Gender differences in immune responses in MS

描述（由申请人提供）：大多数自身免疫性疾病发生在女性中的频率较高。这表明自身免疫表型至少部分与性激素的免疫效应有关。迄今为止，大多数体外和体内研究表明，妊娠期高剂量的雌激素和孕激素具有免疫抑制作用。不幸的是，这些数据并不能解释为什么与男性相比，更多的女性患有多发性硬化症（MS）。雌激素对Th 1免疫促进作用的证据很少，尽管这些数据有助于解释自身免疫性疾病易感性的性别偏见。在前一个资助期，我们提出的证据，以支持性别的影响，在细胞因子反应髓鞘：妇女与MS显示显着偏斜IFN？MS患者对某些髓磷脂表位的反应，而MS患者显示IL-5反应。在这个提议中，我们提出的证据表明：1）内源性性激素水平与性别特异性细胞因子反应相关; 2）T细胞受体刺激的强度，沿着激素剂量，可能决定所产生的免疫反应是增强还是抑制; 3）低剂量的雌激素促进记忆性CD 4 T细胞迁移穿过脑内皮。这些数据使我们假设正常卵巢周期剂量的雌激素调节MS发病机制中的四个重要步骤：1）促进Th 1细胞活化; 2）促进淋巴细胞粘附到脑内皮; 3）调节淋巴细胞对内皮的化学吸引;和4）促进记忆性CD 4 T细胞穿过血脑屏障（BBB）的迁移。该提案将通过研究人外周血淋巴细胞在由人脑微血管内皮细胞组成的BBB的良好表征的迁移模型中的迁移来解决这一假设。总之，本研究将确定雌激素在调节中的作用：通过细胞因子分泌和增殖的细胞活化;淋巴细胞和脑内皮细胞上粘附分子的表达和功能;通过趋化因子和趋化因子受体吸引淋巴细胞穿过脑内皮;以及通过基质金属蛋白酶侵入BBB和致病淋巴细胞穿过BBB的迁移。这些研究将为了解雌激素的多种作用提供有价值的信息，并可能为开发未来的治疗方法提供分子靶点，以及更好地了解性激素在MS发病机制中的作用。

DESCRIPTION (provided by applicant): Most autoimmune diseases occur with higher frequency in women. This suggests that the autoimmune phenotype is related, at least in part, to immunologic effects from sex hormones. To date, most in vitro and in vivo studies have shown that high, pregnancy doses of estrogen and progesterone are immune suppressive. Unfortunately, these data do not explain why more women get multiple sclerosis (MS) compared to men. Evidence showing a Th1 -immune promoting effect by estrogen is minimal, although such data would help explain the gender bias in susceptibility to autoimmune disease. In the previous funding period, we presented evidence to support gender effects in the cytokine response to myelin: women with MS show dramatically skewed IFN? responses to certain myelin epitopes, whereas men with MS show an IL-5 response. In this proposal, we present evidence that: 1) endogenous sex hormone levels are associated with gender-specific cytokine responses; 2) the strength of the T cell receptor stimulus, along with hormone dose, may determine whether the resulting immune response is enhanced or suppressed; and 3) low doses of estrogen promote memory CD4 T cell migration across brain endothelium. These data have lead us to hypothesize that normal ovarian cycle doses of estrogen regulate four important steps in the pathogenesis of MS: 1) promote Th1 cellular activation; 2) promote lymphocyte adhesion to brain endothelium; 3) regulate chemoattraction of lymphocytes to endothelium; and 4) facilitate migration of memory CD4 T cells across the blood brain barrier (BBB). This proposal will address this hypothesis by studying the migration of human peripheral blood lymphocytes across a well-characterized migration model of the BBB consisting of human brain microvascular endothelial cells. In summary, this study will define the role of estrogen in regulating: cell activation via cytokine secretion and proliferation; adhesion molecule expression and function on lymphocytes and on brain endothelial cells; attraction of lymphocytes across brain endothelium via chemokines and chemokine receptors; and invasion of the BBB via matrix metalloproteinases and migration of pathogenic lymphocytes across the BBB. These studies will provide valuable understanding of the multiple effects of estrogens and may provide molecular targets for development of future therapies as well as a better understanding of the role of sex hormones in the pathogenesis of MS.