Wang Xuyang, Jia Liqiu, Liu Yang, Wang Jing, Qiu Chao, Li Tao, Zhang Wenhong, Zhu Zhaoqin, Wu Jing, Wan Yanmin
National Medical Center for Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
Shanghai Public Health Clinical Center, Department of Laboratory Medicine, Shanghai 201508, China.
Vaccines (Basel). 2022 Jul 19;10(7):1147. doi: 10.3390/vaccines10071147.
Interleukin-12 receptor β1 (IL12RB1)-deficient individuals show increased susceptibilities to local or disseminated BCG infection and environmental mycobacteria infection. However, the low clinical penetrance of IL12RB1 deficiency and low recurrence rate of mycobacteria infection suggest that protective immunity still exists in this population. In this study, we investigated the mechanism of tuberculosis suppression using the IL12RB1-deficient mouse model. Our results manifested that mice had significantly increased CFU counts in spleens and lungs, especially when BCG (Danish strain) was inoculated subcutaneously. The innate TNF-a and IFN-γ responses decreased, while the IL-17 responses increased significantly in the lungs of mice. We also found that PPD-specific IFN-γ release was impaired in mice, but the specific TNF-a release was not compromised, and the antibody responses were significantly enhanced. Moreover, correlation analyses revealed that both the innate and PPD-specific IFN-γ responses positively correlated with CFU counts, whereas the innate IL-12a levels negatively correlated with CFU counts in mice lungs. Collectively, these findings proved that the adaptive immunities against mycobacteria are not completely nullified in mice. Additionally, our results imply that IFN-γ responses alone might not be able to contain BCGitis in the setting of IL12RB1 deficiency.
白细胞介素-12受体β1(IL12RB1)缺陷个体对局部或播散性卡介苗感染及环境分枝杆菌感染的易感性增加。然而,IL12RB1缺陷的低临床外显率和分枝杆菌感染的低复发率表明该人群中仍存在保护性免疫。在本研究中,我们使用IL12RB1缺陷小鼠模型研究了结核病抑制机制。我们的结果表明,小鼠脾脏和肺部的菌落形成单位(CFU)计数显著增加,尤其是在皮下接种卡介苗(丹麦菌株)时。小鼠肺部的先天性肿瘤坏死因子-α(TNF-a)和干扰素-γ(IFN-γ)反应降低,而白细胞介素-17(IL-17)反应显著增加。我们还发现,小鼠中PPD特异性IFN-γ释放受损,但特异性TNF-a释放未受影响,且抗体反应显著增强。此外,相关性分析显示,先天性和PPD特异性IFN-γ反应均与CFU计数呈正相关,而小鼠肺部先天性白细胞介素-12a水平与CFU计数呈负相关。总体而言,这些发现证明小鼠针对分枝杆菌的适应性免疫并未完全丧失。此外,我们的结果表明,在IL12RB1缺陷的情况下,仅IFN-γ反应可能无法控制卡介苗感染。