Department of Infectious Diseases, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
J Immunol. 2012 May 15;188(10):4782-91. doi: 10.4049/jimmunol.1103452. Epub 2012 Apr 13.
Leprosy is not eradicable with currently available diagnostics or interventions, as evidenced by its stable incidence. Early diagnosis of Mycobacterium leprae infection should therefore be emphasized in leprosy research. It remains challenging to develop tests based on immunological biomarkers that distinguish individuals controlling bacterial replication from those developing disease. To identify biomarkers for field-applicable diagnostics, we determined cytokines/chemokines induced by M. leprae proteins in blood of leprosy patients and endemic controls (EC) from high leprosy-prevalence areas (Bangladesh, Brazil, Ethiopia) and from South Korea, where leprosy is not endemic anymore. M. leprae-sonicate-induced IFN-γ was similar for all groups, excluding M. leprae/IFN-γ as a diagnostic readout. By contrast, ML2478 and ML0840 induced high IFN-γ concentrations in Bangladeshi EC, which were completely absent for South Korean controls. Importantly, ML2478/IFN-γ could indicate distinct degrees of M. leprae exposure, and thereby the risk of infection and transmission, in different parts of Brazilian and Ethiopian cities. Notwithstanding these discriminatory responses, M. leprae proteins did not distinguish patients from EC in one leprosy-endemic area based on IFN-γ. Analyses of additional cytokines/chemokines showed that M. leprae and ML2478 induced significantly higher concentrations of MCP-1, MIP-1β, and IL-1β in patients compared with EC, whereas IFN-inducible protein-10, like IFN-γ, differed between EC from areas with dissimilar leprosy prevalence. This study identifies M. leprae-unique Ags, particularly ML2478, as biomarker tools to measure M. leprae exposure using IFN-γ or IFN-inducible protein-10, and also shows that MCP-1, MIP-1β, and IL-1β can potentially distinguish pathogenic immune responses from those induced during asymptomatic exposure to M. leprae.
麻风病目前的诊断或干预手段无法根治，其发病率也较为稳定，这一点就证明了这一点。因此，在麻风病研究中应强调早期诊断麻风分枝杆菌感染。基于免疫学生物标志物开发能够区分个体细菌复制控制者和疾病发展者的测试仍然具有挑战性。为了确定可用于现场诊断的生物标志物，我们确定了麻风分枝杆菌蛋白在来自高麻风病流行地区（孟加拉国、巴西、埃塞俄比亚）和韩国（麻风病不再流行）的麻风病患者和地方流行对照（EC）血液中诱导的细胞因子/趋化因子。除了麻风分枝杆菌/IFN-γ作为诊断读数外，所有组的麻风分枝杆菌-超声诱导 IFN-γ 相似。相比之下，ML2478 和 ML0840 在孟加拉国 EC 中诱导了高 IFN-γ 浓度，而韩国对照中则完全没有。重要的是，ML2478/IFN-γ 可以指示不同地区麻风分枝杆菌暴露的不同程度，从而指示感染和传播的风险，在巴西和埃塞俄比亚城市的不同地区。尽管存在这些歧视性反应，但基于 IFN-γ，麻风分枝杆菌蛋白并不能将患者与一个地方流行地区的 EC 区分开来。对其他细胞因子/趋化因子的分析表明，与 EC 相比，麻风分枝杆菌和 ML2478 诱导患者中 MCP-1、MIP-1β 和 IL-1β 的浓度显著更高，而 IFN 诱导蛋白-10 与 IFN-γ 一样，在流行率不同的地区的 EC 之间存在差异。这项研究确定了麻风分枝杆菌独特的 Ag，特别是 ML2478，作为使用 IFN-γ 或 IFN 诱导蛋白-10 测量麻风分枝杆菌暴露的生物标志物工具，并且还表明 MCP-1、MIP-1β 和 IL-1β 可以潜在地区分致病性免疫反应和在无症状暴露于麻风分枝杆菌时诱导的免疫反应。
