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

Stereotyped antibody responses target posttranslationally modified gluten in celiac disease.

Author information

1
Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.
2
Bioengineering Faculty of Engineering, Bar-Ilan University, Ramt Gan, Israel.
3
Division of Structural Biology, University of Oxford, Wellcome Trust Centre for Human Genetics, Headington, Oxford, United Kingdom.
4
Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
5
KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway.

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.

KEYWORDS:

Autoimmune diseases; Autoimmunity; Immunoglobulins

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