1 Department of Medicine and Department of Immunology, Mayo Clinic Rochester, Rochester, Minnesota.
Am J Respir Cell Mol Biol. 2013 Dec;49(6):989-98. doi: 10.1165/rcmb.2012-0444OC.
Allergic asthma is commonly thought to result from dysregulated airway inflammatory responses to ubiquitous environmental antigens mediated by CD4(+) T cells polarized to a Th2 or Th17 cell. However, the mechanisms involved in the development of these T-cell responses remain unknown. This study examines the effects of IL-1 family cytokines, such as IL-33 and IL-1β, on the development of antigen-specific Th2 and Th17 cells in the airway. We administered IL-1 family cytokines and model antigens, such as ovalbumin, into the airways of naive BALB/c mice, and examined the cellular and humoral immune responses. To investigate the immunologic mechanisms, we used IL-4 green fluorescent protein reporter mice and mice deficient in the Il4 gene. Innocuous antigens, such as endotoxin-free ovalbumin and short ragweed extract, did not sensitize naive mice when administered through the airways. However, when mice were exposed to the same antigens with IL-1β or IL-33, they developed IgE antibodies. In particular, IL-33 induced robust and long-lasting Th2 cells that produced a large quantity of IL-5 and IL-13 and asthma-like airway pathology. IL-1β induced Th17 cells. In naive, nonsensitized animals, IL-33 stimulated endogenous IL-4 expression by CD4(+) T cells, which was critical for the polarization of CD4(+) T cells to the Th2 type. In the absence of IL-4, mice developed Th17 cells and neutrophilic airway inflammation. In conclusion, IL-1 family cytokines possess a potent adjuvant activity to promote both Th2 and Th17 cells to innocuous airborne antigens, and they may play fundamental roles in the immunopathology of asthma.
变应性哮喘通常被认为是由于气道炎症反应失调引起的，这种失调是由 CD4+T 细胞对 Th2 或 Th17 细胞的极化介导的，这些细胞对无处不在的环境抗原有反应。然而，这些 T 细胞反应发展的机制仍不清楚。本研究探讨了白细胞介素-1 家族细胞因子（如 IL-33 和 IL-1β）对气道中抗原特异性 Th2 和 Th17 细胞发育的影响。我们将白细胞介素-1 家族细胞因子和模型抗原（如卵清蛋白）注入到 naive BALB/c 小鼠的气道中，然后检测细胞和体液免疫反应。为了研究免疫机制，我们使用了 Il4 基因缺陷小鼠和 IL-4 绿色荧光蛋白报告小鼠。当将无害抗原（如无内毒素卵清蛋白和短豚草提取物）通过气道给予时，它们不会使 naive 小鼠致敏。然而，当将这些抗原与 IL-1β 或 IL-33 一起给予时，它们会诱导 IgE 抗体产生。特别是，IL-33 诱导了大量产生 IL-5 和 IL-13 的强而持久的 Th2 细胞，并导致类似哮喘的气道病理。IL-1β 诱导了 Th17 细胞。在未致敏的 naive 动物中，IL-33 刺激 CD4+T 细胞内源性表达 IL-4，这对于 CD4+T 细胞向 Th2 型极化至关重要。在缺乏 IL-4 的情况下，小鼠会发展出 Th17 细胞和中性粒细胞性气道炎症。总之，白细胞介素-1 家族细胞因子具有很强的佐剂活性，可以促进无害的空气传播抗原诱导 Th2 和 Th17 细胞的产生，它们可能在哮喘的免疫病理学中发挥重要作用。
