title: Responsive population dynamics and wide seeding into the duodenal lamina propria of transglutaminase-2-specific plasma cells in celiac disease.
abstract: A hallmark of celiac disease is autoantibodies to transglutaminase 2 (TG2). By visualizing TG2-specific antibodies by antigen staining of affected gut tissue, we identified TG2-specific plasma cells in the lamina propria as well as antibodies in the subepithelial layer, inside the epithelium, and at the brush border. The frequency of TG2-specific plasma cells were found not to correlate with serum antibody titers, suggesting that antibody production at other sites may contribute to serum antibody levels. Upon commencement of a gluten-free diet, the frequency of TG2-specific plasma cells in the lesion dropped dramatically within 6 months, yet some cells remained. The frequency of TG2-specific plasma cells in the celiac lesion is thus dynamically regulated in response to gluten exposure. Laser microdissection of plasma cell patches, followed by antibody gene sequencing, demonstrated that clonal cells were seeded in distinct areas of the mucosa. This was confirmed by immunoglobulin heavy chain repertoire analysis of plasma cells isolated from individual biopsies of two untreated patients, both for TG2-specific and non-TG2-specific cells. Our results shed new light on the processes underlying the B-cell response in celiac disease, and the approach of staining for antigen-specific antibodies should be applicable to other antibody-mediated diseases.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: R
authors.initials: R
authors.lastname: Di Niro
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.
authors.forename: O
authors.initials: O
authors.lastname: Snir
authors.affiliation: Departments of Internal Medicine and Gastroenterology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Kaukinen
authors.affiliation: Bioengineering Program, Faculty of Engineering, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Yaari
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.|Centre for Immune Regulation and Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
authors.forename: K E A
authors.initials: KE
authors.lastname: Lundin
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.
authors.forename: N T
authors.initials: NT
authors.lastname: Gupta
authors.affiliation: Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.|Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cols
authors.affiliation: Immunology Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cerutti
authors.affiliation: Tampere Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Mäki
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Shlomchik
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.
authors.forename: L M
authors.initials: LM
authors.lastname: Sollid
mesh_terms: D001323:Autoantibodies / Q000096:biosynthesis / Q000235:genetics*; D001706:Biopsy; D002446:Celiac Disease / Q000139:chemically induced / Q000178:diet therapy / Q000235:genetics / Q000276:immunology*; D002452:Cell Count; D055050:Diet, Gluten-Free; D004386:Duodenum / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D005983:Glutens / Q000009:adverse effects; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D061346:Laser Capture Microdissection; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017422:Sequence Analysis, DNA; D011503:Transglutaminases / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins