In recent years, evidence has accumulated that the effector functions of IgG antibodies (Abs) critically depend on the terminal sugar moieties of their biantennary Fc N-glycoside chains coupled to Asp297 of both heavy chains. Obviously, IgG Abs of identical subclass and antigen-specificity can exert opposite, proinflammatory or antiinflammatory, actions solely dependent on their terminal sugar moieties. Herein, the Fc N-glycoside chains of anti-inflammatory IgG Abs contain terminal galactosyl and additional sialyl moieties, while IgG Abs without these terminal sugar residues execute proinflammatory actions. Due to these structural characteristics, proinflammatory IgG Abs are often referred to as “agalactosylated” or “G0” IgG Abs, while antiinflammatory IgG Abs are categorized into “galactosylated” and “sialylated” IgG Abs. The molecular mechanisms enacted by these differential terminal sugar moieties are still largely elusive, and, as a matter of fact, sialylated IgG Abs can apply unique inhibitory mechanisms in addition to those of IgG Abs, which are merely galactosylated. Herein, differentially glycosylated IgG Abs not only target the classical Fc receptors, but also members of the C-type lectin receptor (CLR) family. In detail, the mannose receptor, for instance, has been suggested to mediate effects of agalactosylated IgG Abs, Dectin-1 those of galactosylated IgG Abs, and SIGN-R1 (DC-SIGN) and DCIR those of sialylated IgG Abs.

Due to the opposite effects of agalactosylated and galactosylated/sialylated IgG Abs, their relative frequencies in the pool of antigen-specific IgG Abs is hypothesized to decide whether a pro-inflammatory immune response is mounted or not and may serve as most valuable diagnostic marker to characterize an antigen-specific immune response. In line with this notion, we have recently found preliminary evidence that agalactosylated IgG Abs are dominant among anti-type XVII collagen IgG autoantibodies (AAbs) in patients with active BP. In parallel, using our passive AAb transfer EBA mouse model, we have found evidence for both proinflammatory and antiinflammatory effects of agalactosylated and galactosylated IgG AAbs, respectively, in the effector phase of the disease. Thus, removal of the glycoside chains from otherwise pathogenic anti-type VII collagen IgG AAbs completely abrogated skin inflammation despite uncompromised IgG deposition at the dermal-epidermal junction. Conversely, application of immune complexes containing galactosylated IgG Abs suppressed skin inflammation by a mechanism including crosslinking of Dectin-1 with the IgG inhibitory receptor FcγRIIB on neutrophils. In contrast, the additional actions of sialylated IgG Abs in the effector phase of PD skin inflammation have not been addressed yet.
In CRU Project 4, we will define the molecular mechanisms IgG Fc N-glycoside chains are required to engage in order to induce skin inflammation. Herein, we will first focus on the potential role of the mannose receptor in this process. In addition, we will set out to evaluate the therapeutic potential of ex vivo sialylated in comparison to only galactosylated IgG AAbs in the effector phase of PD and their mode of action, especially on neutrophils. Our research aims to develop therapeutic strategies activating the molecular pathways, physiologically engaged by galactosylated and sialylated IgG Abs, in PD patients with patient self-derived, ex vivo sialylated and re-applied IgG AAbs. These studies will be essential to understand the emergence of PD skin inflammation and will identify new therapeutic targets. They will also clarify whether sialylated IgG AAbs can be used to treat PD patients in an autoantigen-specific manner.