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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.
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Research Article

Stereotyped antibody responses target posttranslationally modified gluten in celiac disease

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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

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Figure 2

Recognition of the peptide PLQPEQPFP by IGHV3-23/IGLV4-69 and IGHV3-15/IGKV4-1 hmAbs.

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Recognition of the peptide PLQPEQPFP by IGHV3-23/IGLV4-69 and IGHV3-15/I...
(A) Binding (1/Kd values determined by MST) of hmAbs 1E01 (IGHV3-23/IGLV4-69) and 1E03 (IGHV3-15/IGKV4-1) to Ala-substituted variants of the DGP (upper panel), and B-factor distribution for the cocrystal structures 1E01Fab-E and 1E03Fab-E (lower panel). Residues predicted to be involved in substrate recognition by TG2 are shown in blue, with residues being particularly important in bold. The Glu5 residue formed by TG2-mediated deamidation is shown in red. (B) Docking of DGP to structures of 1E01Fab and 1E03Fab. (C) Two pockets in the surface of 1E01Fab-E accommodate side chains of peptide residues Gln3 (pocket A) and Pro7/Phe8 (pocket B). (D) The interaction surface of 1E03Fab-E displays no major pockets for harboring side chains of DGP residues. In the zoom-in, bonds between Glu5 of the peptide and with R55-H (salt bridge) and T113-L (hydrogen bond) are shown as black dotted lines. Interacting residues are drawn as sticks, with nitrogen atoms in blue and oxygen atoms in red.

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ISSN 2379-3708

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