The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease

Schmitz, Frederike; Kooy–Winkelaar, Yvonne; Wiekmeijer, Anna-Sophia; Brugman, Martijn H.; Mulder, Chris J.; Lopes, Susana M. Chuva de Sousa; Mummery, Christine L.; Bergen, Jeroen van; Koning, Frits

doi:10.1136/gutjnl-2014-308153

Cited by 29 publications

(30 citation statements)

References 59 publications

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“…3f) matched previously described21 biological annotations (Fig. 5, black annotations)including the CRTH2 + ILC2 (cluster 16), c-KIT + ILC3 (cluster 5) and CD56 -CD127lineage -IELs (cluster 19, 13, 18, 14, 6 and 8), the latter representing innate type of lymphocytes with dual T cell precursor and NK/ILC traits[23][24][25] .…”

supporting

confidence: 74%

Interactive Visual Analysis of Mass Cytometry Data by Hierarchical Stochastic Neighbor Embedding Reveals Rare Cell Types

van

Höllt

Pezzotti

et al. 2017

Preprint

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Mass cytometry allows high-resolution dissection of the cellular composition of the immune system. However, the high-dimensionality, large size, and non-linear structure of the data poses considerable challenges for data analysis. In particular, dimensionality reduction-based techniques like t-SNE offer single-cell resolution but are limited in the number of cells that can be analysed. Here we introduce Hierarchical Stochastic Neighbor Embedding (HSNE) for the analysis of mass cytometry datasets. HSNE constructs a hierarchy of non-linear similarities that can be interactively explored with a stepwise increase in detail up to the single-cell level. We applied HSNE to a study on gastrointestinal disorders and three other available mass cytometry datasets. We found that HSNE efficiently replicates previous observations and identifies rare cell populations that were previously missed due to downsampling. Thus, HSNE removes the scalability limit of conventional t-SNE analysis, a feature that makes it highly suitable for the analysis of massive high-dimensional datasets.

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supporting

confidence: 74%

Interactive Visual Analysis of Mass Cytometry Data by Hierarchical Stochastic Neighbor Embedding Reveals Rare Cell Types

van

Höllt

Pezzotti

et al. 2017

Preprint

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“…It has been shown that IELs, specifically cytotoxic T cell receptor (TCR)‐αβ + T cells, which undergo natural killer (NK)‐like reprogramming on interacting with epithelial stress‐induced ligands, and IL‐15, up‐regulated upon exposure to toxic gliadin peptides, promote epithelial destruction . Contributions of other types of lymphoid cells to the innate immune response in CD are suspected, but these are currently unclear . Recent studies have implicated ILCs in the pathogenesis of a variety of intestinal inflammatory disorders ; however, data regarding the repertoire of human proximal small intestinal (SI) ILCs and their alterations in CD are limited .…”

Section: Introductionmentioning

confidence: 99%

Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential

Uhde

Bunin

et al. 2020

Clinical &Amp; Experimental Immunology

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The small intestinal (SI) epithelium harbors a heterogeneous population of lymphocytes that mediate mucosal damage and repair in celiac disease (CD). The composition and roles of human proximal SI intra-epithelial innate lymphoid cells (ILCs), and their alterations in CD, are not well understood. We report that duodenal intra-epithelial ILCs predominantly consist of natural killer (NK)p44 + CD127 − cytotoxic ILC1s and NKp44 − CD127 + helper ILC1s, while ILC3s only represent a minor population. In patients with newly diagnosed or active CD (ACD) and refractory CD type 1 (RCD I), the frequency of SI NKp44 + ILCs is decreased, with restoration of NKp44 + ILC frequency observed in patients adhering to a gluten-free diet who show evidence of mucosal healing. Moreover, the frequency of SI NKp44 − ILCs is increased in ACD and RCD I patients and correlates with the severity of villous atrophy and epithelial damage, as assessed by serum levels of fatty acid binding protein 2 (FABP2). We show that the ILC alterations in CD represent a phenotypic shift of cytotoxic ILC1s rather than an increase in helper ILC1s or transdifferentiation of ILC1s to ILC3s, and activation-induced loss of NKp44 by cytotoxic ILC1s is associated with increased interferon (IFN)-γ expression and release of lytic granules. These findings suggest that intra-epithelial NKp44 − CD127 − cytotoxic ILC1s may contribute to mucosal damage in CD.

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“…The abnormal cell phenotype includes the loss of surface CD3 with preservation of cytoplasmic CD3ε [39,40] and rearranged TCRγ chains [38,41]. These abnormal and highly proliferative IEL are suggested to give rise to T-cell lymphoma [42], while others suggest innate IEL giving rise to enteropathy-associated T-cell lymphoma (EATL) [26,43]. However, lymphoma in celiac disease patients is not confined to the EATL [44].…”

Section: Celiac Diseasementioning

confidence: 99%

“…These IEL are CD8 + T cells carrying the αβ T-cell receptor (TCR) or CD4 - CD8 - γδTCR + T cells [24]. Innate IEL are drastically reduced upon intestinal inflammation in celiac disease [25,26]. Both αβ + and γδ + IEL express NKG2D [27], a receptor recognizing self-proteins induced by stress, infection and transformation [28], while the inhibitory NKG2A receptors are downregulated [29].…”

Section: Celiac Diseasementioning

confidence: 99%

The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences?

Hisamatsu

Erben²,

Kühl³

2016

Inflamm Intest Dis

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Background: Chronic intestinal inflammation due to noninfectious causes represents a growing health issue all over the world. Celiac disease as well as inflammatory bowel diseases (IBD) like Crohn's disease and ulcerative and microscopic colitis involve uncontrolled T-cell activation and T-cell-mediated damage as common denominators. Therefore, diagnosis and treatment decisions clearly benefit from the knowledge of the intricacies of the systemic and the local T-cell activity. Summary: Depending on the cytokine milieu, CD4⁺ T cells can differentiate into proinflammatory T helper 1 (Th1), anti-inflammatory Th2, antimicrobial Th17, pleiotropic Th9, tissue-instructing Th22 cells, and in the regulatory compartment forkhead box protein 3⁺ Treg, suppressive Tr1 or Th3 cells. Additionally, follicular Th cells provide B-cell help in antibody class switching; cytotoxic CD8⁺ T cells target virus-infected or tumor cells. This review discusses our current knowledge on the contribution of defined T-cell subpopulations to establishing and maintaining chronic intestinal inflammation in either of the above entities. It also puts emphasis on the differences in the prevalence of these diseases between Eastern and Western countries. Key Messages: In celiac disease, the driving role of T cells in the lamina propria and in the epithelium mainly specific for two defined antigens is well established. Differences in genetics and lifestyle between Western and Eastern countries were instrumental in understanding underlying mechanisms. In IBD, the vast amount of potential antigens and the corresponding antigen-specific T cells makes it unlikely to find universal triggers. Increased mucosal CD4⁺ regulatory T cells in all four entities fail to control or abrogate local inflammatory processes. Thus, prevailing differences in the functional T-cell subtypes driving chronic intestinal inflammation in celiac disease and IBD at best allow some overlap in the treatment options for either disease.

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The composition and differentiation potential of the duodenal intraepithelial innate lymphocyte compartment is altered in coeliac disease

Abstract: Thus, we demonstrate previously unappreciated diversity and plasticity of the innate IEL compartment and its loss of differentiation potential in patients with RCDII.

Cited by 29 publications

References 59 publications

Interactive Visual Analysis of Mass Cytometry Data by Hierarchical Stochastic Neighbor Embedding Reveals Rare Cell Types

Interactive Visual Analysis of Mass Cytometry Data by Hierarchical Stochastic Neighbor Embedding Reveals Rare Cell Types

Phenotypic shift of small intestinal intra-epithelial type 1 innate lymphoid cells in celiac disease is associated with enhanced cytotoxic potential

The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences?

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