Peyer's Patch B Cells Sample Transglutaminase-Gluten Complexes and Drive Celiac Disease Autoimmunity.

Abstract

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. 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. Orally immunized HLA-DQ2.5 knockin mice developed TG2-specific gut immunoglobulin (Ig)A 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. The model supports a mechanism in which 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 patients with celiac disease. The model provides a platform to explore novel approaches for celiac disease therapies.