High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions

Nat Med. 2012 Feb 26;18(3):441-5. doi: 10.1038/nm.2656.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody-Producing Cells / immunology*
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • B-Lymphocytes / immunology
  • Celiac Disease / blood
  • Celiac Disease / immunology*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • GTP-Binding Proteins / blood
  • GTP-Binding Proteins / immunology*
  • GTP-Binding Proteins / metabolism*
  • Glutens / immunology
  • HLA-DQ Antigens / immunology
  • Humans
  • Immunoglobulin A / blood
  • Immunoglobulin A / immunology*
  • Immunoglobulin D / blood
  • Immunoglobulin D / immunology
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Immunoglobulin M / blood
  • Immunoglobulin M / immunology
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / immunology
  • Mutation
  • Plasma Cells / immunology
  • Plasma Cells / metabolism
  • Single-Cell Analysis
  • Somatic Hypermutation, Immunoglobulin
  • Transglutaminases / blood
  • Transglutaminases / immunology*
  • Transglutaminases / metabolism*

Substances

  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Immunoglobulin A
  • Immunoglobulin D
  • Immunoglobulin G
  • Immunoglobulin M
  • Glutens
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins