title: Identification of a potential physiological precursor of aberrant cells in refractory coeliac disease type II.
abstract: 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 CD3(-)CD7(+)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.
  
  
  METHODS
  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 CD3(-)CD7(+)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(+)CD127(-)CD34(-) 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 Lin(-)CD7(+)CD127(-)CD34(-) subset was one of four subsets within the CD3(-)CD7(+)icCD3(+) population that could be distinguished on the basis of differential expression of CD56 and/or CD127.
  
  
  CONCLUSIONS
  Our studies indicate that the CD3(-)CD7(+)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.
authors: Department of Immunohematology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors: Frederike
authors: F
authors: Schmitz
authors: Jennifer M L
authors: JM
authors: Tjon
authors: Yuching
authors: Y
authors: Lai
authors: Allan
authors: A
authors: Thompson
authors: Yvonne
authors: Y
authors: Kooy-Winkelaar
authors: Richard J L F
authors: RJ
authors: Lemmers
authors: Hein W
authors: HW
authors: Verspaget
authors: M Luisa
authors: ML
authors: Mearin
authors: Frank J
authors: FJ
authors: Staal
authors: Marco W
authors: MW
authors: Schreurs
authors: Tom
authors: T
authors: Cupedo
authors: Anton W
authors: AW
authors: Langerak
authors: Chris J
authors: CJ
authors: Mulder
authors: Jeroen
authors: J
authors: van Bergen
authors: Frits
authors: F
authors: Koning
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D002446:Celiac Disease / Q000276:immunology* / Q000473:pathology*; D002460:Cell Line; D002478:Cells, Cultured; D004386:Duodenum / Q000276:immunology* / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D046888:Tissue Array Analysis
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D019409:Interleukin-15; D011948:Receptors, Antigen, T-Cell