back; Bone Marrow; CNS Demyelinating Autoimmune Diseases; Cells; Chimera organism; Clinic; Clinical; Complement; Demyelinating Diseases; Development; Disease; Female; Generations; Genes; Genotype; Gonadal Steroid Hormones; Hormonal; Immune; Immune response; Immune system; Immunology; Incidence; Inflammation; Laboratories; Lead; Link; Location; Mediating; Modeling; Multiple Sclerosis; Mus; Nerve Degeneration; Neuraxis; Outcome; Ovary; Patients; Ploidies; Predisposition; Role; SJL Mouse; Severity of illness; Sex Characteristics; Sex Chromosomes; Staging; Testing; Testis; Tissues; Transgenic Mice; Translating; X Chromosome; Y Chromosome; dosage; insight; irradiation; lymph nodes; male; men; mouse model; nervous system disorder; neuropathology; novel; novel strategies; protective effect; proteolipid protein 139-151; public health relevance; reproductive; resilience; response to injury; sex; sry Genes; therapeutic target; tool

DESCRIPTION (provided by applicant): Most autoimmune diseases affect more females than males. Multiple sclerosis (MS) is a putative autoimmune demyelinating disease of the central nervous system (CNS) characterized in the initial stages by inflammation, in the later stages by neurodegeneration, and has a female bias. This increased susceptibility of females is also present in the mouse model of MS, experimental autoimmune encephalitomyelitis (EAE). While MS occurs in females more frequently and with more robust immune response, MS in men is more progressive (2). Thus, we wonder if there could be opposing sex-related factors in females that impart more robust immune responses but more resilience regarding the CNS response to injury. Sex-related factors underlying sex differences in autoimmune diseases could present a therapeutic target for MS patients. All sex differences ultimately arise from sex chromosomes, either directly from sex-linked transcriptional products or secondarily from sex hormones produced after the differentiation of female- or male-specific reproductive tissues. Our laboratory previously focused on generation of immune responses in EAE and showed that the transfer of PLP 139-151 sensitized lymph node cells with XX sex chromosome complement leads to greater disease severity than cells with XY- complement. These studies used a transgenic mouse model known as the "four core genotypes" (4CG) in which the Sry gene, which encodes for testicular development, has been deleted from the Y chromosome. This result in XX and XY- ovary-bearing females, where Y- denotes that the Sry gene was deleted and other Y genes remain. In addition, the Sry gene can be "added back" in an autosomal location resulting in XX Sry and XY- Sry mice which are testes bearing (see review (3)). The 4CG model makes it possible to compare between XX and XY- sex chromosomes on the same hormonal background. While EAE studies in 4CG mice showed a role of sex chromosomes in immune responses, they do not address potential effects mediated by sex chromosomes in the CNS. Irradiation bone marrow chimera is a widely used tool in basic immunology to manipulate the immune system independently from other tissues. I propose that there are sex chromosome effects in the CNS that are independent of effects in the immune system during EAE. Specifically, X chromosome genes may exert a protective effect in the CNS in response to injury. In this proposal, I will test my hypothesis by combining bone marrow chimera and EAE studies in the 4CG females and XY*x mice. The XY*x genotype are females that essentially have 1 X chromosome (1X) and 0 Y chromosome (0Y), and thus can be used to compare with XX (2X, 0Y) and XY- (1X, 1Y) mice for effects of X vs. Y dosage during EAE. These studies will examine the interplay between sex chromosomes, the immune system, and the CNS in an autoimmune demyelinating disease and provide insight into the extent to which sex differences in autoimmune diseases are regulated by sex chromosomes.

描述（由申请人提供）：大多数自身免疫性疾病对女性的影响多于男性。多发性硬化症 (MS) 是一种假定的中枢神经系统 (CNS) 自身免疫性脱髓鞘疾病，其特征是早期阶段以炎症为特征，后期阶段以神经变性为特征，并且女性偏多。女性的这种易感性增加也存在于多发性硬化症（实验性自身免疫性脑脊髓炎（EAE））小鼠模型中。虽然多发性硬化症在女性中发生的频率更高且免疫反应更强，但男性多发性硬化症的进展更为严重 (2)。因此，我们想知道女性中是否存在与性别相关的相反因素，这些因素可以赋予更强大的免疫反应，但中枢神经系统对损伤的反应更有弹性。自身免疫性疾病性别差异背后的性别相关因素可能为多发性硬化症患者提供治疗靶点。所有性别差异最终都源于性染色体，要么直接来自与性别相关的转录产物，要么其次来自女性或男性特异性生殖组织分化后产生的性激素。我们的实验室 先前专注于 EAE 中免疫反应的产生，并表明具有 XX 性染色体补体的 PLP 139-151 致敏淋巴结细胞的转移比具有 XY-补体的细胞导致更严重的疾病。这些研究使用了被称为“四核心基因型”(4CG) 的转基因小鼠模型，其中编码睾丸发育的 Sry 基因已从 Y 染色体上删除。这会产生带有 XX 和 XY- 卵巢的雌性，其中 Y- 表示 Sry 基因被删除，其他 Y 基因保留。此外，Sry 基因可以在常染色体位置“添加回”，从而产生具有睾丸的 XX Sry 和 XY-Sry 小鼠（参见评论 (3)）。 4CG 模型使得在相同激素背景下比较 XX 和 XY 性染色体成为可能。虽然 4CG 小鼠的 EAE 研究显示了性染色体在免疫反应中的作用，但它们并没有解决中枢神经系统中性染色体介导的潜在影响。辐射骨髓嵌合体是基础免疫学中广泛使用的工具，可独立于其他组织操纵免疫系统。我认为 EAE 期间 CNS 中存在性染色体效应，与免疫系统中的效应无关。具体来说，X染色体基因可能在中枢神经系统中发挥保护作用以应对损伤。在本提案中，我将通过结合 4CG 雌性小鼠和 XY*x 小鼠的骨髓嵌合体和 EAE 研究来检验我的假设。 XY*x 基因型是基本上具有 1 X 染色体 (1X) 和 0 Y 染色体 (0Y) 的雌性，因此可用于与 XX (2X, 0Y) 和 XY- (1X, 1Y) 小鼠比较 EAE 期间 X 与 Y 剂量的影响。这些研究将检查自身免疫性脱髓鞘疾病中性染色体、免疫系统和中枢神经系统之间的相互作用，并深入了解自身免疫性疾病中性别差异受性染色体调节的程度。