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

• Published in: Science advances 2022-02, Vol.8 (6), p.eabm1759-eabm1759
• Main Authors: Kissel, Theresa, Ge, Changrong, Hafkenscheid, Lise, Kwekkeboom, Joanneke C, Slot, Linda M, Cavallari, Marco, He, Yibo, van Schie, Karin A, Vergroesen, Rochelle D, Kampstra, Arieke S B, Reijm, Sanne, Stoeken-Rijsbergen, Gerrie, Koeleman, Carolien, Voortman, Lennard M, Heitman, Laura H, Xu, Bingze, Pruijn, Ger J M, Wuhrer, Manfred, Rispens, Theo, Huizinga, Tom W J, Scherer, Hans Ulrich, Reth, Michael, Holmdahl, Rikard, Toes, Rene E M
• Format: Article
• Language: English
• Subjects: Biomedicine and Life Sciences; Immunology; Life Sciences; Medicin och hälsovetenskap; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abm1759

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.