Role of Sex Chromosome Complement in the CNS during Autoimmune Disease

描述（由申请人提供）：大多数自身免疫性疾病影响女性多于男性。多发性硬化（MS）是一种中枢神经系统（CNS）的自身免疫性脱髓鞘疾病，其特征在于在初始阶段为炎症，在后期阶段为神经变性，并且具有女性偏好。这种增加的雌性易感性也存在于MS，实验性自身免疫性脑脊髓炎（EAE）的小鼠模型中。虽然MS在女性中发生得更频繁，免疫反应更强，但MS在男性中更具进展性（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，这些因素赋予了更强大的免疫反应，但对中枢神经系统对损伤的反应更具弹性。自身免疫性疾病性别差异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，或者直接来自性连锁的转录产物，或者其次来自雌性或雄性特异性生殖组织分化后产生的性激素。本实验室 先前集中于EAE中免疫应答的产生，并且显示具有XX性染色体补体的PLP 139-151致敏淋巴结细胞的转移导致比具有XY-补体的细胞更严重的疾病严重性。这些研究使用了一种被称为“四个核心基因型”（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。这导致XX和XY-卵巢雌性，其中Y-表示Sry基因缺失，其他Y基因保留。此外，Sry基因可以在常染色体位置“加回”，产生携带睾丸的XX Sry和XY- Sry小鼠（参见综述（3））。4CG模型使得在相同的激素背景下比较XX和XY性染色体成为可能。虽然在4CG小鼠中的EAE研究显示了性染色体在免疫应答中的作用，但它们没有解决性染色体在CNS中介导的潜在影响。辐射骨髓嵌合体是基础免疫学中广泛使用的工具，可以独立于其他组织操纵免疫系统。我建议，有性染色体的影响，在中枢神经系统是独立的影响，在免疫系统在EAE。具体而言，X染色体基因可能在CNS中响应于损伤而发挥保护作用。在这个提议中，我将通过结合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基因型是基本上具有1个X染色体（1X）和0个Y染色体（0 Y）的雌性，因此可用于与XX（2X，0 Y）和XY-（1X，1 Y）小鼠比较EAE期间X与Y剂量的影响。这些研究将检查性染色体，免疫系统和CNS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见解。

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.