Background
Autoantibodies against the enzyme transglutaminase 2 (TG2) are a hallmark of celiac disease and are tightly linked to gluten exposure in individuals that carry the disease-associated HLA allotypes HLA-DQ2.5, HLA-DQ2.2, or HLA-DQ8. The requirement for both gluten and these HLA risk alleles strongly suggests that gluten-specific T cells are involved in driving TG2 autoantibody production. However, it is not clear where in the gut enzymatically active TG2 first encounters gluten and initiates this autoimmune response.
Hypothesis
We hypothesized that pathogenic TG2 in celiac disease is released from intestinal epithelial cells (IECs) that are shed into the gut lumen. In this model, TG2 would bind gluten in the lumen, forming TG2-gluten enzyme-substrate complexes that are then taken up into gut-associated lymphoid tissue, where the autoimmune response is initiated.
Methods
To test this model in vivo, we generated mice with inducible expression of TG2 fused to a deamidated gluten peptide (DGP) specifically in IECs. We studied these mice on an HLA-DQ2.5-transgenic background with gluten-reactive T cells and TG2-specific B cells and examined localization of the fusion protein and the resulting antibody responses.
Results
Following induction, the TG2-DGP fusion protein was expressed in IECs and detected in small-intestinal lavage fluids, consistent with release into the gut lumen. In HLA-DQ2.5 transgenic mice, expression of this IEC-derived TG2-DGP triggered both intestinal and systemic anti-TG2 autoantibodies when gluten-specific T cells were activated. TG2-specific B cells expanded mainly in Peyer’s patches and differentiated into TG2-specific IgA-producing plasma cells in the lamina propria of the small intestine, indicating that gut-associated lymphoid tissues are a key site for priming this autoimmune response.
Conclusion
The results support a role for IEC-derived TG2 in driving anti-TG2 autoimmunity in celiac disease.