Investigators recently demonstrated that Peyer’s patch B cells can directly sample transglutaminase 2 from the gut lumen and may play a key role in driving autoantibody production in celiac disease, according to a study published in Gastroenterology.
Production of transglutaminase 2 (TG2) autoantibodies is a key characteristic of celiac disease. It is believed to result from TG2-specific B cells receiving help from gluten-specific CD4+ T cells in gut-associated lymphoid tissues (GALT). However, the location in the body where enzymatically active TG2 encounters gluten peptides is unknown.
To study celiac disease–relevant T-cell–B-cell interactions in GALT, M. Fleur du Pré, PhD, and co-authors developed a mouse model that expresses HLA-DQ2.5 to reproduce key features of celiac disease.
“Based on the observations that there are no signs of B-cell tolerance in transgenic mice expressing a celiac-patient derived anti-TG2 B-cell receptor, and that enterocytes contain abundant amounts of TG2 we proposed that pathogenic TG2-gluten enzyme-substrate complexes could be generated in the gut lumen and initiate an anti-TG2 antibody response in gut-associated lymphoid tissues (GALT),” wrote the investigators.
The mice received adoptive transfers of TG2-specific B cells and gluten-specific T cells and were orally immunized with an engineered antigen that combined B-cell and T-cell epitopes. To ensure effective delivery of gluten epitopes to TG2-specific B cells, the team used a “Troybody” strategy: an antibody targeting the TG2-specific B-cell receptor was modified to carry a deamidated gluten peptide recognized by T cells. This enabled the researchers to track immune activation and antibody production in response to TG2 and gluten.
Mice that received both TG2-specific B cells and gluten-specific T cells developed TG2-specific IgA in the gut and IgG in serum. TG2-specific B cells expanded in Peyer’s patches and mesenteric lymph nodes, which reflects human celiac disease patients, where TG2-specific plasma cells are abundant in small intestine mucosa.
“Having established a mouse model in which mice have anti-TG2 effector B cells in the gut and GALT, we next questioned whether TG2-specific B cells in the SED [subepithelial dome] area of PPs could take up TG2 antigen directly from the gut lumen,” wrote the investigators.
Using a ligated intestinal loop assay, the team introduced recombinant TG2 bound to a fluorescent inhibitor into the intestinal lumen of immunized mice. Microscopy showed that TG2-specific B cells in the SED of Peyer’s patches bound labeled TG2, whereas control reagents without a reactive group did not produce the same signal. The findings suggest that the TG2-specific B-cell receptor was required for antigen uptake.
“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 investigators wrote.
Limitations of the work acknowledged by the investigators include the fact that uptake of naturally occurring TG2–gluten complexes was not directly demonstrated, and the role of other antigen-presenting cells, such as dendritic cells, was not addressed. It is also uncertain whether TG2-specific B cells are positioned close to the gut lumen in human PPs. Additional studies are needed to confirm the relevance of the findings in patients.
Nevertheless, they still anticipate that the model could be beneficial for developing and testing new therapies for celiac disease. “B-cell-directed therapies have not yet been explored for the treatment of celiac disease, but they might well be pursued in the future given their success for the other autoimmune diseases. Another promising strategy to disrupt the crosstalk between TG2-specific B cells and gluten-specific T cells is inhibition of the TG2 enzyme,” concluded du Pré and colleagues.
The work was supported by the Research Council of Norway and the US National Institutes of Health. Ludvig M. Sollid disclosed consulting roles with Precigen Actobio, Sanofi, and Topas Therapeutics. Other authors reported no conflicts of interest.
Source: Gastroenterology
