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Stereotyped antibody responses target posttranslationally modified gluten in celiac disease

DOI: 10.1172/jci.insight.93961 DOI Help

Authors: Omri Snir (University of Oslo; Oslo University Hospital–Rikshospitalet) , Xi Chen (University of Oslo; Oslo University Hospital–Rikshospitalet) , Moriah Gidoni (Bar-Ilan University) , M. Fleur Du Pré (University of Oslo; Oslo University Hospital–Rikshospitalet) , Yuguang Zhao (University of Oxford) , Øyvind Steinsbø (University of Oslo; Oslo University Hospital–Rikshospitalet) , Knut E. A. Lundin (Oslo University Hospital–Rikshospitalet) , Gur Yaari (Bar-Ilan University) , Ludvig M. Sollid (University of Oslo; Oslo University Hospital–Rikshospitalet)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Jci Insight , VOL 2

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 10627

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.

Diamond Keywords: Coeliac Disease

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ID29 at ERSF

Added On: 14/09/2017 09:41

Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)