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: 8651766
• 负责人: Sienmi Du
• 金额: $ 1.74万
• 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/8651766
• 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大于男性。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，其特征是早期以炎症为特征，后期以神经退行性变为特征，并且有女性偏见。这种增加的雌性易感性也存在于MS小鼠模型，实验性自身免疫性脑脊髓炎（EAE）中。虽然MS在女性中发生的频率更高，免疫反应也更强，但男性的MS更具有进行性(2)。因此，我们想知道在女性中是否存在相反的性别相关因素，赋予更强大的免疫反应，但在中枢神经系统对损伤的反应方面更具弹性。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。所有的性别差异最终都是由性染色体引起的，要么直接来自与性别相关的转录产物，要么间接来自雌性或雄性特异性生殖组织分化后产生的性激素。我们实验室