Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mich.
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Mich.
J Allergy Clin Immunol. 2014 Aug;134(2):429-39. doi: 10.1016/j.jaci.2014.04.020. Epub 2014 Jun 6.
Early-life human rhinovirus infection has been linked to asthma development in high-risk infants and children. Nevertheless, the role of rhinovirus infection in the initiation of asthma remains unclear.
We hypothesized that, in contrast to infection of mature BALB/c mice, neonatal infection with rhinovirus promotes an IL-25-driven type 2 response, which causes persistent mucous metaplasia and airways hyperresponsiveness.
Six-day-old and 8-week-old BALB/c mice were inoculated with sham HeLa cell lysate or rhinovirus. Airway responses from 1 to 28 days after infection were assessed by using quantitative PCR, ELISA, histology, immunofluorescence microscopy, flow cytometry, and methacholine responsiveness. Selected mice were treated with a neutralizing antibody to IL-25.
Compared with mature mice, rhinovirus infection in neonatal mice increased lung IL-13 and IL-25 production, whereas IFN-γ, IL-12p40, and TNF-α expression was suppressed. In addition, the population of IL-13-secreting type 2 innate lymphoid cells (ILC2s) was expanded with rhinovirus infection in neonatal but not mature mice. ILC2s were the major cell type secreting IL-13 in neonates. Finally, anti-IL-25 neutralizing antibody attenuated ILC2 expansion, mucous hypersecretion, and airways responsiveness.
These findings suggest that early-life viral infection could contribute to asthma development by provoking age-dependent, IL-25-driven type 2 immune responses.
早期人类鼻病毒感染与高危婴儿和儿童哮喘的发展有关。然而，鼻病毒感染在哮喘发病机制中的作用尚不清楚。
我们假设，与成熟 BALB/c 小鼠的感染相反，鼻病毒感染新生鼠会促进 IL-25 驱动的 2 型反应，从而导致持续的黏液化生和气道高反应性。
将 6 日龄和 8 周龄的 BALB/c 小鼠用假 HeLa 细胞裂解物或鼻病毒接种。感染后 1 至 28 天通过定量 PCR、ELISA、组织学、免疫荧光显微镜、流式细胞术和乙酰甲胆碱反应性评估气道反应。选择的小鼠用 IL-25 的中和抗体进行治疗。
与成熟小鼠相比，新生鼠鼻病毒感染增加了肺中 IL-13 和 IL-25 的产生，而 IFN-γ、IL-12p40 和 TNF-α 的表达受到抑制。此外，鼻病毒感染在新生而非成熟小鼠中扩增了 IL-13 分泌的 2 型先天淋巴样细胞（ILC2）群体。ILC2 是新生鼠中分泌 IL-13 的主要细胞类型。最后，抗 IL-25 中和抗体减弱了 ILC2 的扩增、黏液分泌过度和气道反应性。
这些发现表明，早期病毒感染可能通过引发年龄依赖性的、IL-25 驱动的 2 型免疫反应，促进哮喘的发展。
