IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57564-5.html
   My bibliography  Save this article

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

Author

Listed:
  • Rasmus Iversen

    (University of Oslo
    Oslo University Hospital - Rikshospitalet)

  • Julie Elisabeth Heggelund

    (University of Oslo
    Oslo University Hospital - Rikshospitalet)

  • Saykat Das

    (University of Oslo
    Oslo University Hospital - Rikshospitalet)

  • Lene S. Høydahl

    (University of Oslo
    Oslo University Hospital - Rikshospitalet
    Nextera AS)

  • Ludvig M. Sollid

    (University of Oslo
    Oslo University Hospital - Rikshospitalet)

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.

Suggested Citation

  • Rasmus Iversen & Julie Elisabeth Heggelund & Saykat Das & Lene S. Høydahl & Ludvig M. Sollid, 2025. "Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57564-5
    DOI: 10.1038/s41467-025-57564-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57564-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57564-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Julie Elisabeth Heggelund & Saykat Das & Jorunn Stamnaes & Rasmus Iversen & Ludvig M. Sollid, 2023. "Autoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.

      More about this item

      Statistics

      Access and download statistics

      Corrections

      All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57564-5. See general information about how to correct material in RePEc.

      If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

      If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

      If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

      For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

      Please note that corrections may take a couple of weeks to filter through the various RePEc services.

      IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.