title: High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions.
abstract: Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to the exogenous antigen gluten in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo-isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Niro
authors.forename: Luka
authors.initials: L
authors.lastname: Mesin
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Zheng
authors.forename: Jorunn
authors.initials: J
authors.lastname: Stamnaes
authors.forename: Michael
authors.initials: M
authors.lastname: Morrissey
authors.forename: Jane-Hwei
authors.initials: JH
authors.lastname: Lee
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Rasmus
authors.initials: R
authors.lastname: Iversen
authors.forename: M Fleur
authors.initials: MF
authors.lastname: du Pré
authors.forename: Shuo-Wang
authors.initials: SW
authors.lastname: Qiao
authors.forename: Knut E A
authors.initials: KE
authors.lastname: Lundin
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
mesh_terms: D000921:Antibody-Producing Cells / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002446:Celiac Disease / Q000097:blood / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000097:blood / Q000276:immunology* / Q000378:metabolism*; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology*; D007072:Immunoglobulin D / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology; D009154:Mutation; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D059010:Single-Cell Analysis; D027041:Somatic Hypermutation, Immunoglobulin; D011503:Transglutaminases / Q000097:blood / Q000276:immunology* / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D007070:Immunoglobulin A; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins