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

Kissel, T.; Ge, C.; Hafkenscheid, L.; Kwekkeboom, J.C.; Slot, L.M.; Cavallari, M.; ... ; Toes, R.E.M. (2022)

Article / Letter to editor

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, the functional consequences of VDGs on autoreactive B cells remain elusive. Combining crystallography, glycobiology, and functional B cell assays allowed us to dissect key characteristics of VDGs on human B cell biology. Crystal structures showed that VDGs are positioned in the vicinity of the antigen-binding pocket, and dynamic modeling combined with binding assays elucidated their impact on binding. We found that VDG-expressing B cell receptors stay longer on the B cell surface and that VDGs enhance B cell activation. These results provide a rationale on how the acquisition of VDGs might contribute to the breach of tolerance of autoreactive B cells in a major human autoimmune disease.

• All authors: Kissel, T.; Ge, C.; Hafkenscheid, L.; Kwekkeboom, J.C.; Slot, L.M.; Cavallari, M.; He, Y.; Schie, K.A. van; Vergroesen, R.D.; Kampstra, A.S.B.; Reijm, S.; Stoeken-Rijsbergen, G.; Koeleman, C.; Voortman, L.M.; Heitman, L.H.; Xu, B.; Pruijn, G.J.M.; Wuhrer, M.; Rispens, T.; Huizinga, T.J.W.; Scherer, H.U.; Reth, M.; Holmdahl, R.; Toes, R.E.M.
• Date: 2022-02-09
• Journal: Science Advances
• Volume: 8
• Issue: 6
• Pages: 1 - 21
• DOI: doi:10.1126/sciadv.abm1759