Novel type of EATL evolving from mucosal γδ-T-cells in a RCD type I patient
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56425 | GEO | 2014/04/02
SECONDARY ACCESSION(S): PRJNA243296
REPOSITORIES: GEO
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Project description:Enteropathy associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma that may complicate celiac disease and typically occurs in patients with refractoriness to the gluten- free diet. The majority of these patients harbor intra-epithelial lymphocytes (IEL) with an aberrant phenotype in the small intestine which are thus considered as the M-bM-^@M-^XprecursorM-bM-^@M-^Y lymphoma cells. We here report on a case of extra-intestinal EATL that originated from a clonal M-NM-3M-NM-4-IEL population rather than from aberrant IEL. This EATL displayed a distinctive pattern of immunophenotypical, T-cell receptor immunogenetic, and chromosomal aberrancies defining this lymphoma as a novel variant of EATL. sample vs reference
2014-04-02 | E-GEOD-56425 | biostudies-arrayexpress
Project description:Approximately 2–5% of adult-onset coeliac disease (CD) patients develops refractory coeliac disease (RCD). In contrast to RCD type I, RCD type II is characterised by the presence of aberrant small intestinal intraepithelial T-lymphocytes (IEL) expressing cytoplasmic CD3 but lacking surface expression of CD3, CD4 and CD8. Development of Enteropathy Associated T-cell Lymphoma (EATL) is directly associated with the presence of >20% aberrant IEL in RCD II patients and has a very poor prognosis. We report on an exceptional case of EATL presenting as leukemic ascites and on the unique opportunity to perform extensive phenotypic and genomic analysis of this malignancy. Flow cytometric immunophenotyping of the ascitic EATL presentation showed CD30 expression typical for EATL and loss of the above mentioned surface markers similar to the aberrant IEL it originated from, as indicated by an identical monoclonal TCR-gamma rearrangement. In addition, expression of a substantial number of markers, including CD2, CD7, CD11a/CD18, CD52, CD103 and granzyme B was lost, which has not been reported sofar. Expression of proliferation markers Ki-67 en PCNA was clearly detected in the majority of EATL cells. Karyotype and comparative genomic hybridisation (CGH) analyses showed many genomic alterations, including chromosomal gains and losses up to 47Mb not previously reported for EATL. In conclusion, the current exceptional EATL presentation displays both immunophenotypic and genomic alterations not described previously and not included in the current WHO classifications of lymphoid malignancies. Comparative genomic hybridisation (CGH) analyses of an exceptional case of enteropathy associated T cell lymphoma
2010-06-17 | E-GEOD-17715 | biostudies-arrayexpress
Project description:Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is trans-presented by epithelial cells to IEL in complex with the IL-15 receptor α chain (IL-15Rα) and plays essential roles both in maintaining IEL homeostasis, and in inducing IEL activation in response to epithelial stress. When overproduced, IL-15 is a key driver of the gluten-induced enteropathy Coeliac disease, through cytotoxic activation of IEL. To better understand how IL-15 directly regulates both homeostatic and inflammatory functions of IEL, we performed quantitative proteomics of IL-15/Rα-stimulated murine IEL, sorted into their 3 main subpopulations, TCRγδ CD8αα, TCRαβ CD8αβ and TCRαβ CD8αα expressing IEL. The data reveal that high IL-15/Rα stimulation licenses cell cycle activation, upregulates the biosynthetic machinery in IEL, increases mitochondrial respiratory capacity and induces expression of cell surface immune receptors and adhesion proteins that potentially drive IEL activation.
2021-05-10 | PXD025891 | Pride
Project description:Approximately 2–5% of adult-onset coeliac disease (CD) patients develops refractory coeliac disease (RCD). In contrast to RCD type I, RCD type II is characterised by the presence of aberrant small intestinal intraepithelial T-lymphocytes (IEL) expressing cytoplasmic CD3 but lacking surface expression of CD3, CD4 and CD8. Development of Enteropathy Associated T-cell Lymphoma (EATL) is directly associated with the presence of >20% aberrant IEL in RCD II patients and has a very poor prognosis. We report on an exceptional case of EATL presenting as leukemic ascites and on the unique opportunity to perform extensive phenotypic and genomic analysis of this malignancy. Flow cytometric immunophenotyping of the ascitic EATL presentation showed CD30 expression typical for EATL and loss of the above mentioned surface markers similar to the aberrant IEL it originated from, as indicated by an identical monoclonal TCR-gamma rearrangement. In addition, expression of a substantial number of markers, including CD2, CD7, CD11a/CD18, CD52, CD103 and granzyme B was lost, which has not been reported sofar. Expression of proliferation markers Ki-67 en PCNA was clearly detected in the majority of EATL cells. Karyotype and comparative genomic hybridisation (CGH) analyses showed many genomic alterations, including chromosomal gains and losses up to 47Mb not previously reported for EATL. In conclusion, the current exceptional EATL presentation displays both immunophenotypic and genomic alterations not described previously and not included in the current WHO classifications of lymphoid malignancies.
2010-06-17 | GSE17715 | GEO
Project description:About 5% of celiac disease (CeD) patients do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T-lymphocytes (IELs). RCD type II (RCDII) patients show clonal expansions of IELs that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma.<br>RCDII has a poor prognosis (5-year survival rate <50%) also because of the development of enteropathy-associated T-cell lymphoma. Diagnosis of RCDII is complex and involves a combination of several techniques such as multiplex PCR analysis to determine the clonality of T-cell receptor gene rearrangements and immunohistochemistry or flow-cytometry to define the cell surface markers of IELs. Therefore studying the genetics and genomics of RCD2 susceptibility may provide novel insights into mechanistic basis for RCD2 development. The aim of this experiment was to profile the global gene expression changes in order to understand the dysregulated pathways in RCD2 biopsies and to uncover downstream pathways affected by RCD2 genetic susceptibility loci. <br>All patients were diagnosed with RCD2 and gut biopsies were collected from these patients to perform microarray based gene expression analysis. RNA from eleven RCD2 biopsy samples were analyzed using Illumina Human Ref8 v1 array.
2016-12-05 | E-MTAB-4613 | biostudies-arrayexpress
Project description:Celiac disease (CD) is an autoimmune disease in which intestinal inflammation is induced by dietary gluten. The means through which gluten-specific CD4+T cell activation culminates in intraepithelial T cell (T-IEL)–mediated intestinal damage remain unclear. Here, we performed multiplexed single-cell analysis of intestinal and gluten-induced peripheral blood T cells from patients in different CD states and healthy controls. Untreated, active, and potential CD were associated with an enrichment of activated intestinal T cell populations, including CD4+follicular T helper (TFH) cells, regulatory T cells (Tregs), and natural CD8+αβ and γδ T-IELs. Natural CD8+αβ and γδ T-IELs expressing activating natural killer cell receptors (NKRs) exhibited a distinct TCR repertoire in CD and persisted in patients on a gluten-free diet without intestinal inflammation. Our data further show that NKR-expressing cytotoxic cells, which appear to mediate intestinal damage in CD, arise from a distinct NKR-expressing memory population of T-IELs. After gluten ingestion, both αβ and γδ T cell clones from this memory population of T-IELs circulated systemically along with gluten-specific CD4+T cells and assumed a cytotoxic and activating NKR-expressing phenotype. Collectively, these findings suggest that cytotoxic T cells in CD are rapidly mobilized in parallel with gluten-specific CD4+T cells after gluten ingestion.
2024-01-13 | GSE252762 | GEO
Project description:Celiac disease (CD) is the most common chronic autoimmune enteropathy in Western Countries with an estimated prevalence ranging from 1:100 to 1:200. It is usually characterized by a benign course with clinical and histological remission, provided that a strict gluten-free diet (GFD) is followed by patients. Less frequently, CD can be characterized by a complicated course, when facing with a refractory disease (RCD) or with malignancies of the gastrointestinal (GI) tract, namely lymphoma and adenocarcinoma of the small bowel (SB). Different studies estimated a relative risk (RR) for neoplastic GI complications in CD ranging from 2 to 40 and from 10 to 60 for primary gut lymphoma and adenocarcinoma, respectively. Although uncommon, the discussed malignancies has a severe prognosis, reflecting the need for an early diagnosis. This project aims to establish an enteroscopic approach to improve the diagnostic timing and survival of CD patients at risk to develop SB tumors.
| 2180911 | ecrin-mdr-crc
Project description:Type II Enteropathy-associated T-cell lymphoma (Type II EATL) is an aggressive intestinal T-cell lymphoma with poor prognosis and has not been molecularly profiled. Through targeted amplicon sequencing, we identified a large portion of Type II EATL samples that harbor mutations in the STAT5B, JAK3 and GNAI2 genes. Here we performed gene expression profiling on four Type II EATL samples in order to better characterize this disease. As Type II EATL is suggested to arise from CD8+ IELs, we integrated our data with publicly available profile of CD8αα and CD8αβ T-cells from healthy donors (GSE33374). Gene expression profiling independently demonstrated strong enrichment of several aspects of GPCR and JAK-STAT signaling pathways. Moreover, an significant association was identified with genes containing STAT5B binding sites in their promoters. Microarray gene expression profiling was performed on 4 Type II Enteropathy-associated T-cell lymphoma and a combination of unsupervised and supervised clustering was performed to determine any differentially activated pathways between samples with tumor and healthy human CD161++CD8aa and CD161++CD8ab T cells (found under accession number GSE33374)
2016-03-03 | E-GEOD-70652 | biostudies-arrayexpress
Project description:Coeliac disease (CeD) is a complex, polygenic inflammatory enteropathy with autoimmune features caused by exposure to dietary gluten that occurs in a subset of genetically susceptible HLA-DQ8 and HLA-DQ2 individuals. Attempts to develop a pathophysiologically relevant animal model that develops villous atrophy (VA) have failed. The need to develop non-dietary treatments for this common disorder is now widely recognized, but it is hampered by the lack of a preclinical model. Furthermore, while human studies have led to major advances in our understanding of CeD pathogenesis, direct demonstration of the respective roles of disease-predisposing HLA molecules, and adaptive and innate immunity in the development of tissue damage is missing. To address these unmet needs, we engineered a mouse model that reproduces the dual overexpression of IL-15 in the gut epithelium and the lamina propria (Lp) characteristic of active CeD, expresses the predisposing HLA-DQ8 molecule, and develops VA upon gluten ingestion. We show that overexpression of IL-15 in both the epithelium and Lp is required for development of VA, demonstrating the location-dependent central role of IL-15 in CeD pathogenesis. Furthermore, our study reveals the critical role played by both CD4+ and cytotoxic CD8+ T cells in VA development. Finally, it establishes that HLA-DQ8 is central for tissue destruction, but dispensable for loss of oral tolerance to gluten. This mouse model, by reflecting the complex interplay between gluten, genetics and the IL-15-driven tissue inflammation found in CeD, represents a powerful preclinical model to test new therapeutics and study disease pathogenesis.
2019-07-26 | GSE134900 | GEO
Project description:Type II Enteropathy-associated T-cell lymphoma (Type II EATL) is an aggressive intestinal T-cell lymphoma with poor prognosis and has not been molecularly profiled. Through targeted amplicon sequencing, we identified a large portion of Type II EATL samples that harbor mutations in the STAT5B, JAK3 and GNAI2 genes. Genome-wide DNA copy number profiling of Type II EATL tumors and matched normal samples was performed to determine copy-number changes in this disease.
2016-03-03 | GSE70653 | GEO