Peyer's patch B cells sample transglutaminase-gluten complexes and drive celiac disease autoimmunity

M Fleur du Pré; Liv Kleppa; Alisa E Dewan; Maureen T Meling; Lene S Høydahl; Harrison A Besser; Chaitan Khosla; Ludvig M Sollid

doi:10.1053/j.gastro.2025.06.021

Peyer's patch B cells sample transglutaminase-gluten complexes and drive celiac disease autoimmunity

Gastroenterology. 2025 Jun 30:S0016-5085(25)00960-6. doi: 10.1053/j.gastro.2025.06.021. Online ahead of print.

Authors

M Fleur du Pré¹, Liv Kleppa², Alisa E Dewan², Maureen T Meling², Lene S Høydahl³, Harrison A Besser⁴, Chaitan Khosla⁵, Ludvig M Sollid⁶

Affiliations

¹ Norwegian Coeliac Disease Research Center, Institute of Clinical Medicine, University of Oslo; Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway. Electronic address: m.f.d.pre@medisin.uio.no.
² Norwegian Coeliac Disease Research Center, Institute of Clinical Medicine, University of Oslo; Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
³ Norwegian Coeliac Disease Research Center, Institute of Clinical Medicine, University of Oslo; Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway; Nextera AS, Oslo, Norway.
⁴ Department of Chemistry, Stanford University, Stanford, California, United States; Stanford Medical Scientist Training Program, Stanford University School of Medicine, Stanford, California, United States.
⁵ Department of Chemistry, Stanford University, Stanford, California, United States; Department of Chemical Engineering and Sarafan ChEM-H, Stanford University, Stanford, California, United States.
⁶ Norwegian Coeliac Disease Research Center, Institute of Clinical Medicine, University of Oslo; Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway. Electronic address: l.m.sollid@medisin.uio.no.

PMID: 40602545
DOI: 10.1053/j.gastro.2025.06.021

Abstract

Background and aims: The production of autoantibodies against the enzyme transglutaminase 2 (TG2) in celiac disease likely results from TG2-specific B cells receiving help from gluten-specific CD4⁺ T cells in gut-associated lymphoid tissues (GALT) via the formation of transient enzyme-substrate complexes formed between TG2 and gluten. Where in the body enzymatically active TG2 encounters gluten peptides remains unknown.

Methods: A model to study the celiac disease-relevant T cell-B cell interactions in GALT has been developed. Mice expressing HLA-DQ2.5 received TG2-specific B cells and gluten-specific T cells by adoptive transfer and were subsequently orally immunized with a model antigen containing the the B-cell and T-cell epitopes.

Results: Orally immunized HLA-DQ2.5 knock-in mice developed TG2-specific gut IgA and serum IgG responses. Activated TG2-specific B cells were present in Peyer's patches and in gut-draining mesenteric lymph nodes, resembling what is seen in human celiac disease. We demonstrate that TG2-specific B cells in Peyer's patches sample TG2 when the protein is perfused into the gut lumen.

Conclusion: The model supports a mechanism where TG2-gluten complexes formed in the gut lumen are taken up by TG2-specific B cells in GALT. We propose that this pathway plays an important role in driving the anti-TG2 IgA autoantibody response in celiac disease patients. The model provides a platform to explore novel approaches for celiac disease therapies.

Keywords: B cells; Peyer’s patch; celiac disease; mouse model; transglutaminase 2.