IgG Fc N-Glycosylation Translates MHCII Haplotype into Autoimmune Skin Disease

Ann Katrin Clauder, Anna Kordowski, Yannic C. Bartsch, Gabriele Köhl, Gina Maria Lilienthal, Larissa N. Almeida, Timo Lindemann, Janina Petry, Christina N. Rau, Anna Gramalla-Schmitz, Lara Dühring, Claudia Elbracht, Samyr Kenno, Jenny Tillmann, Manfred Wuhrer, Ralf J. Ludwig, Saleh M. Ibrahim, Katja Bieber, Jörg Köhl, Marc EhlersRudolf Armin Manz*

*Corresponding author for this work


The major histocompatibility complex haplotype represents the most prevalent genetic risk factor for the development of autoimmune diseases. However, the mechanisms by which major histocompatibility complex–associated genetic susceptibility translates into autoimmune disease are not fully understood. Epidermolysis bullosa acquisita is an autoimmune skin-blistering disease driven by autoantibodies to type VII collagen. Here, we investigated autoantigen-specific plasma cells, CD4+ T cells, and IgG fraction crystallizable glycosylation in murine epidermolysis bullosa acquisita in congenic mouse strains with the disease-permitting H2s or disease-nonpermitting H2b major histocompatibility complex II haplotypes. Mice with an H2s haplotype showed increased numbers of autoreactive CD4+ T cells and elevated IL-21 and IFN-γ production, associated with a higher frequency of IgG autoantibodies with an agalactosylated, proinflammatory N-glycan moiety. Mechanistically, we show that the altered antibody glycosylation leads to increased ROS release from neutrophils, the main drivers of autoimmune inflammation in this model. These results indicate that major histocompatibility complex II–associated susceptibility to autoimmune diseases acuminates in a proinflammatory IgG fraction crystallizable N-glycosylation pattern and provide a mechanistic link to increased ROS release by neutrophils.

Original languageEnglish
JournalJournal of Investigative Dermatology
Publication statusPublished - 2020

Research Areas and Centers

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


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