Efficient T cell-B cell collaboration guides autoantibody epitope bias and onset of celiac disease

Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15134-15139. doi: 10.1073/pnas.1901561116. Epub 2019 Jul 8.

Abstract

B cells play important roles in autoimmune diseases through autoantibody production, cytokine secretion, or antigen presentation to T cells. In most cases, the contribution of B cells as antigen-presenting cells is not well understood. We have studied the autoantibody response against the enzyme transglutaminase 2 (TG2) in celiac disease patients by generating recombinant antibodies from single gut plasma cells reactive with discrete antigen domains and by undertaking proteomic analysis of anti-TG2 serum antibodies. The majority of the cells recognized epitopes in the N-terminal domain of TG2. Antibodies recognizing C-terminal epitopes interfered with TG2 cross-linking activity, and B cells specific for C-terminal epitopes were inefficient at taking up TG2-gluten complexes for presentation to gluten-specific T cells. The bias toward N-terminal epitopes hence reflects efficient T-B collaboration. Production of antibodies against N-terminal epitopes coincided with clinical onset of disease, suggesting that TG2-reactive B cells with certain epitope specificities could be the main antigen-presenting cells for pathogenic, gluten-specific T cells. The link between B cell epitopes, antigen presentation, and disease onset provides insight into the pathogenic mechanisms of a T cell-mediated autoimmune condition.

Keywords: B cells; antigen presentation; autoantibodies; celiac disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / pathology
  • Autoantibodies / biosynthesis
  • Autoantibodies / genetics
  • Autoantigens / genetics
  • Autoantigens / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Celiac Disease / genetics
  • Celiac Disease / immunology*
  • Celiac Disease / pathology
  • Duodenum / immunology
  • Duodenum / pathology
  • Epitopes, B-Lymphocyte / chemistry
  • Epitopes, B-Lymphocyte / genetics
  • Epitopes, B-Lymphocyte / immunology*
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / immunology*
  • Glutens / chemistry
  • Glutens / immunology
  • Humans
  • Immune Sera / chemistry
  • Immunoglobulin Light Chains / biosynthesis
  • Immunoglobulin Light Chains / genetics
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Transglutaminases / chemistry
  • Transglutaminases / genetics
  • Transglutaminases / immunology*

Substances

  • Autoantibodies
  • Autoantigens
  • Epitopes, B-Lymphocyte
  • Immune Sera
  • Immunoglobulin Light Chains
  • Glutens
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins