Matrix expansion and syncytial aggregation of syndecan-1+ cells underpin villous atrophy in coeliac disease

Article English OPEN
Salvestrini, C ; Lucas, M ; Lionetti, Paolo ; Torrente, F ; James, S ; Phillips, Ad ; Murch, Sh (2014)
  • Publisher: Public Library of Science
  • Journal: PLoS ONE, volume 9, issue 9 (eissn: 1932-6203)
  • Related identifiers: pmc: PMC4157760, doi: 10.1371/journal.pone.0106005
  • Subject: Cellular Types | Research Article | Biology and Life Sciences | Hypersensitivity | Gastroenterology and Hepatology | Immune Cells | Animal Cells | Enteropathies | RC | coeliac disease | Cell Biology | Immunopathology | Autoimmunity | Clinical Immunology | Biochemistry | Celiac Disease | Medicine and Health Sciences | Immunology | Glycobiology | Immunochemistry | Pediatric Gastroenterology
    mesheuropmc: carbohydrates (lipids)

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.\ud \ud 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.\ud \ud 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.\ud \ud 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.
  • References (57)
    57 references, page 1 of 6

    1. Abadie V, Sollid LM, Barreiro LB, Jabri B (2011) Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol 29: 493-525.

    2. Dhesi I, Marsh MN, Kelly C, Crowe P (1984) Morphometric analysis of small intestinal mucosa II. Determination of lamina propria volumes, plasma cell and neutrophil populations within control and coeliac disease mucosa. Virchow's Arch 403: 173-80.

    3. Loehry CA, Creamer B (1969) Three-dimensional structure of the human small intestinal mucosa in health and disease. Gut 10: 6-12.

    4. Shiner M (1973) Ultrastructural changes suggestive of immune reactions in the jejunal mucosa of coeliac children following gluten challenge. Gut 14: 1-12.

    5. Comper WD, Laurent TC (1978) Physiological function of connective tissue polysaccharides. Physiol Rev 58: 255-315.

    6. Bishop JR, Schuksz M, Esko JD (2007) Heparan sulfate proteoglycans fine-tune mammalian physiology. Nature 446: 1030-1037.

    7. Bode L, Murch S, Freeze HH (2006) Heparan sulfate plays a central role in a dynamic in vitro model of protein-losing enteropathy. J Biol Chem 281: 7809- 7815.

    8. Bode L, Salvestrini C, Park PW, Li JP, Esko JD, et al (2008) Heparan sulfate and syndecan-1 are essential in maintaining intestinal epithelial barrier function. J Clin Invest 118: 229-238.

    9. Bahn RS, Heufelder AE (1993) Pathogenesis of Graves' ophthalmopathy. N Engl J Med 329: 1468-1475.

    10. Antunes SL, Gallo ME, de Almeida SM, Mota EE, Pelajo M, et al (1999) Dermal extracellular matrix in cutaneous leprosy lesions. Int J Lepr Other Mycobact Dis 67: 24-35.

  • Related Research Results (2)
  • Metrics
    No metrics available
Share - Bookmark