A novel population of human CD56+ human leucocyte antigen D-related (HLA-DR+) colonic lamina propria cells is associated with inflammation in ulcerative colitis

Ng, Siew C.; Plamondon, Sophie; Al-Hassi, Hafid O.; English, Nicholas R.; Gellatly, Nichola; Kamm, Michael A.; Knight, Stella C.; Stagg, Andrew J.

doi:10.1111/j.1365-2249.2009.04012.x

Cited by 21 publications

(26 citation statements)

References 43 publications

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“…Key to these roles is the NK cells’ receptor repertoire for detection of surface molecules specific to microbial agents or categorically induced by the molecular stress response shared by viral infection and neoplastic states [2,5,6]. Modern studies in NK cell biology have increasingly highlighted that NK cells influence the pathophysiologic processes underlying diverse chronic inflammatory conditions such as transplant rejection [7,8], rheumatoid arthritis [9], diabetes [10], and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) [11–15]. The mechanisms by which NK cells affect these inflammatory processes are incompletely understood, but may include direct tissue damage via parenchymal cell cytolysis and production of cytokines inducing T cell or myeloid cell recruitment and activation [16–18].…”

Section: Introductionmentioning

confidence: 99%

“…Genome-wide studies have associated characteristic NK receptors (killer immunoglobulin-like receptors, KIR) and their cognate HLA alleles with IBD susceptibility [19,20]. At the cellular level, populations of NK cells with cytolytic potential are enriched in colonic lamina propria of individuals with active IBD [11,15], and subsets of NK cells exert inflammatory effect by promoting CD4 + T cell proliferation and CD-relevant Th17 differentiation via production of pro-inflammatory cytokines [16]. Notably, this inflammatory action is dependent on KIR and HLA-dependent genetic programming of NK cells termed ‘licensing’, and results in distinct subsets of human subpopulations genetically distinct for inflammatory and anti-viral proficiency of their NK cell compartment [16,21–23].…”

Section: Introductionmentioning

confidence: 99%

“…When 6-MP was first adopted as maintenance therapy in IBD, patients on such treatment were reported to have decreased number of peripheral NK cells that correlated with diminished disease activity [11,15,29,30]. However, the mechanism underlying this clinical finding has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

Yusung

McGovern

Lin

et al. 2017

Clinical Immunology

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NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn’s disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

Yusung

McGovern

Lin

et al. 2017

Clinical Immunology

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“…Endoscopic signs of inflammation were used to define the biopsies as inflamed. LP mononuclear cells were isolated from the biopsies as previously described [39]. …”

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confidence: 99%

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

et al. 2012

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Dendritic cells (DCs) and monocyte-derived macrophages (M s) are key components of intestinal immunity. However, the lack of surface markers differentiating M s from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, M s can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating M s and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C hi monocytes to intestinal M s. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory M s endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. Eur. J. Immunol. 2012. 42: 3150-3166 HIGHLIGHTS 3151 IntroductionThe intestinal lamina propria (LP) contains cells that express high levels of CX 3 CR1, the receptor for the fractalkine chemokine [1,2]. Based on their monocytic origin and on their inability to migrate to the mesenteric lymph nodes (MLNs) such CX 3 CR1 hi cells have been defined as macrophages (M s) [1][2][3]. CX 3 CR1 hi M s contribute to the intestinal LP homeostasis through the production of anti-inflammatory cytokines and the clearance of commensal bacteria that breach the epithelial barrier [4]. In contrast, during intestinal inflammation, microenvironmental signals promote the differentiation of extravasated monocytes into proinflammatory M s with the ability to produce interleukin (IL)-12, IL-23, tumor necrosis (TNF)-α and inducible nitric oxide synthase (iNOS) [5][6][7]. However, little is known about the developmental trajectories that lead extravasated monocytes to either antior proinflammatory intestinal M s. This is primarily due to the fact that a surface marker permitting unequivocal identification of M s within the intestine and their distinction from dendritic cells (DCs) is lacking. The interstitial DCs (Int-DCs) present throughout the LP derive from blood precursors known as pre-DCs [2]. Under steady-state conditions, the Int-DCs found in the intestinal LP induce oral tolerance by carrying antigens originating from food or from harmless bacteria to the MLNs [8,9]. The CD103 + Int-DCs found in the steady-state LP have the selective ability to express aldehyde dehydrogenase (ALDH) and thereby produce retinoic acid (RA). As a result, upon migration to MLNs they trigger the differentiation of naive CD4 + T cells specific for food and microbiota antigens into induced Foxp3 + regulatory T (iTreg) cells [10][11][12][13]. In contrast, the Int-DCs that develop in inflamed LP upon exposure to pathogens lose their capacity to generate iTreg cells and, upon migration to the MLNs, trigger the differentiation of naive, antigen-responsive CD4 + T cells into T helper type 1 (Th1) cells that are specific for the invading patho...

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“…Human blood-enriched dendritic cells (low-density cells [LDC]) were obtained following NycoPrep centrifugation of nonadherent overnight cultured PBMC. That LDC population, which was used as a source of APC, was 98 to 100% HLA-DR ϩ , had morphologic characteristics of dendritic cells (upon both optical microscopy and electron microscopy), and has been characterized in detail in previous studies from our laboratory [15,16].…”

Section: Apc and T-cell Enrichment From Peripheral Bloodmentioning

confidence: 99%

T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space?

et al. 2012

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A novel population of human CD56+ human leucocyte antigen D-related (HLA-DR+) colonic lamina propria cells is associated with inflammation in ulcerative colitis

Abstract: Summary Ulcerative colitis (UC) involves inappropriate mucosal immune responses to intestinal microbiota. Gut dendritic cells (DC

Cited by 21 publications

References 43 publications

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients

CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis

T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space?

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