Role of gender in TH17-mediated inflammation in severe asthma

 描述（由申请人提供）：重度哮喘是一个重要的医疗保健问题，与轻度哮喘表型相比，患者的哮喘控制较差，哮喘发作频繁，医疗保健费用增加。与女孩相比，男孩患严重哮喘的患病率较高。这种严重哮喘的患病率在青春期从男孩转移到女性，表明性激素的作用。然而，性别和卵巢激素如何影响严重哮喘的发病机制仍不清楚。IL-17 A是一种由CD 4 + T细胞和γ <$T细胞分泌的细胞因子，在哮喘患者的支气管肺泡灌洗液中增加。 与轻度哮喘表型相比，重度哮喘。IL-17 A还与气道炎症、气道反应性（AR）和粘液产生增加相关。我们的初步数据显示，与男性相比，女性Th 17分化细胞中IL-17 A蛋白表达增加。我们还显示，在卵巢切除的雌性小鼠中给予17β-雌二醇（E2）和孕酮（P4）增加了IL-17 A的Th 17分化细胞表达。我们假设女性通过卵巢激素增加了Th 17细胞的分化以及Th 17细胞和γ o T细胞的IL-17 A分泌。我们进一步假设，体内17β-E2和P4给药增加了小鼠Th 17介导的气道炎症、AR和粘液产生。在目的1中，我们将区分健康女性和男性的Th 17细胞，并确定性别在Let-7 f调节Th 17分化细胞上IL-23受体（R）和IL-17 A蛋白表达中的作用。在目标2中，将分离记忆T细胞以确定与患有严重哮喘的男性相比，患有严重哮喘的女性是否具有增加的分泌IL-17 A的记忆CD 4 + T细胞。在目的3中，我们将描述体内给予17β-E2和P4增加小鼠中IL-17 A介导的气道炎症的机制。我们的研究结果将首次确定性别和卵巢激素在严重哮喘患者IL-17 A介导的气道炎症中的作用。我们的研究结果也可能有助于设计未来的临床试验，通过确定女性和男性重度哮喘患者在中重度哮喘临床试验中是否有不同的IL-17 A产生和对治疗药物的反应。

 DESCRIPTION (provided by applicant): Severe asthma is a significant health care concern with patients having poorer asthma control, frequent asthma attacks, and increased heath care costs compared to milder asthma phenotypes. Boys have an increased prevalence of severe asthma compared to girls. This increased prevalence of severe asthma switches from boys to women around puberty, suggesting a role for sex hormones. However, it remains unknown how gender and ovarian hormones affect severe asthma pathogenesis. IL-17A, a cytokine secreted by CD4+ T cells and γō T cells, is increased in the bronchoalveolar lavage fluid of patients with severe asthma compared to milder asthma phenotypes. IL-17A is also associated with increased airway inflammation, airway responsiveness (AR), and mucus production. Our preliminary data show increased IL-17A protein expression in Th17 differentiated cells from women compared to men. We also show 17β-estradiol (E2) and progesterone (P4) administration in ovariectomized female mice increased Th17 differentiated cell expression of IL-17A. We hypothesize that female gender, via ovarian hormones, increases Th17 cell differentiation and IL-17A secretion from Th17 cells and γō T cells. We further hypothesize that in vivo 17β-E2 and P4 administration increases Th17-mediated airway inflammation, AR, and mucus production in mice. In Aim 1, we will differentiate Th17 cells from healthy women and men and determine the role of gender in Let-7f regulation of IL-23 receptor (R) and IL-17A protein expression on Th17 differentiating cells. In Aim 2, memory T cells will be isolated to determine if women with severe asthma have increased IL-17A secreting memory CD4+ T cells compared to men with severe asthma. In Aim 3, we will delineate the mechanisms by which in vivo administration of 17β-E2 and P4 increases IL-17A-mediated airway inflammation in mice. Our results will be the first to determine the role of gender and ovarian hormones on IL-17A-mediated airway inflammation in severe asthma. Our findings may also be helpful in designing future clinical trials by determining if women and men with severe asthma have differential IL-17A production and responses to therapeutics in clinical trials for moderate to severe asthma.