The role of the anaphylatoxins C3a and C5a in the pathogenesis of experimental allergic asthma

过敏毒素C3a和C5a在实验性过敏性哮喘发病机制中的作用

• 批准号: 256784565
• 负责人: Professor Dr. Jörg Köhl
• 金额: --
• 依托单位: Institut für Systemische Entzündungsforschung (ISEF)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/256784565?language=en
• 关键词: role; anaphylatoxins; C3a; C5a; pathogenesis

Aeroallergens from house dust mite faeces activate the complement system during allergen sensitization and lead to the generation of the anaphylatoxins (AT) C3a and C5a that activate immune cells specifically via their cognate AT receptors C3aR, C5aR and C5L2. Our preliminary studies show that the ATs regulate the development of maladaptive immune responses in allergic asthma at the level of dendritic cells (DC). Surprisingly, C5aR-/- bone marrow-derived DCs (BMDC) suffer from a markedly impaired ability to drive allergic asthma, whereas wildtpye, C3aR-/- and C5L2-/- BMDCs are perfectly suited to promote pulmonary allergy. Further, we found an increased frequency of a myeloid-derived suppressor cell (MDSC) population in C5aR-/- BM cultures. Co-transfer of C5aR-/- MDSCs and antigen-pulsed wildtypet BMDCs suppressed airway inflammation and Th2 cytokine production except IL-13. Our data suggest that the protective effect of C5aR signalling during allergen sensitization does not only result from a direct effect of C5a on DCs but the regulation of MDSCs and other pulmonary resident cells. Recent evidence points toward a critical role of airway epithelial cells (EC) in the regulation of DC function. Our preliminary data demonstrate that C3 as well as C3aR and C5aR are expressed on ECs indicating that the AT C3a and C5a may control Th2 development in allergic asthma also through a regulatory impact on EC functions. Indeed, preliminary data show that HDM stimulation drives the production of cytokines, chemokines and adhesion molecules in ECs. Last but not least, we found a novel mechanism by which the predominant IgG isotype in allergic asthma, that is IgG1, blocks C5aR-mediated effector functions. We observed that Fc-galactosylation of IgG1 enables IgG1 immune complexes to associate FcgRIIB with Dectin-1 resulting in a novel anti-inflammatory pathway that inhibits C5aR-mediated immune functions in vitro and in vivo. Based on these findings, we hypothesize that the ATs regulate the asthmatic phenotype not only at the level of DCs but at the level of the EC:DC, MDSC:T cell and the DC:T cell interfaces. Further, we hypothesize that the adaptive immune system feeds back on AT receptor-mediated activation of EC, DC, MDSC and granulocytic effector cells in the lung through differential glycosylation of allergen-specific IgG1 antibodies. We expect that our results will provide a detailed understanding of the role of complement at the EC:DC, DC:T cell and MDSC:T cell interfaces and the development of maladaptive immune responses in allergic asthma. Further, our studies will add to our understanding of how the adaptive immune system controls AT receptor-mediated immune and effector functions in allergic asthma.

屋尘螨粪便中的空气过敏原在过敏原致敏过程中激活补体系统，并导致过敏毒素 (AT) C3a 和 C5a 的产生，这些过敏毒素通过其同源 AT 受体 C3aR、C5aR 和 C5L2 特异性激活免疫细胞。我们的初步研究表明，AT 在树突状细胞 (DC) 水平上调节过敏性哮喘中适应不良免疫反应的发展。令人惊讶的是，C5aR-/- 骨髓源性 DC (BMDC) 驱动过敏性哮喘的能力明显受损，而 Wildtpye、C3aR-/- 和 C5L2-/- BMDC 非常适合促进肺部过敏。此外，我们发现 C5aR-/- BM 培养物中骨髓源性抑制细胞 (MDSC) 群体的频率增加。 C5aR-/- MDSC 和抗原脉冲的野生型 BMDC 的共转移抑制了气道炎症和 Th2 细胞因子的产生（IL-13 除外）。我们的数据表明，C5aR 信号在过敏原致敏过程中的保护作用不仅来自 C5a 对 DC 的直接影响，还来自对 MDSC 和其他肺部驻留细胞的调节。最近的证据表明气道上皮细胞 (EC) 在 DC 功能调节中发挥着关键作用。我们的初步数据表明，C3 以及 C3aR 和 C5aR 在 EC 上表达，表明 AT C3a 和 C5a 也可以通过对 EC 功能的调节影响来控制过敏性哮喘中 Th2 的发育。事实上，初步数据表明，HDM 刺激会驱动 EC 中细胞因子、趋化因子和粘附分子的产生。最后但并非最不重要的一点是，我们发现了一种新机制，过敏性哮喘中主要的 IgG 同种型（即 IgG1）可阻断 C5aR 介导的效应器功能。我们观察到 IgG1 的 Fc-半乳糖基化使 IgG1 免疫复合物能够将 FcgRIIB 与 Dectin-1 结合，从而形成一种新的抗炎途径，在体外和体内抑制 C5aR 介导的免疫功能。基于这些发现，我们假设 AT 不仅在 DC 水平上调节哮喘表型，而且在 EC:DC、MDSC:T 细胞和 DC:T 细胞界面水平上调节。此外，我们假设适应性免疫系统通过过敏原特异性 IgG1 抗体的差异糖基化，反馈 AT 受体介导的肺内 EC、DC、MDSC 和粒细胞效应细胞的激活。我们希望我们的结果能够详细了解补体在 EC:DC、DC:T 细胞和 MDSC:T 细胞界面的作用以及过敏性哮喘中适应不良免疫反应的发展。此外，我们的研究将加深我们对适应性免疫系统如何控制过敏性哮喘中 AT 受体介导的免疫和效应器功能的理解。