Altered immune-endocrine axis in type 2 diabetes and tuberculosis risk

 描述(申请人提供)：结核病(TB)控制面临的一个新挑战是2型糖尿病(DM2)患者人数稳步上升，特别是在结核病流行的发展中国家。DM2使患结核病的风险增加三倍，现在受结核病和糖尿病并存的影响的人比感染结核病和艾滋病毒的人多。更好地了解结核病和DM2之间的联系对于确定结核病进展风险增加的个人至关重要。在DM2患者中，神经内分泌调节下的激素、脂肪因子和胰岛素的相互作用以及慢性低度炎症可能导致对结核分枝杆菌(Mtb)的免疫反应受损。我们建议在两个不同背景种族的人群中对结核病病例(HHC)进行家庭接触研究：南非的有色人种和德克萨斯州的拉美裔人。我们推测，具有潜伏性结核分枝杆菌感染和DM2的HHC的特征是免疫内分泌网络的系统性失调，导致对结核分枝杆菌的免疫力下降。我们将通过DM2状态来确定血清细胞因子和激素以及全血基因转录本是否有独特的特征。这将使我们能够确定两个不同种族(目标1)中患有DM2(与不患有DM2)的HHC的血液中免疫和内分泌变化之间的关系。为了进一步确定这些免疫-内分泌关系是否与细胞激活和结核分枝杆菌生长抑制能力降低有关，我们将评估血清细胞因子和激素对有无DM2的HHC中外周血单核细胞和T细胞对结核分枝杆菌反应的影响。我们将通过进行细胞与自体和异体血清(即有DM2细胞的正常血清和没有DM2细胞的DM2血清)的平行孵育来评估单核细胞和T细胞的激活以及MTB的吞噬和生长(目标2)。最后，我们假设来自带有DM2的HHC的人肺泡巨噬细胞(HAMs)已经改变了细胞的激活和降低了抑制结核杆菌生长的能力。我们将收集一部分研究参与者的支气管肺泡灌洗液，并评估HAM表型、结核分枝杆菌生长和细胞因子产生。同时，将产生并评估单核细胞来源的巨噬细胞(MDM)，以确定火腿和MDM对结核分枝杆菌反应中局部和全身免疫内分泌变化之间的关系。这些发现将证明从外周获得的信息是否与感染部位的免疫反应相关。在研究完成时，我们将对免疫和内分泌系统之间的相互作用，包括外周和肺部，获得关键和根本的新见解；从而帮助确定DM2患者进展为活动性结核病的潜在风险因素。

 DESCRIPTION (provided by applicant): An emerging challenge for tuberculosis (TB) control is the steadily rising number of individuals with type 2 diabetes (DM2), particularly in developing countries where TB is endemic. DM2 increases the risk of TB by three fold and there are now more people affected by TB-DM co-morbidity than TB-HIV infection. A better understanding of the link between TB and DM2 is essential to identify individuals at increased risk for TB progression. In DM2 patients, the interplay of hormones under neuroendocrine regulation, adipokines and insulin, and chronic low grade inflammation are likely to contribute to compromised immune responses to Mycobacterium tuberculosis (Mtb). We propose studies in house hold contacts of TB cases (HHCs) in two populations with different background ethnicities: Coloureds in South Africa and Hispanics in Texas. We hypothesize that HHCs with latent Mtb infection and DM2 are characterised by a systemic dysregulation of immune-endocrine networks that lead to compromised immunity to Mtb. We will determine if there are unique signatures in serum cytokines and hormones as well as whole blood gene transcripts by DM2 status. This will allow us to identify relationships between immune and endocrine alterations in the blood of HHCs with DM2 (vs. no DM2) in two different ethnicities (Aim 1). To further ascertain whether these immune-endocrine relationships are associated with diminished cell activation and Mtb growth inhibitory capacity we will evaluate the impact of serum cytokines and hormones on the response of peripheral monocytes and T cells to Mtb in HHCs with and without DM2. We will evaluate monocyte and T cell activation as well as Mtb phagocytosis and growth by conducting parallel incubation of cells with autologous and heterologous sera (i.e., normal sera with DM2 cells and DM2 sera with no DM2 cells) (Aim 2). Finally, we hypothesize that human alveolar macrophages (HAMs) from HHCs with DM2 have altered cell activation and reduced capacity to contain Mtb growth. We will collect bronchoalveolar lavage from a subset of study participants and evaluate HAM phenotype, Mtb growth and cytokine production. In parallel, monocyte derived macrophages (MDMs) will be generated and evaluated to identify relationships between local and systemic immune-endocrine alterations in responses to Mtb by HAMs and MDMs. These findings will demonstrate whether information gained from the periphery correlates with immune responses at the site of infection. At study completion, we will have gained critical and fundamental new insights into the interplay between the immune and endocrine systems, both in the periphery and lung; thereby helping to identify underlying risk factors in DM2 patients for progression to active TB.