Gender differences in immune responses in MS

描述(申请人提供)：大多数自身免疫性疾病在女性中发生的频率较高。这表明，自身免疫表型至少部分与性激素的免疫效应有关。到目前为止，大多数体外和体内研究都表明，怀孕期间高剂量的雌激素和孕激素会抑制免疫。不幸的是，这些数据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)。显示雌激素促进Th1免疫的证据很少，尽管这样的数据有助于解释自身免疫性疾病易感性的性别偏见。在之前的资助期间，我们提出了支持髓鞘细胞因子反应中性别效应的证据：患有多发性硬化症的女性表现出显著的干扰素偏斜？对某些髓鞘表位的反应，而患有多发性硬化症的男性表现出IL-5反应。在这项建议中，我们提出的证据是：1)内源性性激素水平与性别特异性细胞因子反应有关；2)T细胞受体刺激的强度以及激素剂量可能决定所产生的免疫反应是增强还是抑制；以及3)低剂量的雌激素促进记忆CD4T细胞跨脑内皮细胞迁移。这些数据使我们假设，在MS的发病机制中，正常卵巢周期剂量的雌激素调节四个重要步骤：1)促进Th1细胞激活；2)促进淋巴细胞与脑内皮细胞的黏附；3)调节淋巴细胞对内皮的化学吸引；以及4)促进记忆CD4T细胞跨越血脑屏障(BBB)的迁移。这项建议将通过研究人类外周血淋巴细胞在由人脑微血管内皮细胞组成的血脑屏障迁移模型中的迁移来解决这一假设。综上所述，本研究将确定雌激素在调节中的作用：通过细胞因子的分泌和增殖激活细胞；黏附分子在淋巴细胞和脑内皮细胞上的表达和功能；通过趋化因子和趋化因子受体吸引淋巴细胞穿过脑内皮细胞；通过基质金属蛋白酶侵袭血脑屏障和致病淋巴细胞跨越血脑屏障的迁移。这些研究将对雌激素的多重作用提供有价值的理解，并可能为未来治疗的开发提供分子靶点，以及更好地理解性激素在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.