Impact of Immune Changes of Pregnancy on Tuberculosis

描述(申请人提供)：全世界每五名妇女中就有一人携带潜伏性结核病感染(LTBI)，每年有300万人被诊断为活动性结核病(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变为活动性结核病。导致这一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筛查测试和准确预测哪些患者应该成为结核病预防目标的能力。这种需求是迫切的。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：产妇结核病使母婴传播艾滋病毒的风险增加一倍以上，并大大增加新生儿和其他家庭幼儿的死亡风险。我们最近的研究表明，患有LTBI的孕妇在妊娠晚期降低了对结核分枝杆菌(MTB)特异性抗原的干扰素-γ应答，并在产后3-6个月恢复到基线水平。我们假设妊娠期间调节性T细胞(Treg)的增加减少了多功能CD4T细胞对结核分枝杆菌抗原的Th1细胞因子的产生，从而增加了进展为活动性结核病的风险。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、范围和原因。我们还将前瞻性地跟踪妇女，并确定结核病重新激活的免疫学相关因素。患有LTBI的孕妇将在怀孕第二个月期间从印度浦那的产前诊所登记，并在第三个月、产后3个月、6个月和12个月时进行额外的探视。每次就诊时，我们都会筛查活动性结核病。我们还将收集血液样本，用于干扰素-伽马释放分析、细胞因子分析、流式细胞术和基因转录研究。我们的第一个目标是量化Th1抑制的程度和时机 细胞因子的产生是对结核分枝杆菌特异性抗原的反应，这一过程可能有助于在怀孕期间重新激活LTBI。通过将感染艾滋病毒的妇女和未感染艾滋病毒的妇女包括在内，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这种抑制的细胞机制，我们认为这与怀孕期间Treg频率增加有关。我们的第三个目标是使用细胞因子和RNA表达谱来识别与进展为活动性结核病相关的生物特征。这些发现将提供怀孕免疫变化的全面图景，这些变化损害了妇女遏制潜伏形式的结核杆菌的能力。这项研究还将提供一条确定诊断生物标记物的途径，使临床医生能够识别和治疗患有活动性结核病风险最高的孕妇。

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.