6yxm
Crystal structure of ACPA 1F2 in complex with CII-C-39-CIT
Structural highlights
Publication Abstract from PubMedThe 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. 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 JC, Slot LM, Cavallari M, He Y, van Schie KA, Vergroesen RD, Kampstra ASB, Reijm S, Stoeken-Rijsbergen G, Koeleman C, Voortman LM, Heitman LH, Xu B, Pruijn GJM, Wuhrer M, Rispens T, Huizinga TWJ, Scherer HU, Reth M, Holmdahl R, Toes REM Sci Adv. 2022 Feb 11;8(6):eabm1759. doi: 10.1126/sciadv.abm1759. Epub 2022 Feb 9. PMID:35138894[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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