Optimal Strategies to Identify Aberrant Intra-Epithelial Lymphocytes in Refractory Coeliac Disease

Wanrooij, Roy L.J. van; Müller, Domenique M J; Neefjes-Borst, E. Andra; Meijer, Jos W. R.; Koudstaal, Lyan G.; Heideman, Daniëlle A.M.; Bontkes, Hetty J.; Blomberg, B. Mary E. von; Bouma, Gerd; Mulder, Chris J.

doi:10.1007/s10875-014-0075-7

Cited by 49 publications

(33 citation statements)

References 22 publications

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“…36 Flow cytometry immunophenotyping is regarded as the superior modality to detect an aberrant IEL phenotype, and a threshold of >20-25% aberrant IELs has been suggested to render a diagnosis of type II RCD. 15,[37][38][39] Intraepithelial localisation is confirmed by gating on surface CD103+ T-cells. 37 Aberrant T-cells retain expression of CD7 and cytoplasmic CD3, but lack surface CD3, CD4 and CD8.…”

Section: Refractory Coeliac Disease and Eatlmentioning

confidence: 93%

T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

Vliet

Spagnolo

2020

Pathology

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Section: Refractory Coeliac Disease and Eatlmentioning

confidence: 93%

T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

Vliet

Spagnolo

2020

Pathology

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“…Besides these diverse inter-individual differences, aberrant IELs in RCDII might also be characterized by intra-individual heterogeneity as RCDII cell lines show fractioned expression of different γ-chain receptors within one cell line [8]. This confirms the heterogeneity of the aberrant IEL population in RCDII and underlines the importance of extensive evaluation of CD patients refractory to a gluten-free diet using sensitive diagnostic procedures [10]. It is tempting to speculate that the heterogeneity of aberrant IEL found in RCDII might reflect the fact that proliferation and (pre-) malignant transformation of these IELs could take place at different stages of IEL development.…”

Section: Intra- and Inter-individual Heterogeneity In Rcdiimentioning

confidence: 89%

“…In contrast, the latter population showed co-expression of the IL-21 receptor and IL-15 receptor α-chain. What also stresses heterogeneity is the observation that the clonality of T-cell receptor rearrangements differed between RCDII cell lines [9] and within a relatively large group of RCDII patients [9,10]. Furthermore, aberrant IELs display different stages of maturity between RCDII patients, of which only the patients harbouring the most mature aberrant IEL population developed an EATL [1].…”

Section: Intra- and Inter-individual Heterogeneity In Rcdiimentioning

confidence: 99%

Therapy in RCDII: Rationale for Combination Strategies?

Nijeboer

Malamut²,

Bouma

et al. 2015

Dig Dis

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Refractory coeliac disease type II (RCDII) is characterized by a continuous gluten-independent duodenal immune activation with an extremely high risk of malignant transformation. It is therefore considered as an indolent lymphoma. RCDII is characterized by the presence of villous atrophy (Marsh III A-C) in combination with an aberrant intra- epithelial lymphocyte (IEL) population consisting of >20% sCD3-CD7+iCD3+ IELs. The sCD3-CD7+iCD3+ IELs are a heterogeneous lineage-negative cell population, consisting of cells that do or do not express CD127/IL7Rα. Experiments using IEL from non-RCDII patients have indicated that while the CD127- cells are IL-15 responsive, the CD127+ cells are not. Together with the observation that some patients express an aberrant (monoclonal) TCRγδ phenotype, this confirms the heterogeneity of the aberrant IEL population in RCDII and suggests that the aberrant cells are heterogeneous with respect to their response to common γ-chain cytokines. Although cladribine with or without autologous stem cell transplantation is effective in the treatment of signs and symptoms of RCDII and improves survival as compared to symptomatic topical steroid therapy, cladribine failures still bear a high risk of malignant transformation, and the rate of enteropathy-associated T-cell lymphoma (EATL) development in this subgroup is extremely high. It might be hypothesized that the heterogenous nature of aberrant IEL and the high risk of malignant transformation require a treatment strategy which is effective despite this heterogeneity. RCDII should be seen more in the light of a low-grade/no mass lymphoma or pre-EATL. We would suggest an upfront combination therapy approach integrating inhibition of downstream Jak-STAT signalling pathways with conventional therapy (2-CDA) to hopefully effectively treat signs and symptoms of RCDII and accomplish a more effective EATL prevention.

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“…The autoimmune screening showed positivity of anti‐smooth muscle antibodies at low titre (1:80) that could have been previously misinterpreted as anti‐endomysial positivity. The duodenal biopsy displayed the persistence of class B2/Marsh 3c lesions with CD3 + IEL burden 60/100 (Figure I) and large cells harbouring CD5 and CD30 positivity in the lamina propria (Figure L,M) and the same TCR‐γ clonal peak as detected earlier (Figure B), although the percentage of aberrant IELs at flow cytometry, defined by the surface phenotype CD3 − CD4 − CD8 − CD7 + CD103 + and cytoplasmic CD3 + , was less than 1%. An ulceration at the first jejunal loop was found by wireless capsule endoscopy, while total‐body computerized tomography revealed circumferential thickening of a 7 cm segment of the same loop with intra‐abdominal lymphadenopathy.…”

Section: Case Presentationmentioning

confidence: 99%

Intestinal T‐cell lymphoma with enteropathy‐associated T‐cell lymphoma‐like features arising in the setting of adult autoimmune enteropathy

Ciccocioppo

Croci

Biagi

et al. 2018

Hematological Oncology

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Enteropathy-associated T-cell lymphoma is regarded as a dismal, late complication of coeliac disease, though a single case of T-cell lymphoma with such features arising in the setting of autoimmune enteropathy of the adult has been reported to date. We aim to describe the case of a 41-year-old woman complaining of severe malabsorption syndrome, who was diagnosed with autoimmune enteropathy based on the presence of flat intestinal mucosa unresponsive to any dietary restriction and positivity for enterocyte autoantibodies. Steroid therapy led to a complete recovery of both mucosal and clinical findings over 12 years, when disease relapse was accompanied by the appearance of monoclonal rearrangement of T-cell receptor-γ and peculiar T-cell phenotypic abnormalities, leading to a rapid transition to an overt T-cell lymphoma with features of the enteropathy-associated subtype. Despite intensive treatment, the patient developed cerebral metastasis and died 9 months later. Our case enhances the concept of enteropathy-associated T-cell lymphoma as a disease that may arise in the setting of enteropathies other than coeliac disease, thus representing a heterogeneous entity. Moreover, our observations support the need of a close follow-up of these patients, coupled with comprehensive characterization of mucosal biopsies.

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Optimal Strategies to Identify Aberrant Intra-Epithelial Lymphocytes in Refractory Coeliac Disease

Cited by 49 publications

References 22 publications

T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

Therapy in RCDII: Rationale for Combination Strategies?

Intestinal T‐cell lymphoma with enteropathy‐associated T‐cell lymphoma‐like features arising in the setting of adult autoimmune enteropathy

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