ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP PRSYM
    • 2016-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • Register
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 0993

N-linked Glycosylation of the Immunoglobulin Variable Domain Affects Antigen Binding and Autoreactive B Cell Activation

Theresa Kissel1, Changrong Ge2, Lise Hafkenscheid1, Linda Slot1, Marco Cavallari3, Joanneke Kwekkeboom4, Manfred Wuhrer1, Thomas Huizinga1, Hans Scherer1, Michael Reth3, Rikard Holmdahl2 and René Toes1, 1Leiden University Medical Center, Leiden, Netherlands, 2Karolinska Institutet, Solna, Sweden, 3University Freiburg, Freiburg, Germany, 4Leiden Univeristy Medical Center, Leiden, Netherlands

Meeting: ACR Convergence 2020

Keywords: Anti-citrullinated Protein Autoantibodies (ACPAs), autoimmune diseases, rheumatoid arthritis

  • Tweet
  • Email
  • Print
Save to PDF
Session Information

Date: Sunday, November 8, 2020

Session Title: B Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Anti-citrullinated protein antibodies, the hallmarking autoantibodies in Rheumatoid Arthritis (RA), are characterized by N-linked glycans in the variable domain (V-domain). The occurrence of these glycans results from the selective introduction of N-glycosylation sites during somatic hypermutation and their presence is predictive for the transition from pre-disease autoimmunity towards RA. We have now determined the biological implication of V-domain glycans on antigen-binding and B-cell activation.

Methods: ACPA crystal structures, including the starting monosaccharides of the V-domain glycans, were generated. These crystal structures were used as a basic framework and the complete glycan structure modelled onto the V-domain. Fab crystal structures with modelled V-domain glycans were subsequently used for molecular dynamics simulations. Antigen binding assays using monoclonal ACPA IgG including V-domain glycans and their non-glycosylated counterparts were performed. Further, we generated human Ramos B cells lines including V-domain glycosylated and non-glycosylated mIgG B cell receptors and identified their activation upon stimulation.

Results: Autoantibody crystal structures show that V-domain glycans are positioned in the vicinity of the binding-pocket and dynamic modelling shows their potential to interact with antigen-binding, which is confirmed by binding assays. Noteworthy, human Ramos B cells carrying V-domain glycosylated B cell receptors undergo increased signalling after stimulation compared to their non-glycosylated counterparts.

Conclusion: Our data indicate that autoreactive B cells in RA are selected for the presence of V-domain glycans that convey a signalling advantage, potentially explaining the outgrowth of autoreactive B cells and the increase of autoantibody levels towards disease-onset. These findings are relevant for the understanding of how autoreactive B cells escape immune checkpoints in humans and indicate that the introduction of V-domain glycans enables B cells to breach tolerance in the prominent autoimmune disease RA.


Disclosure: T. Kissel, None; C. Ge, None; L. Hafkenscheid, None; L. Slot, None; M. Cavallari, None; J. Kwekkeboom, None; M. Wuhrer, None; T. Huizinga, Bristol-Myers Squibb Company, 2, 8, Pfizer, 2, 8, Eli Lilly, 2, 8, LUMC, 9; H. Scherer, LUMC, 9; M. Reth, None; R. Holmdahl, None; R. Toes, LUMC, 9.

To cite this abstract in AMA style:

Kissel T, Ge C, Hafkenscheid L, Slot L, Cavallari M, Kwekkeboom J, Wuhrer M, Huizinga T, Scherer H, Reth M, Holmdahl R, Toes R. N-linked Glycosylation of the Immunoglobulin Variable Domain Affects Antigen Binding and Autoreactive B Cell Activation [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/n-linked-glycosylation-of-the-immunoglobulin-variable-domain-affects-antigen-binding-and-autoreactive-b-cell-activation/. Accessed February 24, 2021.
  • Tweet
  • Email
  • Print
Save to PDF

« Back to ACR Convergence 2020

ACR Meeting Abstracts - https://acrabstracts.org/abstract/n-linked-glycosylation-of-the-immunoglobulin-variable-domain-affects-antigen-binding-and-autoreactive-b-cell-activation/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Convergence: Where Rheumatology Meets. All Virtual. November 5-9.

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2021 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
loading Cancel
Post was not sent - check your email addresses!
Email check failed, please try again
Sorry, your blog cannot share posts by email.
This site uses cookies: Find out more.