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

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.

Ingår i:Science advances: American Association for the Advancement of Science (AAAS)8:6, s. eabm1759-2375-2548

Av författaren/redakt...: Kissel, T; Ge, CR; Hafkenscheid, L; Kwekkeboom, JC; Slot, LM; Cavallari, M; visa fler...; He, YB; Van Schie, KA; Vergroesen, RD; Kampstra, ASB; Reijm, S; Stoeken-Rijsberg ...; Koeleman, C; Voortman, LM; Heitman, LH; Xu, BZ; Pruijn, GJM; Wuhrer, M; Rispens, T; Huizinga, TWJ; Scherer, HU; Reth, M; Holmdahl, R; Toes, REM; visa färre...

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