Differential Induction and Antimicrobial Function of Interferons in Leprosy

麻风病是一种由细胞内病原体麻风分枝杆菌（mLEP）引起的人类疾病，为研究皮肤感染的先天和适应性免疫反应的调节提供了一个有吸引力的模型。该疾病表现出一个谱系，其临床表现与对病原体的免疫反应有关。通过研究麻风病的适应性免疫反应，我们发现耐药、自限性结核样（T-lep）患者在病变中表达Th2细胞因子ifn - γ，而弥散性麻风病（L-lep）患者在病变中表达Th2细胞因子IL-4和IL-10(1)。我们新的初步数据表明干扰素（ifn）及其下游基因网络在麻风病皮肤病变中的差异表达。令人震惊的发现是，II型IFN、IFN- γ以及IFN- γ诱导基因（包括抗菌基因程序）的表达在T-lep病变中富集。相反，IFN型、IFN- β以及IFN- β诱导基因的表达在L-lep病变中占主导地位。我们假设特定的mLEP分泌蛋白/配体分别在T-lep和L-lep患者中不同地触发II型和I型ifn的产生。为了验证这一假设，我们提出了翻译实验：1)鉴定在假定的mLEP分泌组中诱导II型IFN， IFN- γ并触发麻风病患者抗菌活性的T细胞表位/抗原，2)确定特定的mLEP分泌蛋白是否诱导I型IFN并抑制抗菌反应；3)研究分泌的mLEP糖脂，酚类糖脂-1 （PGL-1）触发单核/巨噬细胞I型IFN反应的机制。我们提出的研究旨在全面分析麻风病中I型和II型ifn的触发机制，包括这些途径在宿主防御和发病机制中的作用。我们希望这些见解将有助于麻风病的诊断和预防，并为开发针对各种人类皮肤病的免疫调节方法提供新的途径。

Leprosy, a human disease caused by the intracellular pathogen Mycobacterium leprae (mLEP), offers an attractive model for investigating the regulation of innate and adaptive immune responses to infection in skin. The disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. By investigating the adaptive immune response in leprosy, we established that resistant, self-limited, tuberculoid (T-lep) patients express the Thi cytokine IFN-gamma in lesions, whereas disseminated lepromatous (L-lep) patients manifest Th2 cytokines IL-4 and IL-10 in lesions (1). Our new preliminary data indicates the differential expression of interferons (IFNs) and their downstream gene networks in leprosy skin esions. The striking finding was that expression ofthe Type II IFN, IFN-gamma, as well as IFN-gamma inducible genes including the antimicrobial gene program, were enriched in T-lep lesions. In contrast, expression ofthe Type IFN, IFN-Beta, as well as IFN-Beta inducible genes, predominated in L-lep lesions. We hypothesize that specific mLEP secreted proteins/ligands differentially trigger production of Type II vs. Type I IFNs in T-lep vs. L-lep patients, respectively. To test this hypothesis, we propose translational experiments to: 1) identify the T cell epitopes/antigens in the putative mLEP secretome which induce the Type II IFN, IFN-gamma, in leprosy patients and trigger an antimicrobial activity, 2) determine whether specific mLEP secreted proteins induce Type I IFNs and inhibit antimicrobial responses; and, 3) investigate the mechanism by which the secreted mLEP glycolipid, phenolic glycolipid-1 (PGL-1), triggers Type I IFN responses in monocytes/macrophages. The studies we propose are intended to provide a comprehensive analysis of the mechanisms that trigger Type I vs. Type II IFNs in leprosy, including the role of these pathways in host defense and pathogenesis. We would hope that insights would assist in the diagnosis and prevention of leprosy, as well as provide new avenues for development of immunomodulatory approaches for a variety of human skin diseases.