Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity
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 c...
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| Format: | Article |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57564-5 |
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| author | Rasmus Iversen Julie Elisabeth Heggelund Saykat Das Lene S. Høydahl Ludvig M. Sollid |
| author_facet | Rasmus Iversen Julie Elisabeth Heggelund Saykat Das Lene S. Høydahl Ludvig M. Sollid |
| author_sort | Rasmus Iversen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dc723d01ff4c4ac380070ac8563b93b2 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dc723d01ff4c4ac380070ac8563b93b22025-08-20T02:56:12ZengNature PortfolioNature Communications2041-17232025-03-0116111110.1038/s41467-025-57564-5Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunityRasmus Iversen0Julie Elisabeth Heggelund1Saykat Das2Lene S. Høydahl3Ludvig M. Sollid4Norwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of OsloNorwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of OsloNorwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of OsloNorwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of OsloNorwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of OsloAbstract 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.https://doi.org/10.1038/s41467-025-57564-5 |
| spellingShingle | Rasmus Iversen Julie Elisabeth Heggelund Saykat Das Lene S. Høydahl Ludvig M. Sollid Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity Nature Communications |
| title | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity |
| title_full | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity |
| title_fullStr | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity |
| title_full_unstemmed | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity |
| title_short | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity |
| title_sort | enzyme activating b cell receptors boost antigen presentation to pathogenic t cells in gluten sensitive autoimmunity |
| url | https://doi.org/10.1038/s41467-025-57564-5 |
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