Celiac disease (CD) is an inflammatory disorder triggered by ingested
gluten, causing immune-mediated damage to the small-intestinal mucosa.
Gluten proteins are strikingly similar in
amino acid composition and sequence to
proline-rich
proteins (PRPs) in human saliva. On the basis of this feature and their shared destination in the gastrointestinal tract, we hypothesized that salivary PRPs may modulate
gluten-mediated immune responses in CD. Parotid salivary secretions were collected from CD patients, refractory CD patients, non-CD patients with functional gastrointestinal complaints, and healthy controls. Structural similarities of PRPs with
gluten were probed with anti-
gliadin antibodies. Immune responses to PRPs were investigated toward CD patient-derived peripheral blood mononuclear cells and in a humanized transgenic HLA-DQ2/DQ8 mouse model for CD. Anti-
gliadin antibodies weakly cross-reacted with the abundant salivary
amylase but not with PRPs. Likewise, the R5 antibody, recognizing potential antigenic
gluten epitopes, showed negligible reactivity to
salivary proteins from all groups. Inflammatory responses in peripheral blood mononuclear cells were provoked by
gliadins whereas responses to PRPs were similar to control levels, and PRPs did not compete with
gliadins in immune stimulation. In vivo, PRP
peptides were well tolerated and nonimmunogenic in the transgenic HLA-DQ2/DQ8 mouse model. Collectively, although structurally similar to dietary
gluten, salivary PRPs were nonimmunogenic in CD patients and in a transgenic HLA-DQ2/DQ8 mouse model for CD. It is possible that salivary PRPs play a role in tolerance induction to
gluten early in life. Deciphering the structural basis for the lack of immunogenicity of salivary PRPs may further our understanding of the toxicity of
gluten.