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.

来自屋尘螨粪便的空气变应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，这些过敏原通过其同源AT受体C3aR、C5aR和C5L2特异性地激活免疫细胞。我们的初步研究表明，ATS在树突状细胞(DC)水平上调节过敏性哮喘患者不良适应免疫反应的发展。令人惊讶的是，C5aR-/-骨髓来源的DC(BMDC)导致过敏性哮喘的能力明显受损，而野生型、C3aR-/-和C5L2-/-BMDCs非常适合促进肺过敏。此外，我们发现在C5aR-/-BM培养中髓系来源的抑制细胞(MDSC)群体的频率增加。共转移C5aR-/-MDSCs和抗原致敏的野生型BMDCs可抑制呼吸道炎症和Th2细胞因子的产生，但IL-13除外。我们的数据表明，在变应原致敏过程中，C5aR信号的保护作用不仅来自于C5a对DC的直接作用，也来自于对MDSCs和其他肺常驻细胞的调节。最近的证据表明，气道上皮细胞(EC)在DC功能的调节中起着关键作用。我们的初步数据表明，C3以及C3aR和C5aR在内皮细胞上表达，这表明AT C3a和C5a可能也通过调节EC功能来控制过敏性哮喘Th2的发展。事实上，初步数据显示，HDM刺激推动内皮细胞产生细胞因子、趋化因子和黏附分子。最后但并非最不重要的是，我们发现了一种新的机制，即在过敏性哮喘中占主导地位的Ig G亚型阻断C5aR介导的效应功能。我们观察到，IgG1的Fc-半乳糖化使IgG1免疫复合物能够将FcgRIIB与Dectin-1结合，从而在体外和体内产生一种新的抗炎途径，抑制C5aR介导的免疫功能。根据这些发现，我们推测ATS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哮喘的表型。此外，我们假设适应性免疫系统通过AT受体介导的肺内EC、DC、MDSC和粒细胞效应细胞的激活来反馈，这些细胞是通过不同的过敏原特异性IgG1抗体的糖基化来实现的。我们希望我们的结果将提供一个详细的了解补体在EC：DC，DC：T细胞和MDSC：T细胞界面上的作用，以及在过敏性哮喘中不良适应性免疫反应的发展。此外，我们的研究将增加我们对适应性免疫系统如何在过敏性哮喘中控制AT受体介导的免疫和效应器功能的理解。