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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 6

DGP-specific B cells efficiently induce IL-2 secretion from gluten-specific T cells.

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DGP-specific B cells efficiently induce IL-2 secretion from gluten-speci...
(A) Binding of deamidated ω34mer gluten peptide by transfectant B cells expressing either (i) HLA-DQ2.5 alone (blue line), (ii) HLA-DQ2.5 and DGP-reactive Ig (BCR) 1E03 (green line), or (iii) DGP-negative Ig (BCR) 693-2F02 (red line). Cells were stained with biotinylated ω34mer that was multimerized with APC-conjugated streptavidin. (B) Antigen presentation by transfectant B cells pulsed with the indicated concentrations of ω34mer peptide and cocultured with transfectant T cells specific for the DQ2.5-glia-ω2 epitope. IL-2 production was assayed (mean ± SEM). One representative of 3 independent experiments is shown.

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ISSN 2379-3708

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