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

DOI: 10.1126/sciadv.abm1759

Authors: Theresa Kissel (Leiden University Medical Center) , Lise Hafkenscheid (Leiden University Medical Center; Technical University of Denmark) , Joanneke C. Kwekkeboom (Leiden University Medical Center) , Changrong Ge (Karolinska Institutet) , Linda M. Slot (Leiden University Medical Center) , Marco Cavallari (University of Freiburg) , Yibo He (Karolinska Institutet) , Karin A. Van Schie (Leiden University Medical Center) , Rochelle D. Vergroesen (Leiden University Medical Center) , Arieke S. B. Kampstra (Leiden University Medical Center) , Sanne Reijm (Leiden University Medical Center) , Gerrie Stoeken-Rijsbergen (Leiden University Medical Center) , Carolien Koeleman (Leiden University Medical Center) , Lennard M. Voortman (Leiden University Medical Center,) , Laura H. Heitman (Leiden University) , Bingze Xu (Karolinska Institutet) , Ger J. M. Pruijn (Radboud University) , Manfred Wuhrer (Leiden University Medical Center) , Theo Rispens (Sanquin Research) , Tom W. J. Huizinga (Leiden University Medical Center) , Hans Ulrich Scherer (Leiden University Medical Center) , Michael Reth (University of Freiburg) , Rikard Holmdahl (Karolinska Institutet; The Second Affiliated Hospital of Xi’an Jiaotong University (Xibei Hospital)) , Rene E. M. Toes (Leiden University Medical Center)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances

State: Published (Approved)
Published: February 2022
Diamond Proposal Number(s): 15806

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.

Diamond Keywords: Rheumatoid Arthritis

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: BioMAX at MAX IV

Added On: 16/02/2022 08:38

Documents:
sciadv.abm1759-2.pdf

Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)