Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease.
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.
Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts;
Na
N
Tian
Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;
Daniel A
DA
Leffler
Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;
Ciaran P
CP
Kelly
Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts;
Joshua
J
Hansen
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
Eric V
EV
Marietta
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
Joseph A
JA
Murray
Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Institute of Translational Immunology and Research Center for Immunotherapy (FZI), University Medical Center, Mainz, Germany.
Detlef
D
Schuppan
Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts; helmer@bu.edu.
Eva J
EJ
Helmerhorst
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000097:blood; D000918:Antibody Specificity; D016022:Case-Control Studies; D002446:Celiac Disease / Q000097:blood / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes; D005260:Female; D005903:Gliadin / Q000737:chemistry / Q000276:immunology; D005983:Glutens / Q000737:chemistry / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D010306:Parotid Gland / Q000276:immunology / Q000378:metabolism; D055273:Salivary Proline-Rich Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D017385:Sequence Homology; D055815:Young Adult
D000906:Antibodies; D016207:Cytokines; D000939:Epitopes; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D055273:Salivary Proline-Rich Proteins; D005983:Glutens; D005903:Gliadin
celiac disease; gluten; immune response; mouse model; salivary protein