Functional genetics of sex differences in autoimmunity

自身免疫性别差异的功能遗传学

• 批准号: 453860947
• 负责人: Professor Dr. Manuel A. Friese
• 金额: --
• 依托单位: Institut für Neuroimmunologie und Multiple Sklerose (INIMS)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/453860947?language=en
• 关键词: Functional; genetics; sex; differences; autoimmunity

Differences in the immune response between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect females. This has been docu-mented for many autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune liver diseases – and for multiple sclerosis (MS). MS is the most common inflammatory disease of the central nervous system (CNS) and manifests in more than twice as many women, making sex one of the top risk factors for developing MS. Various factors can contribute to sex differences, such as hormones, genetic or epigenetic factors, which can influ-ence immune cell function. However, it is unknown which genes are differentially expressed in females and males and could thereby contribute to sex differences in autoimmune incidence. To address that we conducted a gene expression analysis in female and male human spleen and blood using the Genotype-Tissue Expression (GTEx) project dataset. From 62 differentially ex-pressed genes (DEGs) in the blood and 114 DEGs in the spleen, we selected DEGs that had associations with immune regulation. After successful validation of the transmembrane protein CD99, which is markedly increased in men, we will here focus on its sex-specific contribution to T cell activation and transmigration. We hypothesize that sex determines expression of CD99 resulting in different immune cell responses in females and males. This emerging sex-specific expression and functional differences could contribute to sexual disparity in autoimmunity, such as MS.

女性和男性之间免疫反应的差异导致主要影响女性的自身免疫性疾病的发病率存在强烈的性别偏见。这已被证明是许多自身免疫性疾病，如系统性红斑狼疮（SLE），类风湿性关节炎，自身免疫性肝病-和多发性硬化症（MS）。MS是中枢神经系统（CNS）最常见的炎症性疾病，女性患者的发病率是男性的两倍多，这使得性别成为MS发病的最大风险因素之一。多种因素可能导致性别差异，如激素、遗传或表观遗传因素，这些因素可能影响免疫细胞功能。然而，目前尚不清楚哪些基因在女性和男性中差异表达，从而可能导致自身免疫发病率的性别差异。为了解决这一问题，我们使用基因型-组织表达（GTEx）项目数据集在女性和男性人脾脏和血液中进行了基因表达分析。从血液中的62个差异表达基因（DEG）和脾脏中的114个DEG中，我们选择了与免疫调节相关的DEG。在成功验证了跨膜蛋白CD 99（在男性中显著增加）后，我们将在这里重点关注其对T细胞活化和迁移的性别特异性贡献。我们假设性别决定了CD 99的表达，导致女性和男性不同的免疫细胞反应。这种新出现的性别特异性表达和功能差异可能导致自身免疫的性别差异，如MS。