Stereotyped antibody responses target posttranslationally modified gluten in celiac disease

JCI Insight. 2017 Sep 7;2(17):e93961. doi: 10.1172/jci.insight.93961.


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.

Keywords: Autoimmune diseases; Autoimmunity; Immunoglobulins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Autoantibodies / biosynthesis*
  • Autoantibodies / immunology
  • B-Lymphocytes / immunology
  • Celiac Disease / immunology*
  • Crystallography, X-Ray
  • Glutens / immunology
  • Glutens / metabolism*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / genetics
  • Mutation
  • Protein Conformation
  • Protein Processing, Post-Translational*
  • T-Lymphocytes / immunology


  • Amino Acids
  • Autoantibodies
  • Immunodominant Epitopes
  • Immunoglobulin Heavy Chains
  • Glutens