@article{dde6b0ea3ec846a58528d27ea0c0eeef,
title = "Plasma Cells Are the Most Abundant Gluten Peptide MHC-expressing Cells in Inflamed Intestinal Tissues From Patients With Celiac Disease",
abstract = " Background & Aims: Development of celiac disease is believed to involve the transglutaminase-dependent response of CD4 + T cells toward deamidated gluten peptides in the intestinal mucosa of individuals with specific HLA-DQ haplotypes. We investigated the antigen presentation process during this mucosal immune response. Methods: We generated monoclonal antibodies (mAbs) specific for the peptide–MHC (pMHC) complex of HLA-DQ2.5 and the immunodominant gluten epitope DQ2.5-glia-α1a using phage display. We used these mAbs to assess gluten peptide presentation and phenotypes of presenting cells by flow cytometry and enzyme-linked immune absorbent spot (ELISPOT) in freshly prepared single-cell suspensions from intestinal biopsies from 40 patients with celiac disease (35 untreated and 5 on a gluten-free diet) as well as 18 subjects with confirmed noninflamed gut mucosa (controls, 12 presumed healthy, 5 undergoing pancreatoduodenectomy, and 1 with potential celiac disease). Results: Using the mAbs, we detected MHC complexes on cells from intestinal biopsies from patients with celiac disease who consume gluten, but not from patients on gluten-free diets. We found B cells and plasma cells to be the most abundant cells that present DQ2.5-glia-α1a in the inflamed mucosa. We identified a subset of plasma cells that expresses B-cell receptors (BCR) specific for gluten peptides or the autoantigen transglutaminase 2 (TG2). Expression of MHC class II (MHCII) was not restricted to these specific plasma cells in patients with celiac disease but was observed in an average 30% of gut plasma cells from patients and controls. Conclusions: A population of plasma cells from intestinal biopsies of patients with celiac disease express MHCII; this is the most abundant cell type presenting the immunodominant gluten peptide DQ2.5-glia-α1a in the tissues from these patients. These results indicate that plasma cells in the gut can function as antigen-presenting cells and might promote and maintain intestinal inflammation in patients with celiac disease or other inflammatory disorders.",
keywords = "APC, Autoimmunity, Immune Activation, TG2",
author = "H{\o}ydahl, {Lene St{\o}kken} and Lisa Richter and Rahel Frick and Omri Snir and Gunnarsen, {Kristin St{\o}en} and Landsverk, {Ole J.B.} and Rasmus Iversen and Jeliazkov, {Jeliazko R.} and Gray, {Jeffrey J.} and Elin Bergseng and Stian Foss and Qiao, {Shuo Wang} and Lundin, {Knut E.A.} and J{\o}rgen Jahnsen and Jahnsen, {Frode L.} and Inger Sandlie and Sollid, {Ludvig M.} and L{\o}set, {Geir {\AA}ge}",
note = "Funding Information: Funding This work received funding from the South-Eastern Norway Regional Health Authority (grant 2012046) and by the Research Council of Norway through its Centers of Excellence funding scheme, project number 179573/V40. Jeliazko R. Jeliazkov and Jeffrey J. Gray are supported by US National Institutes of Health grant R01-GM078221. Part of the computations were performed on resources provided by UNINETT Sigma2 - the National Infrastructure for High Performance Computing and Data Storage in Norway. Funding This work received funding from the South-Eastern Norway Regional Health Authority (grant 2012046) and by the Research Council of Norway through its Centers of Excellence funding scheme, project number 179573/V40. Jeliazko R. Jeliazkov and Jeffrey J. Gray are supported by US National Institutes of Health grant R01-GM078221. Part of the computations were performed on resources provided by UNINETT Sigma2 - the National Infrastructure for High Performance Computing and Data Storage in Norway. We thank Sivaganesh Sathiaruby, Linn Margrethe Eggesb{\o} and Anna Bujko for excellent technical assistance; Espen B{\ae}kkevold for technical advice; Kjetil Task{\'e}n (Biotechnology Center of Oslo) for access to the Biacore T100 instrument; The Flow Cytometry Core Facility at Oslo University Hospital for access to equipment and assistance with sorting; and the Department of Immunology at Oslo University Hospital-Rikshospitalet for HLA typing. Author contributions: G{\AA}L, IS, and LMS conceived the study. LSH, LR, RF, OS, KSG, OJBL, RI, JRJ, EB, and SWQ designed, performed experiments, and analyzed data. SF provided crucial reagents. JJ and KEAL performed endoscopic examination and provided biopsies. JJG, FLJ, IS, LMS, and G{\AA}L designed experiments, analyzed data, and supervised the study. LSH, IS, LMS, and G{\AA}L wrote the manuscript. All authors critically reviewed the manuscript. Lisa Richter's Present address: Core Facility Flow Cytometry, Biomedical Center Munich, Ludwig-Maximilians-Universit{\"a}t Munich, Planegg-Martinsried, Germany Funding This work received funding from the South-Eastern Norway Regional Health Authority (grant 2012046) and by the Research Council of Norway through its Centers of Excellence funding scheme, project number 179573/V40. Jeliazko R. Jeliazkov and Jeffrey J. Gray are supported by US National Institutes of Health grant R01-GM078221. Part of the computations were performed on resources provided by UNINETT Sigma2 - the National Infrastructure for High Performance Computing and Data Storage in Norway. Publisher Copyright: {\textcopyright} 2019 AGA Institute",
year = "2019",
month = apr,
doi = "10.1053/j.gastro.2018.12.013",
language = "English (US)",
volume = "156",
pages = "1428--1439.e10",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "5",
}