Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Stereotyped antibody responses target posttranslationally modified gluten in celiac disease
Omri Snir, … , Gur Yaari, Ludvig M. Sollid
Omri Snir, … , Gur Yaari, Ludvig M. Sollid
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e93961. https://doi.org/10.1172/jci.insight.93961.
View: Text | PDF
Research Article

Stereotyped antibody responses target posttranslationally modified gluten in celiac disease

  • Text
  • PDF
Abstract

The role of B cells and posttranslational modifications in pathogenesis of organ-specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2–modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations. X-ray crystal structures of 2 prototype IGHV3-15/IGKV4-1 and IGHV3-23/IGLV4-69 antibodies reveal peptide interaction mainly via germline-encoded residues. In-depth mutational analysis showed restricted selection and substitution patterns at positions involved in antigen binding. While the IGHV3-15/IGKV4-1 antibody interacts with Glu5 and Gln6, the IGHV3-23/IGLV4-69 antibody interacts with Gln3, Pro4, Pro7, and Phe8 — residues involved in substrate recognition by TG2. Hence, both antibodies, despite different interaction with the epitope, recognize signatures of TG2 processing that facilitates B cell presentation of deamidated gluten peptides to T cells, thereby providing a molecular framework for the generation of these clinically important antibodies. The study provides essential insight into the pathogenic mechanism of celiac disease.

Authors

Omri Snir, Xi Chen, Moriah Gidoni, M. Fleur du Pré, Yuguang Zhao, Øyvind Steinsbø, Knut E.A. Lundin, Gur Yaari, Ludvig M. Sollid

×

Figure 3

Somatic mutations in IGHV3-15 and the effect of positions involved in binding on the affinity of 1E03 hmAb.

Options: View larger image (or click on image) Download as PowerPoint
Somatic mutations in IGHV3-15 and the effect of positions involved in bi...
(A) Frequency of amino acid substitution along the IGHV3-15 gene segment of DGP-reactive and non–DGP-reactive PCs from a representative CD patient with more than 30 sequences available for analysis. (B) The effect of single amino acid substitution on binding affinity of hmAbs 1E03 to DGP as assessed by MST (average of 3 measurements ± SD). Variants at R55-H and T113-L were tested. GL, germline; VH, heavy chain; VΚ, Κ light chain.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts