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Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II
  1. Frederike Schmitz1,
  2. Jennifer M L Tjon1,
  3. Yuching Lai2,3,
  4. Allan Thompson1,
  5. Yvonne Kooy-Winkelaar1,
  6. Richard J L F Lemmers2,
  7. Hein W Verspaget4,
  8. M Luisa Mearin5,
  9. Frank J Staal1,
  10. Marco W Schreurs6,
  11. Tom Cupedo7,
  12. Anton W Langerak6,
  13. Chris J Mulder8,
  14. Jeroen van Bergen1,
  15. Frits Koning1
  1. 1Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Leiden Genome Technology Center, Leiden, The Netherlands
  4. 4Department of Gastroenterology and Hepatology, University Medical Center, Leiden, The Netherlands
  5. 5Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands
  7. 7Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
  8. 8Department of Gastroenterology, VU Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Dr Frits Koning, Department of Immunohematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; f.koning{at}


Objective Refractory coeliac disease type II (RCDII) is a severe complication of coeliac disease (CD) characterised by aberrant intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3CD7+icCD3+ phenotype. In approximately 40% of patients with RCDII these lymphocytes develop into an invasive lymphoma. In the current study we aimed to identify the physiological counterpart of these cells.

Design RCDII cell lines were compared with T-cell receptor positive (TCR+) IEL (T-IEL) lines by microarray analysis, real-time quantitative PCR and flow cytometry. This information was used to identify cells with an RCDII-associated phenotype in duodenal biopsies from non-refractory individuals by multicolour flow cytometry.

Results RCDII lines were transcriptionally distinct from T-IEL lines and expressed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3CD7+icCD3+ phenotype, the RCDII lines were distinguishable from other lymphocyte subsets by the absence of CD56, CD127 and CD34. Cells matching this surface lineage-negative (Lin) CD7+CD127CD34 phenotype expressed a functional interleukin-15 (IL-15) receptor and constituted a significant proportion of IELs in duodenal specimens of patients without CD, particularly children, and were also found in the thymus. In patients without CD, the LinCD7+CD127CD34 subset was one of four subsets within the CD3CD7+icCD3+ population that could be distinguished on the basis of differential expression of CD56 and/or CD127.

Conclusion Our studies indicate that the CD3CD7+icCD3+ population is heterogeneous and reveal the existence of a Lin subset that is distinct from T, B, NK and lymphoid tissue inducer cells. We speculate that this IL-15 responsive population represents the physiological counterpart of aberrant cells expanded in RCDII and transformed in RCDII-associated lymphoma.

  • Refractory coeliac disease
  • aberrant intraepithelial lymphocytes
  • NK cell receptor
  • lymphoma
  • IEL
  • CD3CD7+ population

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  • FS and JMLT contributed equally to this manuscript, as did senior authors JvB and FK.

  • Funding This research received a specific grant from the Coeliac Disease Consortium (grant number: BSIK03009), Centre for Medical Systems Biology within the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research and by the Dutch Digestive Disease Foundation (WO 06-21,0515), Landsteiner Foundation for Blood Transfusion Research, Innovational Research Incentives Scheme Vidi grant (grant number: 91710377).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Local ethical guidelines of the VU Medical Center in Amsterdam (adult duodenal biopsies), the Leiden University Medical Center (paediatric duodenal biopsies), the Erasmus MC in Rotterdam (fetal intestine, thymuses) in accordance with the declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The complete microarray data from this study are available via the GEO website: The GEO series record is GSE33078.

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