Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation

• DOI: 10.1126/sciadv.abm1759
• Publication Date: 2022-06-07T14:26:56Z
• Authors: Theresa Kissel; Changrong Ge; Lise Hafkenscheid; Joanneke C. Kwekk...; Linda M. Slot; Marco Cavallari; Yibo He; Karin A. van Schie; Rochelle D. Vergr...; Arieke S.B. Kampstra; Sanne Reijm; Gerrie Stoeken-Ri...; Carolien Koeleman; Lennard M. Voortman; Laura H. Heitman; Bingze Xu; Ger J.M. Pruijn; Manfred Wuhrer; Theo Rispens; Tom W.J. Huizinga; Hans Ulrich Scherer; Michael Reth; Rikard Holmdahl; Rene E.M. Toes
• Keywords: Glycobiology

The hallmark autoantibodies in rheumatoid arthritis are characterized by variable domain glycans (VDGs). Their abundant occurrence results from the selective introduction of N-linked glycosylation sites during somatic hypermutation, and their presence is predictive for disease development. However, functional consequences VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, cell assays allowed us to dissect key characteristics human biology. Crystal structures showed that positioned vicinity antigen-binding pocket, dynamic modeling combined with binding elucidated impact binding. We found VDG-expressing receptors stay longer surface enhance activation. These provide a rationale how acquisition might contribute breach tolerance major autoimmune disease.