argenx BV, Zwijnaarde, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent, Ghent, Belgium.
Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent, Ghent, Belgium.
J Allergy Clin Immunol. 2024 Nov;154(5):1129-1145. doi: 10.1016/j.jaci.2024.07.024. Epub 2024 Aug 13.
Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5, and IL-13 cytokines produced by T2 lymphocytes or type 2 innate lymphoid cells (ILC2s). IL-2 family cytokines play a key role in the differentiation, homeostasis, and effector function of innate and adaptive lymphocytes.
IL-9 and IL-21 boost activation and proliferation of T2 and ILC2s, but the relative importance and potential synergism between these γ common chain cytokines are currently unknown.
Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human subjects with allergic asthma compared with nonasthmatic controls. Here, we also measured IL-21 in both groups.
IL-9 played a central role in controlling innate IL-33-induced lung inflammation by promoting proliferation and activation of ILC2s in an IL-21-independent manner. Conversely, chronic house dust mite-induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, which controlled T2 activation, eosinophilia, total serum IgE, and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, as combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage samples we measured elevated IL-21 protein within the allergic asthmatic group compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.
IL-9 and IL-21 play important and nonredundant roles in allergic asthma by boosting ILC2s and T2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
哮喘常伴有富含白细胞介素 4（IL-4）、白细胞介素 5（IL-5）和白细胞介素 13（IL-13）细胞因子的 2 型免疫，这些细胞因子由 T2 淋巴细胞或 2 型先天淋巴样细胞（ILC2）产生。白细胞介素 2 家族细胞因子在先天和适应性淋巴细胞的分化、稳态和效应功能中发挥关键作用。
白细胞介素 9（IL-9）和白细胞介素 21（IL-21）可促进 T2 和 ILC2 的激活和增殖，但这些 γ 共用链细胞因子之间的相对重要性和潜在协同作用目前尚不清楚。
使用新生成的抗体，我们单独或联合抑制各种哮喘小鼠模型中的 IL-9 和 IL-21。在使用分段过敏原挑战的转化方法中，我们最近描述了与非哮喘对照相比，过敏性哮喘患者的 IL-9 水平升高。在这里，我们还测量了这两组的 IL-21。
IL-9 通过在 IL-21 独立的方式促进 ILC2 的增殖和激活，在控制先天 IL-33 诱导的肺炎症中发挥核心作用。相反，慢性屋尘螨诱导的气道炎症主要由适应性免疫驱动，仅依赖于 IL-21，后者控制 T2 激活、嗜酸性粒细胞增多、总血清 IgE 和三级淋巴样结构的形成。在由木瓜蛋白酶过敏原驱动的先天对适应性免疫模型中，两种途径之间发现了明显的协同作用，因为联合抗 IL-9 或抗 IL-21 阻断在降低关键哮喘特征方面更有效。在人类支气管肺泡灌洗液样本中，我们测量到过敏性哮喘组中的 IL-21 蛋白水平高于过敏性对照组。我们还发现各种疾病相关细胞亚群中的 IL21R 转录物和预测的 IL-21 配体活性增加。
IL-9 和 IL-21 通过增强 ILC2 和 T2 细胞在过敏性哮喘中发挥重要且不可或缺的作用，揭示了双重 IL-9 和 IL-21 靶向策略作为一种新的可测试方法。
