2016-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660324摘要：結核病到目前為止，仍是世界上最重要的傳染病之一，每天大約都造成1-2百萬人的死亡。結核 病是由結核菌造成的，感染之後能夠在巨噬細胞和其他骨髓性細胞（myeloid cells)的細胞内繼續存 活。估計全世界約有三分之一的人曾經感染過結核菌，菌體在體内保持潛伏感染的狀態。此時宿主臨 床上並沒有任何症狀，但卻可能在日後伺機活化為活動性結核病。因此，世界衛生組織在終結結核的 策略當中，認為首要之務是以病人為中心的整合照顧與預防。然而，潛伏結核感染預防性治療的成效 受到很多因素的影響，其中最為重要的便是預測日後發生活動性結核病的準確度很低，現行兩種診斷 潛伏結核感染的方法一結核菌素皮膚試驗、丙型干擾素釋放試驗，準確預測的比例大約只有0.8% ~ 6.3%。近年來針對標的基因以及案例對照的研究中發現，許多先天免疫的基因多型性，特別是巨噬 細胞的接受器，例如 Toll-like receptors (TLRs)、mannose receptor (MR)、dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN)、Dectin-1、complement receptors 3 (CR3)、nucleotide oligomerization domain 1 (NODI) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR)，都與宿主對於結核病的易感性有關。然而這些研究當中也發現基因多型性與結核病易感性 的關係，隨著地區與種族有明顯的差異。因此，在這個計晝當中，我們將前瞻性的納入代表結核菌感 染不同階段的四個族群：第一是結核病指標個案族群（代表結核病發病狀態）、第二是這些指標個案 的未受感染之密切接觸者（代表未受感染、健康狀態）、第三是這些指標個案的已受感染之密切接觸 者（代表潛伏感染狀態）、第四是這些指標個案的已發生活動性結核病之密切接觸者（續發個案，同 樣代表結核病發病狀態）。針對這四個族群的受試者，我們將收集臨床資訊、各種常規實驗室檢查結 果，並且針對巨噬細胞接受器的基因多型性進行分析。同時我們將由周邊血液中純化單核球，將之誘 導分化為巨噬細胞，再以結核菌素、結核菌特異性抗原一ESAT-6和CFP-10刺激，然後測定發炎體 和細胞激素的反應。藉此，我們希望能夠找出重要的先天免疫指標，可以提高預測結核病發病的診斷 準確度。研究假說：巨噬細胞接受器之基因多型性與經由結核菌特異性抗原刺激過後之發炎體反應，能夠改善 由潛伏結核感染個案中預測日後發生活動性結核病的準確性。研究目標：找出巨噬細胞之基因多型性、發炎體和細胞激素反應中，能夠用以鑑別活動性結核病和潛 伏結核感染的標記。<br> Abstract: Tuberculosis (TB) remains the most important infectious disease worldwide, leading to approximately 1-2 million people deaths annually. The disease is caused by Mycobacterium tuberculosis (Mtb), an intracellular bacterium which infects and persists in macrophages and other myeloid cells. One-third of the human population have been estimated to expose to Mtb and carry the infection in its latent form, which has a lifelong risk of developing active disease although the absence of clinical symptoms. Therefore, the first pillar to achieve the End-TB strategy by the World Health Organization (WHO) is an integrated patient-centered care and prevention. However, the efficiency of preventive therapy for latent TB infection (LTBI) is limited by several critical issues. The most important one is the low predictive value (0.8% ~ 6.3%) of current diagnostic methods, tuberculin skin test (TST) and interferon-gamma release assay (IGRA), for subsequent development of active TB disease among LTBI subjects. Recent studies targeting candidate genes and “case-control” association have revealed numerous polymorphisms in innate immunity implicated in host susceptibility to active TB disease, especially macrophage receptors, such the Toll-like receptors (TLRs), mannose receptor (MR), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), Dectin-1, complement receptors 3 (CR3), nucleotide oligomerization domain 1 (NODI) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR). However, results of these studies showed significant difference among different countries and races, which emphasizes the need to consider geographical and ethnic diversity in assessing susceptibility to TB. Therefore, in this study, the clinical characteristics, results of routine diagnostic test for LTBI, as well as genetic polymorphisms of macrophage receptors will be assessed in four different populations representing each status of the natural course of TB, i.e. index TB patients (representing disease status), their close contacts without LTBI (representing un-infection, health status), their close contacts with LTBI (representing infection status), and their close contacts who subsequently develop active TB (secondary TB cases, also representing disease status). Peripheral blood monocytes will be purified, differentiated into macrophages, stimulated by purified protein derivatives (PPD) and M. tuberculosis-specific antigens - Early Secretory Antigenic Target-6KD (ESAT-6) and Culture Filtrate Protein-IOKD (CFP-10), and then measured for inflammasomes and cytokine responses. We hope we can identify more innate immune markers to improve the prediction of active TB.Research Hypothesis: Innate immunity polymorphisms and inflammasome response of macrophage after stimulation by M. tuberculosis-specific antigens can improve the prediction of developing active TB disease from LTBI.Study Aim: identifying the macrophage receptor polymorphisms, inflammasome and cytokine response of macrophages that are useful in differentiating active TB disease from latent TB infection.基因多型性先天免疫巨噬細胞toll-like receptor發炎體潛伏結核感染結核病polymorphisminnate immunitymacrophagetoll-like receptorinflammasomelatent