School of Civil and Environmental Engineering, Nanyang Technological University, 639798 Singapore, Singapore.
Key Laboratory of Environmental Nanotechnology and Health Effects, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 100085 Beijing, China.
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24). doi: 10.1073/pnas.2011957118.
Allergic asthma, driven by T helper 2 cell-mediated immune responses to common environmental antigens, remains the most common respiratory disease in children. Perfluorinated chemicals (PFCs) are environmental contaminants of great concern, because of their wide application, persistence in the environment, and bioaccumulation. PFCs associate with immunological disorders including asthma and attenuate immune responses to vaccines. The influence of PFCs on the immunological response to allergens during childhood is unknown. We report here that a major PFC, perfluorooctane sulfonate (PFOS), inactivates house dust mite (HDM) to dampen 5-wk-old, early weaned mice from developing HDM-induced allergic asthma. PFOS further attenuates the asthma protective effect of the microbial product lipopolysaccharide (LPS). We demonstrate that PFOS prevents desensitization of lung epithelia by LPS, thus abolishing the latter's protective effect. A close mechanistic study reveals that PFOS specifically binds the major HDM allergen Der p1 with high affinity as well as the lipid A moiety of LPS, leading to the inactivation of both antigens. Moreover, PFOS at physiological human (nanomolar) concentrations inactivates Der p1 from HDM and LPS in vitro, although higher doses did not cause further inactivation because of possible formation of PFOS aggregates. This PFOS-induced neutralization of LPS has been further validated in primary human cell models and extended to an in vivo bacterial infection mouse model. This study demonstrates that early life exposure of mice to a PFC blunts airway antigen bioactivity to modulate pulmonary inflammatory responses, which may adversely affect early pulmonary health.
过敏性哮喘是由 T 辅助 2 细胞介导的对常见环境抗原的免疫反应引起的，仍是儿童最常见的呼吸道疾病。全氟化学品（PFCs）是一种非常令人关注的环境污染物，因为它们的广泛应用、在环境中的持久性和生物累积性。PFCs 与包括哮喘在内的免疫紊乱有关，并削弱对疫苗的免疫反应。PFCs 对儿童时期过敏原免疫反应的影响尚不清楚。我们在这里报告，一种主要的 PFC，全氟辛烷磺酸（PFOS），使屋尘螨（HDM）失活，从而阻止 5 周龄、早期断奶的小鼠发展为 HDM 诱导的过敏性哮喘。PFOS 进一步减弱了微生物产物脂多糖（LPS）对哮喘的保护作用。我们证明 PFOS 可防止 LPS 引起的肺上皮脱敏，从而消除后者的保护作用。一项密切的机制研究表明，PFOS 特异性地以高亲和力结合主要的 HDM 过敏原 Der p1 以及 LPS 的脂质 A 部分，导致两种抗原失活。此外，PFOS 在生理上（纳摩尔级）的人类浓度下在体外使来自 HDM 和 LPS 的 Der p1 失活，尽管由于可能形成 PFOS 聚集体，较高剂量不会导致进一步失活。这种 PFOS 诱导的 LPS 中和作用在原代人细胞模型中得到了进一步验证，并扩展到体内细菌感染小鼠模型。这项研究表明，小鼠在生命早期暴露于 PFC 会削弱气道抗原的生物活性，从而调节肺部炎症反应，这可能对早期肺部健康产生不利影响。
