B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2

J Exp Med. 2020 Feb 3;217(2):e20190860. doi: 10.1084/jem.20190860.

Abstract

Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient-derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2-/- mice. Autoreactive B cells in Tgm2+/+ mice were indistinguishable from their naive counterparts in Tgm2-/- mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten-TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation / genetics*
  • Autoantibodies / immunology*
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Autoimmunity
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • Celiac Disease / immunology*
  • Celiac Disease / pathology
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / immunology*
  • Gene Knock-In Techniques
  • Glutens / immunology
  • HEK293 Cells
  • Humans
  • Immune Tolerance / genetics*
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, B-Cell / immunology
  • Transglutaminases / genetics
  • Transglutaminases / immunology*

Substances

  • Autoantibodies
  • Autoantigens
  • Receptors, Antigen, B-Cell
  • Glutens
  • transglutaminase 2
  • Transglutaminases
  • GTP-Binding Proteins