Impact of Immune Changes of Pregnancy on Tuberculosis

描述（由申请人提供）：全世界五分之一的妇女携带潜伏性结核病感染（LTBI），每年有300万人被诊断患有活动性结核病（TB）。妇女最有可能在怀孕期间和怀孕后立即从潜伏性结核病转化为活动性结核病。导致这种现象的免疫学条件尚不清楚。这种知识差距削弱了我们为孕妇开发有效的LTBI筛查测试的能力，并准确预测哪些患者应该成为结核病预防的目标。这种需要是迫切的。结核病是孕产妇死亡的主要原因，特别是在感染艾滋病毒的妇女中。产妇结核病也是一个重要的儿童健康问题：产妇结核病使母婴艾滋病毒传播的风险增加一倍以上，并大大增加了新生儿和家庭中其他幼儿的死亡风险。我们最近的研究表明，LTBI孕妇在妊娠晚期对结核分枝杆菌（MTB）特异性抗原的IFN-γ反应减弱，产后3-6个月恢复到基线水平。我们假设，在怀孕期间调节性T细胞（Treg）的增加减少了多功能CD 4 + T细胞产生的Th 1细胞因子，以响应MTB抗原，这增加了进展为活动性TB的风险。我们与BJ医学院和印度国家结核病研究所/NIH支持的ICER项目合作，提出了一项纵向队列研究，以描述这些免疫变化的时间、程度和原因。我们还将前瞻性地随访妇女，并确定结核病复发的免疫学相关因素。将在印度浦那的产前诊所招募患有LTBI的孕妇，在妊娠中期进行额外访视，在妊娠晚期、产后3个月、6个月和12个月分娩。在每次访问中，我们将筛选活动性结核病。我们还将收集用于IFN-γ释放测定、细胞因子测定、流式细胞术和基因转录研究的血液样本。我们的首要目标是量化Th 1抑制的程度和时间 细胞因子的生产响应结核分枝杆菌特异性抗原，一个过程，可能有助于在怀孕期间LTBI的重新激活。通过包括艾滋病毒感染和未感染艾滋病毒的妇女，我们将进一步探讨艾滋病毒如何影响这种抑制。我们的第二个目标是描述抑制的细胞机制，我们认为这与妊娠中Treg频率增加有关。我们的第三个目标是使用细胞因子和RNA表达谱来鉴定与活动性TB进展相关的生物特征。这些发现将提供一个全面的图片免疫变化的怀孕，损害妇女的能力，以遏制结核病的潜伏形式。该研究还将为确定诊断生物标志物提供一条途径，使临床医生能够识别和治疗处于活动性结核病最高风险的孕妇。

DESCRIPTION (provided by applicant): One in five women worldwide carries latent tuberculosis infection (LTBI), and 3 million are diagnosed with active tuberculosis (TB) each year. Women are most likely to convert from latent to active TB during and immediately after pregnancy. The immunologic conditions responsible for this phenomenon are not understood. This knowledge gap impairs our ability to develop effective LTBI screening tests for pregnant women and accurately predict which patients should be targeted for TB prevention. The need is urgent. TB is a leading cause of maternal mortality, especially among HIV-infected women. Maternal TB is also an important children's health issue: Maternal TB more than doubles the risk of mother-to-child HIV transmission and significantly increases the risk of mortality for the newborn and other young children living in the household. Our recent research shows that pregnant women with LTBI have diminished IFN-gamma response to Mycobacterium tuberculosis (MTB)-specific antigens during the 3rd trimester and return to baseline 3-6 months postpartum. We hypothesize that the increase in regulatory T cells (Treg) during pregnancy reduces multi-functional CD4+ T-cell production of Th1 cytokines in response to MTB antigens, which increases the risk of progression to active TB. In partnership with BJ Medical College and the National Institute for Research of Tuberculosis/ intramural NIH-supported ICER program in India, we propose a longitudinal cohort study to describe the timing, extent, and causes of these immune changes. We will also follow women prospectively and identify immunological correlates of TB reactivation. Pregnant women with LTBI will be enrolled from the antenatal clinic in Pune, India, during their 2nd trimester with additional visits at 3rd trimester, delivery 3, 6, and 12 months postpartum. At each visit, we will screen for active TB. We will also collect blood samples for IFN-gamma release assays, cytokine assays, flow cytometry, and gene transcription studies. Our first aim is to quantify the extent and timing of the suppression of Th1 cytokine production in response to MTB-specific antigens, a process that likely contributes to the reactivation of LTBI during pregnancy. By including both HIV-infected and HIV-uninfected women, we will further explore how HIV affects this suppression. Our second aim is to describe the cellular mechanisms underlying the suppression, which we believe is related to increase Treg frequency in pregnancy. Our third aim is to use cytokine and RNA expression profiles to identify a biosignature associated with progression to active TB. These findings will provide a comprehensive picture of the immune changes of pregnancy that compromise a woman's ability to contain MTB in its latent form. The study will also provide a path towards identifying a diagnostic biomarker to enable clinicians to identify and treat pregnant women at highest risk of developing active TB.