CRU 303, Subproject 04: Therapeutic potential of sialylated Pemphigoid Disease autoantibodies

In recent years, evidence has accumulated that IgG antibodies (Abs) can have pro- or antiinflammatory effector functions and that these potentials critically depend on the terminal sugar moieties of their biantennary Fc N-glycoside chains coupled to Asp297 of both heavy chains. Herein, the Fc N-glycoside chains of anti-inflammatory IgG Abs contain terminal galactosyl and additional sialyl moieties and are categorized into galactosylated and sialylated IgG Abs, respectively. IgG Abs without these terminal sugar residues are referred to as agalactosylated and execute proinflammatory actions such as IgG autoantibodies (AAbs) in rheumatoid arthritis. The molecular mechanisms enacted by these differential terminal sugar moieties are still largely elusive. Herein, differentially glycosylated IgG Abs not only target the classical Fcy receptors, but also members of the C-type lectin receptor (CLR) family. Activating Fcy receptors and the mannose receptor, for instance, have been suggested to mediate effects of agalactosylated IgG Abs, Dectin-1 and the IgG inhibitory receptor FcyRIIB those of galactosylated IgG Abs, and sialylated IgG Abs can act primarily independent of FcyRIIB through SIGN-R1 (DC-SIGN) and DCIR. 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 proinflammatory immune response is mounted and may serve as most valuable diagnostic marker to characterize an antigen-specific immune response. In line with this notion, we have found preliminary evidence that agalactosylated IgG Abs are dominant among anti-type XVII collagen IgG 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 Abs, 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. Conversely, application of immune complexes containing galactosylated IgG Abs suppressed skin inflammation by a mechanism including crosslinking of Dectin-1 with Fc¿RIIB on neutrophils. In contrast, the additional actions of sialylated IgG Abs in the effector phase of PD skin inflammation have not been addressed. The main aim of Project 4 is to investigate the activating or inhibitory potential of agalactosylated, galactosylated and sialylated IgG AAbs, respectively, in the effector phase of PD and their receptors, especially on neutrophils. These studies will be essential to understand the emergence of PD skin inflammation and will also clarify whether sialylated IgG AAbs can be used to treat PD patients in an autoantigen-specific manner. Our research aims to develop a new therapeutic strategy for PD patients with patient self-derived, ex vivo sialylated and re-applied IgG AAbs.