Reduced Galactosylation of Autoreactive IgG as Driver of Pemphigoid Diseases

Autoreactive IgG antibodies (AAb) drive tissue inflammation and skin blistering in PD. In addition to the IgG isotype, the composition of the biantennary IgG Fc glycan structure determines the inflammatory potential of autoreactive IgGs. The emerging paradigm is that IgG Fc-glycan structures terminating with a galactosyl residue counteract inflammation, whereas agalactosylated IgG drive inflammation. In young healthy adults, 20-25% of total serum IgG Fc-glycans are agalactosylated. This proportion increases with age and under certain inflammatory conditions such as rheumatoid arthritis (RA). In accordance with such findings, our preliminary data indicate a higher frequency of antigen-specific agalactosylated IgG in PD patients in comparison to total IgG of age-matched controls. AAb accumulation precedes skin inflammation suggesting that the reduction in terminal AAb galactosylation promotes the progression of silent into clinically active PD. The kinetic and the mechanisms shifting Fc-glycan composition remain elusive. β1,4-galactosyl-transferase (β1,4Gal-T) is the key enzyme of IgG galactosylation. It is regulated on transcriptional and posttranscriptional levels. In RA flares and in arthritis-prone mouse strains, β1,4Gal-T activity is decreased supporting the view that understanding β1,4Gal-T regulation is key to decipher the switch from silent to clinically overt disease.
We have recently shown that administration of highly galactosylated IgG1 immune complexes (HiGal IC) prevent disease in the AAb transfer EBA model through a novel, anti-inflammatory pathway. Mechanistically, HiGal ICs associate the inhibitory FcγRIIB and Dectin-1 on PMNs, thus suppressing signaling of chemoattractant G-Protein-coupled receptors (GPCRs). Recent data suggest that activation of the FcγRIIB/Dectin-1 pathway in dendritic cells (DC) promotes the generation of regulatory T (Treg) cells. Such Tregs have the potential to suppress CD4+ T effector cells and thus the generation of autoreactive plasma cells producing agalactosylated AAbs. Notably, Tregs also counteract skin inflammation in PD at the effector cell level (see Project 6) suggesting that induction of Tregs may serve as an additional mechanism by which galactosylated AAbs counteract PD. We hypothesize that reduction in IgG AAb galactosylation drives skin inflammation in PD patients and that this reduction is due to diminished activity of β1,4Gal-T. We propose that restoring β1,4Gal-T activity is a promising therapeutic strategy to suppress skin inflammation in PD. Further, we propose that galactosylated AAbs prevent inflammation by promoting differentiation of protective Treg cells, which, among other properties, preserve β1,4Gal-T activity.
We expect that reduced β1,4Gal-T activity and consequently decreased frequency of AAb galactosylation coincides with the development of skin inflammation. Thus, the frequency of circulating agalactosylated AAb, β1,4Gal-T activity in B cells or plasma cells, and mediators suppressing β1,4Gal-T activity may serve as novel biomarkers in PD that predict upcoming flares of tissue inflammation. Such biomarkers may help to prevent disease development by early, rational therapeutic intervention. This may include administration or induction of antigen-specific HiGal AAbs or neutralization of mediators suppressing β1,4Gal-T activity.