Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease

Na Tian, Daniel A. Leffler, Ciaran P. Kelly, Joshua Hansen, Eric V. Marietta, Joseph A Murray, Detlef Schuppan, Eva J. Helmerhorst

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Celiac disease (CD) is an inflammatory disorder triggered by ingested gluten, causing immunemediated damage to the small-intestinal mucosa. Gluten proteins are strikingly similar in amino acid composition and sequence to prolinerich 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 HLADQ2/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.

Original languageEnglish (US)
Pages (from-to)G910-G917
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number11
DOIs
StatePublished - 2015

Fingerprint

Salivary Proline-Rich Proteins
Glutens
Celiac Disease
Sequence Homology
Salivary Proteins and Peptides
Gliadin
Proteins
Anti-Idiotypic Antibodies
Blood Cells
Intestinal Mucosa
Amylases
Saliva
Gastrointestinal Tract
Epitopes
Amino Acid Sequence

Keywords

  • Celiac disease
  • Gluten
  • Immune response
  • Mouse model
  • Salivary protein

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease. / Tian, Na; Leffler, Daniel A.; Kelly, Ciaran P.; Hansen, Joshua; Marietta, Eric V.; Murray, Joseph A; Schuppan, Detlef; Helmerhorst, Eva J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 309, No. 11, 2015, p. G910-G917.

Research output: Contribution to journalArticle

Tian, Na ; Leffler, Daniel A. ; Kelly, Ciaran P. ; Hansen, Joshua ; Marietta, Eric V. ; Murray, Joseph A ; Schuppan, Detlef ; Helmerhorst, Eva J. / Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2015 ; Vol. 309, No. 11. pp. G910-G917.
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T1 - Despite sequence homologies to gluten, salivary proline-rich proteins do not elicit immune responses central to the pathogenesis of celiac disease

AU - Tian, Na

AU - Leffler, Daniel A.

AU - Kelly, Ciaran P.

AU - Hansen, Joshua

AU - Marietta, Eric V.

AU - Murray, Joseph A

AU - Schuppan, Detlef

AU - Helmerhorst, Eva J.

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N2 - Celiac disease (CD) is an inflammatory disorder triggered by ingested gluten, causing immunemediated damage to the small-intestinal mucosa. Gluten proteins are strikingly similar in amino acid composition and sequence to prolinerich 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 HLADQ2/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.

AB - Celiac disease (CD) is an inflammatory disorder triggered by ingested gluten, causing immunemediated damage to the small-intestinal mucosa. Gluten proteins are strikingly similar in amino acid composition and sequence to prolinerich 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 HLADQ2/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.

KW - Celiac disease

KW - Gluten

KW - Immune response

KW - Mouse model

KW - Salivary protein

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