title: In celiac disease, a subset of autoantibodies against transglutaminase binds toll-like receptor 4 and induces activation of monocytes.
abstract: BACKGROUND
  Celiac disease is a small intestine inflammatory disorder with multiple organ involvement, sustained by an inappropriate immune response to dietary gluten. Anti-transglutaminase antibodies are a typical serological marker in patients with active disease, and may disappear during a gluten-free diet treatment. Involvement of infectious agents and innate immunity has been suggested but never proven. Molecular mimicry is one of the mechanisms that links infection and autoimmunity.
  
  
  RESULTS
  In our attempt to clarify the pathogenesis of celiac disease, we screened a random peptide library with pooled sera of patients affected by active disease after a pre-screening with the sera of the same patients on a gluten-free diet. We identified a peptide recognized by serum immunoglobulins of patients with active disease, but not by those of patients on a gluten-free diet. This peptide shares homology with the rotavirus major neutralizing protein VP-7 and with the self-antigens tissue transglutaminase, human heat shock protein 60, desmoglein 1, and Toll-like receptor 4. We show that antibodies against the peptide affinity-purified from the sera of patients with active disease recognize the viral product and self-antigens in ELISA and Western blot. These antibodies were able to induce increased epithelial cell permeability evaluated by transepithelial flux of [(3)H] mannitol in the T84 human intestinal epithelial cell line. Finally, the purified antibodies induced monocyte activation upon binding Toll-like receptor 4, evaluated both by surface expression of activation markers and by production of pro-inflammatory cytokines.
  
  
  CONCLUSIONS
  Our findings show that in active celiac disease, a subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of the disease, through a mechanism of molecular mimicry. Moreover, such antibodies recognize self-antigens and are functionally active, able to increase intestinal permeability and induce monocyte activation. We therefore provide evidence for the involvement of innate immunity in the pathogenesis of celiac disease through a previously unknown mechanism of engagement of Toll-like receptor 4.
authors.affiliation: Section of Immunology, Department of Pathology, University of Verona, Verona, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zanoni
authors.forename: Riccardo
authors.initials: R
authors.lastname: Navone
authors.forename: Claudio
authors.initials: C
authors.lastname: Lunardi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tridente
authors.forename: Caterina
authors.initials: C
authors.lastname: Bason
authors.forename: Simona
authors.initials: S
authors.lastname: Sivori
authors.forename: Ruggero
authors.initials: R
authors.lastname: Beri
authors.forename: Marzia
authors.initials: M
authors.lastname: Dolcino
authors.forename: Enrico
authors.initials: E
authors.lastname: Valletta
authors.forename: Roberto
authors.initials: R
authors.lastname: Corrocher
authors.forename: Antonio
authors.initials: A
authors.lastname: Puccetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000956:Antigens, Viral / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology*; D002446:Celiac Disease / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000276:immunology; D018834:Chaperonin 60 / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D051183:Desmoglein 1 / Q000276:immunology; D005260:Female; D015200:Fluoroimmunoassay / Q000379:methods; D019204:GTP-Binding Proteins; D005983:Glutens / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D008297:Male; D018716:Molecular Mimicry; D009000:Monocytes / Q000276:immunology*; D019151:Peptide Library; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012401:Rotavirus / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D011503:Transglutaminases / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D001323:Autoantibodies; D036022:Capsid Proteins; D018834:Chaperonin 60; C495297:DSG1 protein, human; D051183:Desmoglein 1; D019151:Peptide Library; D051197:Toll-Like Receptor 4; C050779:VP7 protein, Rotavirus; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins