Most evidence indicates that celiac disease requires the aberrant priming of IFN-γ-producing CD4 T cells by antigenic peptides present in α-gliadin, one of the major proteins in gluten. It is generally accepted that only a limited number of peptides can provoke an immune response leading to celiac disease. This is likely due to the unique structure of the peptide-binding groove of the HLA-DQ2 molecule. The key step in the immune recognition of α-gliadin is the deamidation of its peptides by the enzyme tissue transglutaminase (tTG), which converts selected glutamine residues to negatively charged glutamic acid. Only peptides containing negatively charged residues in certain positions bind strongly to HLA-DQ2, and thus the transamination reaction promotes the formation of peptide:HLA-DQ2 complexes, which can activate antigen-specific CD4 T cells (Fig. 14.25). Activated gliadin-specific CD4 T cells accumulate in the lamina propria, producing IFN-γ, a cytokine that when present in this location leads to intestinal inflammation.
Celiac disease is entirely dependent on the presence of the foreign antigen, gluten. It is not associated with a specific immune response against self antigens in the tissue—the intestinal epithelium—that is damaged during the immune response. Thus, celiac disease is not a classical autoimmune disease. But it does have some features of autoimmunity. Autoantibodies against tissue transglutaminase are found in all patients with celiac disease; indeed, the presence of serum IgA antibodies against this enzyme is used as a sensitive and specific test for the disease. Interestingly, no tTG-specific T cells have been found, and it has been proposed that gluten-reactive T cells provide help to B cells that are reactive to tissue transglutaminase. In support of this hypothesis, gluten can complex with the enzyme and therefore could be taken up and presented by tTG-reactive B cells (Fig. 14.26). There is no evidence, however, that these autoantibodies contribute directly to tissue damage.
Fig. 14.26 A hypothesis to explain antibody production against tissue transglutaminase (tTG) in the absence of T cells specific for tTG in celiac patients. tTG-reactive B cells endocytose gluten–tTG complexes and present gluten peptides to the gluten-specific T cells. The stimulated T cells can now provide help to these B cells, which produce autoantibodies against tTG.
Gluten peptides activate mucosal epithelial cells to express MIC molecules MIC IL1R IL1 NKG2D CD8 T cell (IEL) Intraepithelial lymphocytes (IELs) express NKG2D, which binds to MIC molecules and activates the IELs to kill the epithelial cell
Fig. 14.27 The activation of cytotoxic T cells by the innate immune system in celiac disease. Gluten peptides can induce the expression of the MHC class Ib molecules MIC-A and MIC-B on gut epithelial cells and the synthesis and release of IL-1 from these cells. Intraepithelial lymphocytes (IELs), many of which are CD8 cytotoxic T cells, recognize the MIC proteins via the receptor NKG2D, which, together with the co-stimulator IL-1, activates the IELs to kill the MIC-bearing cells, leading to destruction of the gut epithelium.