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SP0129 Novel Roles of Complement as Driver of Autoinflammatory Diseases and Its Control By Adaptive Immune Mechanisms
  1. J. Koehl
  1. Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany

Abstract

Auto-antibodies (AAbs) drive undesired inflammation mainly through joint activation of IgG Fc receptors (FcγRs) and the complement system. The latter results in the generation of the powerful chemoattractant and pro-inflammatory mediator C5a. In experimental models of auto-immune inflammation such as rheumatoid arthritis, SLE and skin blistering diseases, we and others have previously shown that C5a drives the accumulation and activation of neutrophils and inflammatory monocytes. In Epidermolysis Bullosa Acquisita (EBA), a subepidermal blistering disease caused by AAbs against type VII collagen (Col7), neutrophils secrete proteolytic enzymes leading to dermal-epidermal separation and blister formation. We found that deficiency of C5a receptor 1 (C5aR1) protects from skin blistering in a passive model of EBA demonstrating a critical role for C5a in the effector phase of the disease. More recently, we developed an active model of EBA, in which cutaneous inflammation is induced by active immunization with a fragment of Col7. The role of the C5a/C5aR1 axis and its cross-talk with FcγRs for disease initiation, i.e. the formation of pathogenic AAbs in EBA is unclear. I will present data showing novel roles for C5aR1 activation in disease onset and the development of adaptive immune responses against Col7. Wildtype (wt) mice showed an early disease onset at week 4 and a severe phenotype resulting in 8.7% affected body surface at week 12. In contrast, C5aR1-/- mice showed a later onset at week 6 and a much milder phenotype, eventually resulting in only 3.9% of affected body surface at week 12. Importantly, the levels of Col7-specific IgG2b and IgG2c AAbs were significantly reduced in C5aR1-/- mice. Further, purified IgG AAbs from C5aR1-/- mice induced a significantly lower ROS release from neutrophils in vitro than IgG AAbs from wt mice. Our findings demonstrate a crucial role for the C5a/C5aR1 axis in disease development in an active model of EBA. Mechanistically, our results suggest that C5a is required for the induction of auto-Ag-specific IgG Abs, which drive neutrophil activation by FcγR-dependent mechanisms. Thus, targeting the C5a/C5aR1 axis may prove useful as novel therapeutic concept to disrupt the generation of Col7-specific AAbs in EBA. Interestingly, we also identified a novel anti-inflammatory mechanism, by which IgG1 Abs can suppress C5a-mediated effector functions. I will present data demonstrating that the IgG1 Fc-glycan composition defines the pro- or anti-inflammatory properties of IgG1 Abs. High galactosylation of the IgG1 Fc moiety enabled such IgG1 to cross-link FcγRIIB with the C-type lectin receptor Dectin-1, resulting in the activation of a Syk and SHIP-dependent pathway eventually blocking C5aR1 signaling at the level of ERK1/2 phosphorylation. In EBA, highly galactosylated IgG1 immune complexes efficiently blocked the development of skin blister formation. Thus, the adaptive immune system can efficiently control complement-mediated inflammation by formation of IgG1 antibodies with an anti-inflammatory Fc phenotype.

Disclosure of Interest None declared

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