Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Wellcome Centre for Infectious Disease Research in Africa (CIDRI-Africa), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Front Immunol. 2023 May 18;14:1176615. doi: 10.3389/fimmu.2023.1176615. eCollection 2023.
Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-γ in response to (Mtb) antigens, the absence of which is regarded as no infection. Some individuals appear to resist Mtb infection despite sustained exposure (resisters). In this study, we aimed to assess cytokines, chemokines and antibodies that may be associated with resistance to Mtb infection. We hypothesized that there may be an alternative immune response to Mtb exposure in the absence of IFN-γ in resisters.
We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We screened them for LTBI using the tuberculin skin test and the QuantiFERON-TB Gold Plus assay. We performed multiplex Luminex to measure concentrations of T cell-associated cytokines and chemokines as well as total antibodies in plasma collected from unstimulated fresh whole blood and supernatants from QuantiFERON-TB Gold Plus tubes following incubation of whole blood for 16-24 hours with ESAT6/CFP10 peptides.
Samples from 78 individuals were analyzed: 33 resisters (TST<10mm; IGRA<0.35 IU/mL), 33 with LTBI (TST≥10mm and IGRA≥0.35 IU/mL) and 12 discordant (TST=0mm; IGRA≥1.0 IU/mL). There were no differences in concentrations of cytokines and chemokines in plasma between the different groups. Resisters had significantly lower concentrations of IFN-γ, IL-2, TNF-α, MIP-1α, MIP-1β, ITAC, IL-13 and GM-CSF in supernatants compared with LTBI group. There were no significant differences in the concentrations in supernatants of IL-10, IL-1β, IL-17A, IL-21, IL-23, MIP-3α, IL-4, IL-5, IL-6, IL-7, IL-8, Fractalkine and IL-12p70 between the groups. We observed that resisters had similar concentrations of total antibodies (IgG1, IgG2, IgG3, IgG4, IgA, and IgM) in plasma and supernatants compared to the LTBI and discordant groups.
Resistance to Mtb infection despite sustained exposure is associated with lower Mtb-specific secretion of Th1-associated cytokines and chemokines. However, resisters showed secreted concentrations after Mtb stimulation of total antibodies and cytokines/chemokines associated with innate and Th17 immune responses similar to those with Mtb infection. This suggests an ability to mount non-IFN-γ immune responses to Mtb in apparent resisters.
目前，潜伏性结核感染（LTBI）的诊断基于 IFN-γ 对 （Mtb）抗原的分泌反应，缺乏这种反应则被认为没有感染。尽管持续接触 Mtb，但有些个体似乎具有抵抗 Mtb 感染的能力（抵抗者）。在这项研究中，我们旨在评估可能与抵抗 Mtb 感染相关的细胞因子、趋化因子和抗体。我们假设，在抵抗者中，尽管没有 IFN-γ，也可能存在针对 Mtb 暴露的替代免疫反应。
我们招募了在高结核暴露环境中工作 5 年或以上的 HIV 未感染者的医护人员。我们使用结核菌素皮肤试验和 QuantiFERON-TB Gold Plus 检测来筛查 LTBI。我们进行了多重 Luminex 分析，以测量从未刺激的新鲜全血中采集的血浆和全血孵育 16-24 小时后 QuantiFERON-TB Gold Plus 管中上清液中的 T 细胞相关细胞因子和趋化因子以及总抗体的浓度。
对 78 名个体的样本进行了分析：33 名抵抗者（TST<10mm；IGRA<0.35IU/mL）、33 名 LTBI 个体（TST≥10mm 和 IGRA≥0.35IU/mL）和 12 名不一致个体（TST=0mm；IGRA≥1.0IU/mL）。不同组之间血浆中细胞因子和趋化因子的浓度没有差异。与 LTBI 组相比，抵抗者上清液中 IFN-γ、IL-2、TNF-α、MIP-1α、MIP-1β、ITAC、IL-13 和 GM-CSF 的浓度显著降低。IL-10、IL-1β、IL-17A、IL-21、IL-23、MIP-3α、IL-4、IL-5、IL-6、IL-7、IL-8、Fractalkine 和 IL-12p70 上清液中的浓度在各组之间无显著差异。我们观察到，与 LTBI 和不一致组相比，抵抗者的血浆和上清液中的总抗体（IgG1、IgG2、IgG3、IgG4、IgA 和 IgM）浓度相似。
尽管持续接触 Mtb，但具有抵抗 Mtb 感染的能力与 Th1 相关细胞因子和趋化因子的 Mtb 特异性分泌减少有关。然而，抵抗者在 Mtb 刺激后显示出与先天和 Th17 免疫反应相关的总抗体和细胞因子/趋化因子的分泌浓度与 Mtb 感染相似。这表明在明显的抵抗者中，能够产生非 IFN-γ 免疫反应来抵抗 Mtb。
