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. 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 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. CONCLUSION: 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.
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. 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 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. CONCLUSION: 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: R L J van Wanrooij; D M J Müller; E A Neefjes-Borst; J Meijer; L G Koudstaal; D A M Heideman; H J Bontkes; B M E von Blomberg; G Bouma; C J J Mulder Journal: J Clin Immunol Date: 2014-07-27 Impact factor: 8.317
Authors: A Rubio-Tapia; G Malamut; W H M Verbeek; R L J van Wanrooij; D A Leffler; S I Niveloni; C Arguelles-Grande; B D Lahr; A R Zinsmeister; J A Murray; C P Kelly; J C Bai; P H Green; S Daum; C J J Mulder; C Cellier Journal: Aliment Pharmacol Ther Date: 2016-08-03 Impact factor: 8.171
Authors: Tom van Gils; Petula Nijeboer; Roy L van Wanrooij; Gerd Bouma; Chris J J Mulder Journal: Nat Rev Gastroenterol Hepatol Date: 2015-09-08 Impact factor: 46.802
Authors: M Uhde; X Yu; A Bunin; C Brauner; S K Lewis; B Lebwohl; S Krishnareddy; A Alaedini; B Reizis; S Ghosh; P H Green; G Bhagat Journal: Clin Exp Immunol Date: 2020-01-27 Impact factor: 4.330
Authors: Yvonne M C Kooy-Winkelaar; Dagmar Bouwer; George M C Janssen; Allan Thompson; Martijn H Brugman; Frederike Schmitz; Arnoud H de Ru; Tom van Gils; Gerd Bouma; Jon J van Rood; Peter A van Veelen; M Luisa Mearin; Chris J Mulder; Frits Koning; Jeroen van Bergen Journal: Proc Natl Acad Sci U S A Date: 2017-01-03 Impact factor: 11.205