Role of Sex Chromosome Complement in the CNS during Autoimmune Disease

描述(申请人提供)：大多数自身免疫性疾病影响女性多于男性。多发性硬化症(MS)是一种中枢神经系统(CNS)自身免疫性脱髓鞘疾病，早期以炎症为特征，晚期以神经退行性变为特征，女性偏向。这种女性易感性的增加也存在于多发性硬化症的小鼠模型中，即实验性自身免疫性脑脊髓炎(EAE)。虽然多发性硬化症在女性中发生的频率更高，免疫反应更强健，但男性的多发性硬化症进展更快(2)。因此，我们想知道在女性中是否存在相反的与性相关的因素，这些因素赋予女性更强大的免疫反应，但在中枢神经系统对损伤的反应方面具有更强的弹性。自身免疫性疾病的性别差异背后的性别相关因素可能为MS患者提供治疗靶点。所有的性别差异最终都来自性染色体，要么直接来自与性别相关的转录产物，要么次要地来自雌性或雄性特有生殖组织分化后产生的性激素。我们的实验室 以前专注于EAE中免疫反应的产生，并表明带有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。这些研究使用了一种被称为“四种核心基因类型”(4CG)的转基因小鼠模型，在该模型中，编码睾丸发育的Sry基因已经从Y染色体上删除。这导致了XX和XY卵巢的雌性，其中Y-表示Sry基因被删除，而其他Y基因保留。此外，Sry基因可以在常染色体上被“重新添加”，导致XX Sry和XY-Sry小鼠生育睾丸(见综述(3))。4CG模型使得在相同的荷尔蒙背景下比较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一种独立于其他组织操纵免疫系统的工具。我认为，在EAE期间，中枢神经系统中存在独立于免疫系统影响的性染色体效应。具体地说，X染色体基因可能在中枢神经系统对损伤的反应中发挥保护作用。在这项建议中，我将结合4CG雌性和XY*x小鼠的骨髓嵌合体和EAE研究来验证我的假设。XY*x基因是实质上具有1X染色体(1X)和0Y染色体(0Y)的雌性小鼠，因此可以用来与XX(2X，0Y)和XY-(1X，1Y)小鼠比较在EAE期间X和Y的剂量效应。这些研究将检验性染色体、免疫系统和中枢神经系统在自身免疫性脱髓鞘疾病中的相互作用，并提供对自身免疫性疾病中性别差异受性染色体调节的程度的洞察。

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.