title: Matrix expansion and syncytial aggregation of syndecan-1+ cells underpin villous atrophy in coeliac disease.
abstract: BACKGROUND
  We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy.
  
  
  METHODS
  We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls.
  
  
  RESULTS
  In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1(+) plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6(+) mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19.
  
  
  CONCLUSIONS
  Matrix expansion, through syndecan-1(+) cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1(+) cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders, IL-6 is upregulated and represents a logical target for immunotherapy in patients with coeliac disease refractory to gluten-free diet.
authors.affiliation: Department of Paediatric Gastroenterology, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Camilla
authors.initials: C
authors.lastname: Salvestrini
authors.affiliation: Centre for Paediatric Gastroenterology, University College London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Lucas
authors.affiliation: Department of Paediatrics, University of Florence, Meyer Hospital, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lionetti
authors.affiliation: Department of Paediatric Gastroenterology, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Franco
authors.initials: F
authors.lastname: Torrente
authors.affiliation: Department of Pathology, University Hospital Coventry & Warwickshire, Coventry, United Kingdom.
authors.forename: Sean
authors.initials: S
authors.lastname: James
authors.affiliation: Centre for Paediatric Gastroenterology, University College London, United Kingdom.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Phillips
authors.affiliation: Division of Metabolic and Vascular Health, Warwick Medical School, Coventry, United Kingdom.
authors.forename: Simon H
authors.initials: SH
authors.lastname: Murch
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001706:Biopsy; D002446:Celiac Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005109:Extracellular Matrix / Q000378:metabolism*; D015726:Giant Cells / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D053668:Syndecan-1 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D006025:Glycosaminoglycans; D015850:Interleukin-6; D053668:Syndecan-1