dc.date.accessioned | 2018-08-09T13:55:40Z | |
dc.date.available | 2018-08-09T13:55:40Z | |
dc.date.created | 2018-01-25T15:23:04Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Snir, Omri Chen, Xi Gidoni, Moriah du Pré, Marie Fleur Zhao, Yuguang Steinsbø, Øyvind Lundin, Knut Erik Aslaksen Yaari, Gur Sollid, Ludvig Magne . Stereotyped antibody responses target posttranslationally modified gluten in celiac disease. JCI Insight. 2017, 2(16) | |
dc.identifier.uri | http://hdl.handle.net/10852/62839 | |
dc.description.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.
© 2018 American Society for Clinical Investigation | en_US |
dc.language | EN | |
dc.publisher | American Society for Clinical Investigation (ASCI) | |
dc.title | Stereotyped antibody responses target posttranslationally modified gluten in celiac disease | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Snir, Omri | |
dc.creator.author | Chen, Xi | |
dc.creator.author | Gidoni, Moriah | |
dc.creator.author | du Pré, Marie Fleur | |
dc.creator.author | Zhao, Yuguang | |
dc.creator.author | Steinsbø, Øyvind | |
dc.creator.author | Lundin, Knut Erik Aslaksen | |
dc.creator.author | Yaari, Gur | |
dc.creator.author | Sollid, Ludvig Magne | |
cristin.unitcode | 185,53,2,11 | |
cristin.unitname | Senter for immunregulering | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 1552040 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=JCI Insight&rft.volume=2&rft.spage=&rft.date=2017 | |
dc.identifier.jtitle | JCI Insight | |
dc.identifier.volume | 2 | |
dc.identifier.issue | 16 | |
dc.identifier.doi | http://dx.doi.org/10.1172/jci.insight.93961 | |
dc.identifier.urn | URN:NBN:no-65407 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 2379-3708 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/62839/2/JCI%2BInsight93961.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | e93961 | |
dc.relation.project | NFR/179573 | |
dc.relation.project | SKGJ/SKGJ-MED-017 | |