Department of Molecular Immunology, Research Institute for Microbial Diseases, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
J Clin Immunol. 2013 Jan;33(1):200-9. doi: 10.1007/s10875-012-9798-5. Epub 2012 Sep 25.
The class IV semaphorin Sema4A is critical for efficient Th1 differentiation and Sema4a (-/-) mice exhibit impaired Th1 immune responses. However, the role of Sema4A in Th2 cell-mediated allergic diseases has not been fully studied. The aim of this study was to clarify the regulatory role possessed by Sema4A in mouse models of allergic diseases, particularly allergic asthma.
Sema4a (-/-) mice on a BALB/c background were examined for the development of allergic diseases. To induce experimental asthma, mice were sensitized with ovalbumin (OVA) followed by intranasal challenges with OVA. After challenge, airway hyperreactivity (AHR) and airway inflammation were evaluated. The role of Sema4A in asthma was examined using Sema4a (-/-) mice and Sema4A-Fc fusion proteins. The direct effects of Sema4A-Fc on antigen-specific effector CD4(+) T cells were also examined.
A fraction of Sema4a (-/-) BALB/c mice spontaneously developed skin lesions that resembled atopic dermatitis (AD) in humans. Furthermore, AHR, airway inflammation, and Th2-type immune responses were enhanced in Sema4a (-/-) mice compared to wild type (WT) mice when immunized and challenged with OVA. In vivo systemic administration of Sema4A-Fc during the challenge period ameliorated AHR and lung inflammation and reduced the production of Th2-type cytokines in WT mice. The inhibitory effects of Sema4A on airway inflammation were also observed in mice deficient in Tim-2, a Sema4A receptor. Finally, we showed that Sema4A-Fc directly inhibited IL-4-producing OVA-specific CD4(+) T cells.
These results demonstrate that Sema4A plays an inhibitory role in Th2-type allergic diseases, such as allergic asthma.
IV 型信号素 Sema4A 对 Th1 分化至关重要，而 Sema4a（-/-）小鼠则表现出 Th1 免疫应答受损。然而，Sema4A 在 Th2 细胞介导的过敏性疾病中的作用尚未得到充分研究。本研究旨在阐明 Sema4A 在过敏性疾病，特别是过敏性哮喘的小鼠模型中的调节作用。
在 BALB/c 背景下检查 Sema4a（-/-）小鼠是否发生过敏性疾病。为了诱导实验性哮喘，用卵清蛋白（OVA）致敏小鼠，然后用 OVA 进行鼻内挑战。挑战后，评估气道高反应性（AHR）和气道炎症。使用 Sema4a（-/-）小鼠和 Sema4A-Fc 融合蛋白来研究 Sema4A 在哮喘中的作用。还检查了 Sema4A-Fc 对抗原特异性效应 CD4（+）T 细胞的直接作用。
一部分 Sema4a（-/-）BALB/c 小鼠自发出现类似于人类特应性皮炎（AD）的皮肤损伤。此外，与野生型（WT）小鼠相比，当用 OVA 免疫和挑战时，Sema4a（-/-）小鼠的 AHR、气道炎症和 Th2 型免疫应答增强。在挑战期间体内给予 Sema4A-Fc 可改善 WT 小鼠的 AHR 和肺炎症，并减少 Th2 型细胞因子的产生。在 Tim-2 缺乏的小鼠（Sema4A 受体）中也观察到 Sema4A 对气道炎症的抑制作用。最后，我们表明 Sema4A-Fc 直接抑制产生 IL-4 的 OVA 特异性 CD4（+）T 细胞。
这些结果表明，Sema4A 在 Th2 型过敏性疾病，如过敏性哮喘中发挥抑制作用。
