CRU 303, Subproject 02: The C5a/C5aR1 axis as a regulator of autoreactive IgG antibody glycosylation in pemphigoid diseases

Project: DFG ProjectsDFG Joint Research: Research Units/ Clinical Research Units

Project Details

Description

Deposition of autoreactive IgG antibodies (AAb) at the dermal-epidermal junction and activation of complement are hallmarks of PD. While AAb deposition is necessary to drive tissue inflammation and skin blistering, it is not sufficient, as AAb deposition often precedes clinical symptoms for a long time. In addition to the IgG isotype, the composition of the IgG Fc glycan structure determines the inflammatory potential of AAbs. More specifically, IgG Fc-glycan structures terminating with galactosyl- or additional sialyl-residues suppress, whereas agalactosylated (G0) IgG drive inflammation. In the 1st FP, we found in an experimental model of active epidermolysis bullosa acquisita (EBA) a higher frequency of G0 IgG1 AAbs in EBA-sensitive C57BL6/S than in EBA-resistant C57BL6/J mice. This increase in G0 IgG1 AAbs was associated with a decrease in single galactosylated as well as galactosylated and sialylated AAbs. Surprisingly, we observed a strong impact of complement on AAb Fc glycosylation, in particular of C5a, the small cleavage fragment of C5. Similar to the EBA-resistant mice, the frequency of G0 IgG1 AAb was low in C5a receptor 1 (C5aR1)-deficient mice and was associated with a high frequency of anti-inflammatory, highly galactosylated IgG1 AAbs, some of which were also highly sialylated. Moreover, the C5a/C5aR1 axis not only controlled the glycosylation pattern of IgG1 but also that of IgG2 AAbs and collagen type VII (COL7)-specific IgG2 serum levels, which were significantly lower in C5ar1-/- than in WT mice. Importantly, C5ar1-/- mice were completely protected from the development of blister formation during the entire observation period. Preliminary data further suggest that the C5a/C5aR1 axis regulates the expression of 1,4 galactosyltransferase 1 in B cells. Based on these findings, we hypothesize that the IgG Fc glycan pattern changes in clinically overt PD from an anti-inflammatory to a pro-inflammatory phenotype. Further, we propose that this change increases the potency of IgG AAbs to activate complement locally in the skin. The increased local generation of C5a activates the C5aR1 axis on innate immune cells, inducing a chain of events, ultimately suppressing galactosylation and sialylation of IgG AAbs. During the 2nd FP, we aim to further delineate the IgG Fc glycosylation pattern in experimental and clinical PD and define the molecular mechanisms underlying C5aR1-mediated regulation of AAb glycosylation in PD. Translationally, we aim to evaluate the impact of preventive and therapeutic C5aR1 targeting in the active EBA mouse model, with a particular emphasis on IgG AAb production and N-glycan composition.We expect that the IgG Fc glycan patterns in PD patients will serve as a novel biomarker to identify patients at risk for relapse and guide immunotherapy. Preventive and therapeutic C5aR1 targeting in the active EBA model may pave the way for clinical use of C5aR1 inhibitors in PD, some of which are about to be marketed.
Statusfinished
Effective start/end date01.04.1531.12.23

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 205-19 Dermatology
  • 204-05 Immunology

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