From the Departments of Neuroimmunology (SL, CGvE, KS, IH), Astrocyte Biology and Neurodegeneration (MEvS), and Neuropsychiatric Disorders (DFS), Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.
J Neuropathol Exp Neurol. 2014 Feb;73(2):123-35. doi: 10.1097/NEN.0000000000000037.
The basis of gender differences in the prevalence and clinical progression of multiple sclerosis (MS) is not understood. Here, we identify gender-specific responses in steroid synthesis and signaling in the brains of MS patients as possible contributors to these differences. We investigated gene expression changes in these pathways and of inflammatory cytokines in MS lesions and normal-appearing white matter (NAWM) of male and female patients (n=21) and control NAWM (n=14) using quantitative polymerase chain reaction (25 MS lesions, 21 MS NAWM, and 14 control NAWM) and immunohistochemistry (3-4 sections per group). In MS lesions in males, there was local upregulation of aromatase (an enzyme involved in estrogen biosynthesis), estrogen receptor-β (ERβ), and tumor necrosis factor (TNF) mRNA; whereas in females, there was local upregulation of 3β-hydroxysteroid-dehydrogenase, a progesterone synthetic enzyme, and of progesterone receptor. Astrocytes in the rim and center of MS lesions were found to be the primary source of steroidogenic enzyme and receptor expression. Aromatase and ERα mRNA levels were positively correlated with that of TNF in primary cultures of human microglia and astrocytes; TNF caused increased ERα, suggesting that inflammatory signals stimulate estrogen signaling in this cell type. Together, these findings suggest that there are gender differences in the CNS of MS patients that may affect lesion pathogenesis, that is, in males, estrogen synthesis and signaling are induced; whereas in females, progestogen synthesis and signaling are induced. These differences may represent contributing factors to gender differences in the prevalence and course of MS.
多发性硬化症（MS）的患病率和临床进展存在性别差异，但究其根本原因尚不清楚。本研究旨在确定 MS 患者大脑中类固醇合成和信号转导的性别特异性反应是否可能是导致这些差异的原因之一。我们使用定量聚合酶链反应（qPCR）（25 个 MS 病变、21 个 MS 正常外观白质（NAWM）和 14 个对照 NAWM）和免疫组织化学（每组 3-4 个切片），研究了这些通路和炎症细胞因子在 MS 病变和正常外观白质（NAWM）中的基因表达变化，纳入了男性和女性患者（n=21）和对照 NAWM（n=14）。在男性 MS 病变中，芳香化酶（参与雌激素生物合成的酶）、雌激素受体-β（ERβ）和肿瘤坏死因子（TNF）mRNA 局部上调；而在女性中，孕激素合成酶 3β-羟甾脱氢酶和孕激素受体局部上调。MS 病变边缘和中心的星形胶质细胞被发现是产生甾体激素酶和受体表达的主要来源。在人小胶质细胞和星形胶质细胞的原代培养物中，芳香酶和 ERα mRNA 水平与 TNF 的水平呈正相关；TNF 导致 ERα 增加，表明炎症信号刺激了这种细胞类型的雌激素信号转导。总之，这些发现表明 MS 患者的中枢神经系统存在性别差异，这些差异可能影响病变的发病机制，即在男性中，雌激素的合成和信号转导被诱导；而在女性中，孕激素的合成和信号转导被诱导。这些差异可能是 MS 患病率和病程中性别差异的促成因素。
