Functional genetics of sex differences in autoimmunity

男女之间免疫反应的差异导致在主要影响女性的自身免疫性疾病发病率方面存在强烈的性别偏见。这在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）中都有记载。多发性硬化症是最常见的中枢神经系统（CNS）炎症性疾病，女性发病率是女性的两倍多，这使得性别成为多发性硬化症发病的首要危险因素之一。各种因素都可能导致性别差异，如激素、遗传或表观遗传因素，这些因素都会影响免疫细胞功能。然而，目前尚不清楚哪些基因在女性和男性中表达不同，从而可能导致自身免疫发病率的性别差异。为了解决这个问题，我们使用基因型-组织表达（GTEx）项目数据集对女性和男性的脾脏和血液进行了基因表达分析。从血液中的62个差异表达基因（DEGs）和脾脏中的114个差异表达基因（DEGs）中，我们选择了与免疫调节相关的DEGs。在成功验证跨膜蛋白CD99（在男性中显著增加）后，我们将重点研究其对T细胞活化和转运的性别特异性贡献。我们假设性别决定CD99的表达，从而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，如多发性硬化症。

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.