Abstract
A hallmark of celiac disease is the gluten-dependent production of antibodies specific for deamidated gluten peptides (DGP) and the enzyme transglutaminase 2 (TG2). Both types of antibodies are believed to result from B cells receiving help from gluten-specific CD4+ T cells and differentiating into antibody-producing plasma cells. We have here studied the collaboration between DGP- and TG2-specific B cells with gluten-specific CD4+ T cells using transgenic mice expressing celiac patient-derived T-cell and B-cell receptors, as well as between B-cell transfectants and patient-derived gluten-specific T-cell clones. We show that multivalent TG2-gluten complexes are efficient antigens for both TG2-specific and DGP-specific B cells and allow both types of B cells to receive help from gluten-specific T cells of many different specificities.
Highlights
Celiac disease is an autoimmune enteropathy driven by exposure to dietary wheat gluten proteins and related proteins of barley and rye [1]
transglutaminase 2 (TG2)-specific B cells were cultured with gluten-specific CD4+ T cells recognizing the DQ2.5-glia-α2 epitope isolated from HLA-DQ2.5-positive gluten-specific T-cell receptor transgenic mice [12]
We have previously shown that transduced lymphoma B cells expressing a B-cell receptor recognizing deamidated gluten peptides (DGP) efficiently bind a 34mer ω-gliadin peptide, containing three copies of the B-cell core epitope, and stimulated T cells more efficiently than B cells transduced with an irrelevant BCR [21]
Summary
Celiac disease is an autoimmune enteropathy driven by exposure to dietary wheat gluten (gliadin/glutenin) proteins and related proteins of barley and rye [1]. Patients have a CD4+ T-cell response towards post-translationally modified (deamidated) gluten peptides that selectively bind to the disease-predisposing HLA molecules HLA-DQ2.5, HLA-DQ8 or HLA-DQ2.2 [2] Both deamidated gluten peptides (DGP) and the self-protein transglutaminase 2 (TG2) become the targets of the B-cell response in celiac disease. Rather a role as the antigen receptor of B cells is more likely [4] In this setting, efficient collaboration between B cells and T cells is essential, and B cells will be the major antigen-presenting cell type driving the inflammatory T-cell response in celiac disease [5]. In accordance with this notion it was found that anti-DGP antibodies recognize epitopes that often overlap with or are in close proximity to known gluten T-cell epitopes
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