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

 描述（由申请人提供）：结核病（TB）控制面临的一个新挑战是2型糖尿病（DM 2）患者人数稳步上升，特别是在结核病流行的发展中国家。2型糖尿病使患结核病的风险增加了三倍，现在受结核-糖尿病合并症影响的人数多于结核-艾滋病毒感染者。更好地了解结核病和DM 2之间的联系对于识别结核病进展风险增加的个体至关重要。在DM 2患者中，神经内分泌调节下的激素、脂肪因子和胰岛素以及慢性低度炎症的相互作用可能导致对结核分枝杆菌（Mtb）的免疫应答受损。我们建议在具有不同背景种族的两个人群中进行结核病例（HHC）的家庭接触研究：南非的有色人种和德克萨斯州的西班牙裔。我们假设，HHC与潜伏性结核分枝杆菌感染和DM 2的特点是免疫-内分泌网络的系统性失调，导致免疫力受损的结核分枝杆菌。我们将通过DM 2状态确定血清细胞因子和激素以及全血基因转录物中是否存在独特的特征。这将使我们能够确定两个不同种族中具有DM 2（与没有DM 2）的HHC血液中的免疫和内分泌改变之间的关系（目的1）。为了进一步确定这些免疫-内分泌关系是否与减少的细胞活化和Mtb生长抑制能力相关，我们将评估血清细胞因子和激素对具有和不具有DM 2的HHC中外周单核细胞和T细胞对Mtb的应答的影响。我们将通过将细胞与自体和异源血清（即，具有DM 2细胞的正常血清和不具有DM 2细胞的DM 2血清）（目的2）。最后，我们假设来自具有DM 2的HHC的人肺泡巨噬细胞（HAM）改变了细胞活化并降低了抑制Mtb生长的能力。我们将从一部分研究参与者中收集支气管肺泡灌洗液，并评估HAM表型、Mtb生长和细胞因子产生。同时，将生成单核细胞衍生的巨噬细胞（MDM）并进行评价，以确定HAM和MDM对Mtb应答的局部和全身免疫-内分泌改变之间的关系。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，我们将获得对外周和肺部免疫和内分泌系统之间相互作用的关键和基本的新见解;从而帮助确定DM 2患者进展为活动性TB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.