(05-07-15) Matrix Expansion and Syncytial Aggregation of Syndecan-1+ Cells Underpin Villous Atrophy in Coeliac Disease

Camilla Salvestrini,1 Mark Lucas,2 Paolo Lionetti,3 Franco Torrente,1 Sean James,4 Alan D. Phillips,2 and Simon H. Murch5,*
Markus M. Heimesaat, Editor
1Department of Paediatric Gastroenterology, Addenbrooke's Hospital, Cambridge, United Kingdom
2Centre for Paediatric Gastroenterology, University College London, United Kingdom
3Department of Paediatrics, University of Florence, Meyer Hospital, Florence, Italy
4Department of Pathology, University Hospital Coventry & Warwickshire, Coventry, United Kingdom
5Division of Metabolic and Vascular Health, Warwick Medical School, Coventry, United Kingdom
Charité, Campus Benjamin Franklin, Germany
* E-mail: [email protected]
Competing Interests: The authors declare that they have no relevant competing interests. SM is chair of the Coeliac Disease Working Group of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition and is a member of the NICE Coeliac Disease Guideline Development Group.
Conceived and designed the experiments: CS ML FT ADP SHM. Performed the experiments: CS ML PL FT SJ ADP SHM. Analyzed the data: CS ML FT ADP SHM. Contributed reagents/materials/analysis tools: ML PL SJ ADP. Contributed to the writing of the manuscript: CS SHM.
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Received 2014 May 13; Accepted 2014 Jul 25.
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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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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.


SOURCE:
PLoS One. 2014; 9(9): e106005.
Published online 2014 Sep 8. doi:  10.1371/journal.pone.0106005
PMCID: PMC4157760

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