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

• Applicant: Professor Dr. Jörg Köhl
• Subject Area: Immunology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256784565

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.

• DFG Programme: Research Grants