Surface Ig variable domain glycosylation affects autoantigen binding and acts as threshold for human autoreactive B cell activation
Science Advances, vol. 8, pp. eabm1759
Abstract
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.
Authors 24
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Changrong Ge corresponding
Affiliation as printed
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
-
Leiden University Medical Center · Technical University of Denmark
Affiliation as printed
Department of Biotechnology and Biomedicine, DTU Bioengineering, Technical University of Denmark, Lyngby, Denmark
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Affiliation as printed
Biology III (Department of Molecular Immunology), University of Freiburg, Freiburg, Germany
-
Affiliation as printed
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Immunology, Leiden University Medical Center, Leiden, Netherlands
-
Laura H. Heitman Aachen Oncode Institute Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research
Affiliation as printed
Oncode Institute and Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
-
Affiliation as printed
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
-
Affiliation as printed
Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
-
Affiliation as printed
Department Immunopathology, Sanquin Research, Amsterdam, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
-
Affiliation as printed
Biology III (Department of Molecular Immunology), University of Freiburg, Freiburg, Germany
-
Rikard Holmdahl corresponding
Karolinska Institutet · Second Affiliated Hospital of Xi'an Jiaotong University
Affiliation as printed
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
The Second Affiliated Hospital of Xi’an Jiaotong University (Xibei Hospital), 710004 Xi’an, China
The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), 710004 Xi'an, China
-
Leiden University Medical Center
Affiliation as printed
Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
Cited by 78 stored of 77
No patents citing this paper on Lens.org (checked 2026-10-11).