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<p>Autoantibodies against the enzyme transglutaminase 3 (TG3) are characteristic to the gluten-sensitive skin disorder dermatitis herpetiformis (DH), which is an extraintestinal manifestation of celiac disease. We here demonstrate that TG3-specific B cells can activate gluten-specific CD4<sup>+</sup> T cells through B-cell receptor (BCR)-mediated internalization of TG3-gluten enzyme-substrate complexes. Stereotypic anti-TG3 antibodies using <i>IGHV2-5/IGKV4-1</i> gene segments enhance the catalytic activity of TG3, and this effect translates into increased gluten presentation to T cells when such antibodies are expressed as BCRs. The crystal structure of TG3 bound to an <i>IGHV2-5/IGKV4-1</i> Fab shows that antibody binding to a β-sheet in the catalytic core domain causes the enzyme to adopt the active conformation. This mechanism explains the production of stereotypic anti-TG3 autoantibodies in DH and highlights a role for TG3-specific B cells as antigen-presenting cells for gluten-specific T cells. Similar boosting effects of autoreactive BCRs could be relevant for other autoimmune diseases, including rheumatoid arthritis.</p>

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Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月10日

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  • Rasmus Iversen,
  • Julie Elisabeth Heggelund,
  • Saykat Das,
  • Lene S. Høydahl,
  • Ludvig M. Sollid

摘要

Autoantibodies against the enzyme transglutaminase 3 (TG3) are characteristic to the gluten-sensitive skin disorder dermatitis herpetiformis (DH), which is an extraintestinal manifestation of celiac disease. We here demonstrate that TG3-specific B cells can activate gluten-specific CD4+ T cells through B-cell receptor (BCR)-mediated internalization of TG3-gluten enzyme-substrate complexes. Stereotypic anti-TG3 antibodies using IGHV2-5/IGKV4-1 gene segments enhance the catalytic activity of TG3, and this effect translates into increased gluten presentation to T cells when such antibodies are expressed as BCRs. The crystal structure of TG3 bound to an IGHV2-5/IGKV4-1 Fab shows that antibody binding to a β-sheet in the catalytic core domain causes the enzyme to adopt the active conformation. This mechanism explains the production of stereotypic anti-TG3 autoantibodies in DH and highlights a role for TG3-specific B cells as antigen-presenting cells for gluten-specific T cells. Similar boosting effects of autoreactive BCRs could be relevant for other autoimmune diseases, including rheumatoid arthritis.