A Mouse Model for Generation of Gut Lamina Propria Plasma Cells Specific for a Deamidated Gluten Peptide

Celiac disease is an autoimmune enteropathy caused by aberrant immune responses to dietary gluten peptides. Plasma cells (PCs) reactive with deamidated gluten peptides (DGP) or transglutaminase 2 are abundant in celiac disease gut lesions, yet their role in disease pathogenesis remains unclear. Here, we present a mouse model that allows for exploring the role of DGP-specific IgA PCs. This model employs a novel immunoglobulin knock-in (Ig KI) mouse expressing a celiac-patient-derived anti-DGP B-cell receptor (BCR) that recognizes an immunodominant DGP epitope. In these mice, ∼80% of splenic B cells express the transgenic BCR. In co-culture experiments with transgenic DGP-specific B cells and transgenic gluten-specific CD4⁺ T cells, stimulation with DGP led to T-cell and B-cell proliferation. Mice carrying the celiac disease-associated human leukocyte antigen (HLA) allotype HLA-DQ2.5 developed DGP-specific small intestinal IgA PCs upon adoptive transfer of HLA-DQ2.5-expressing DGP-specific B cells and oral immunizations with DGP and cholera toxin (CT). However, covalent conjugation of DGP to CT was required for effective anti-DGP gut immunity. This novel mouse model provides an important tool for studying the role of PCs beyond antibody production in celiac disease.