Role of gut epithelial-cell derived transglutaminase 2 in the formation of celiac disease autoantibodies
Loberg, R. I.; Abdi-Dezfuli, H. A.; Kleppa, L.; Dewan, A. E.; Meling, M. T.; Sollid, L. M.; du Pre, M. F.
Show abstract
Formation of autoantibodies to transglutaminase 2 (TG2) in celiac disease likely involves TG2-gluten complexes that allow gluten-specific CD4+ T cells to provide help to TG2-specific B cells. To investigate whether TG2 derived from intestinal epithelial cells (IECs) contributes to this process, we generated mice with inducible IEC-specific expression of TG2 fused to a deamidated gluten peptide (DGP) containing a T-cell epitope. Upon induction, the TG2-DGP fusion protein was expressed in IECs and released into the intestinal lumen. In HLA-DQ2.5 transgenic mice with activated gluten-specific CD4+ T cells and naive TG2-specific B cells, expression of TG2-DGP was immunogenic and drove the production of intestinal and systemic anti-TG2 autoantibodies. TG2-specific B cells predominantly expanded in Peyers patches, suggesting that their priming and subsequent differentiation into lamina propria TG2-specific IgA+ plasma cells occurs in gut-associated lymphoid tissues. The findings demonstrate immunogenicity of IEC-derived TG2-DGP fusion antigen supporting the notion of a pathogenic role for luminal TG2 in driving anti-TG2 autoimmunity in celiac disease.
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