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

Rasmus Iversen (), Julie Elisabeth Heggelund, Saykat Das, Lene S. Høydahl and Ludvig M. Sollid ()
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Rasmus Iversen: University of Oslo
Julie Elisabeth Heggelund: University of Oslo
Saykat Das: University of Oslo
Lene S. Høydahl: University of Oslo
Ludvig M. Sollid: University of Oslo

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57564-5

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