Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease

Muise, Aleixo M.; Walters, Thomas D.; Glowacka, Wioletta K.; Griffiths, Anne M.; Ngan, Bo–Yee; Lan, Hui Y.; Xu, Wei; Silverberg, Mark S.; Rotin, Daniela

doi:10.1136/gut.2008.175117

Cited by 123 publications

(96 citation statements)

References 55 publications

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“…In addition, our group and others showed alterations in Wnt pathway components in the epithelium of patients with CD (8)(9)(10). Furthermore, mutations in the Paneth cell granule exocytosis pathway factor ATG16L1 (11,12) or in the endoplasmic reticulum stress response gene XBP1 (13,14), with the latter resulting in increased Paneth cell apoptosis, are associated with this disease.…”

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confidence: 51%

“…There, it interacts with the transcription factors TCF/LEF and has further impacts on the transcription of its target genes, such as DEFA5 or DEFA6 (HD5/HD6) (19). Various Wnt components, including the transcription factors TCF4 (9) and TCF1 (20), the receptor LRP6 (8), and β-catenin/ E-cadherin (10), are linked to CD with ileal involvement, likely through effects on defensin formation.…”

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confidence: 99%

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Crohn's disease-derived monocytes fail to induce Paneth cell defensins

Courth

Ostaff

Mailänder-Sánchez

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Crohn's disease (CD) is associated with a multitude of genetic defects, many of which likely affect Paneth cell function. Paneth cells reside in the small intestine and produce antimicrobial peptides essential for the host barrier, principally human α-defensin 5 (HD5) and HD6. Patients with CD of the ileum are characterized by reduced constitutive expression of these peptides and, accordingly, compromised antimicrobial barrier function. Here, we present a previously unidentified regulatory mechanism of Paneth cell defensins. Using cultures of human ileal tissue, we showed that the secretome of peripheral blood mononuclear cells (PBMCs) from healthy controls restored the attenuated Paneth cell α-defensin expression characteristic of patients with ileal CD. Analysis of the Wnt pathway in both cultured biopsies and intestinal epithelial cells implicated Wnt ligands driving the PBMC effect, whereas various tested cytokines were ineffective. We further detected another defect in patients with ileal CD, because the PBMC secretomes derived from patients with CD were unable to restore the reduced HD5/HD6 expression. Accordingly, analysis of PBMC subtypes showed that monocytes of patients with CD express significantly lower levels of canonical Wnt ligands, including Wnt3, Wnt3a, Wnt1, and wntless Wnt ligand secretion mediator (Evi/Wls). These studies reveal an important cross-talk between bone marrow-derived cells and epithelial secretory Paneth cells. Defective Paneth cell-mediated innate immunity due to inadequate Wnt ligand stimulation by monocytes provides an additional mechanism in CD. Because defects of Paneth cell function stemming from various etiologies are overcome by Wnt ligands, this mechanism is a potential therapeutic target for this disease.is characterized by intense gastrointestinal inflammation, including infiltration of immune cells, such as granulocytes and mononuclear cells. The pathogenesis is complex and not fully understood, although a combination of microbial and other environmental elements, as well as host genetics, is known to influence susceptibility (1, 2). Although CD may principally affect the whole gastrointestinal tract, predilection sites are the terminal ileum and/or colon, where the location remains stable during the course of disease, suggesting local rather than systemic immunebased susceptibility factors.In patients who have CD with small intestinal involvement, different pathophysiological defects and genetic associations are described that focus on the Paneth cell (2). This cell type is normally located on the bottom of small intestinal crypts, where it is the main source for antimicrobial peptides, predominantly the human α-defensin 5 (HD5) and HD6. One main molecular characteristic of patients with ileal CD is reduced expression of these defensins, resulting in an impaired defense barrier through reduced antimicrobial killing (3). However, the impact of inflammation on Paneth cell function in the small intestine is so far poorly investigated. It also remains unclear whether the...

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confidence: 51%

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confidence: 99%

Crohn's disease-derived monocytes fail to induce Paneth cell defensins

Courth

Ostaff

Mailänder-Sánchez

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…rs7199991 is in complete LD (r 2 51 according to www.hapmap.org, version 4.0) with a promoter-region SNP (rs16260), suggesting that this may have functional significance. To date, E-cadherin gene polymorphisms have not been studied in asthma, but recent findings have shown associations of CDH1 SNPs with Crohn's disease [24], another impaired epithelial barrier disorder, which may share pathways with asthma [25,26]. Moreover, in genome-wide association studies, CDH1 has recently been associated with susceptibility to ulcerative colitis [27] and colorectal cancer [28].…”

Section: Discussionmentioning

confidence: 99%

E-cadherin gene polymorphisms in asthma patients using inhaled corticosteroids

et al. 2011

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E-cadherins form intercellular junctions that maintain epithelial integrity. Epithelial integrity is impaired in asthma and can be restored by inhaled corticosteroids (ICSs). Our aim was to investigate the association of CDH1 gene polymorphisms (single-nucleotide polymorphisms (SNPs)) with airway remodelling, inflammation and forced expiratory volume in 1 s (FEV1) decline in asthma patients and assess whether ICSs modulate these effects.Bronchial biopsies of 138 asthmatics were available (population 1). Associations of 17 haplotype-tagging SNPs with epithelial E-cadherin expression, biopsy parameters and FEV1/vital capacity (VC) ratio were tested. FEV1 and VC data were collected in 281 asthmatics with 30-yr follow-up (population 2). Linear mixed-effect models were used to assess associations of SNPs with FEV1 decline.Seven out of the 17 SNPs were associated with airway remodelling, three with CD8+ T-cell counts, two with eosinophil counts and seven with FEV1 decline. All associations occurred only in patients using ICS. In general, alleles associated with less remodelling correlated with less FEV1 decline and higher FEV1/VC. Decreased epithelial E-cadherin expression was associated with five SNPs in non-ICS users.In conclusion, our data show that CDH1 polymorphisms are associated with epithelial Ecadherin expression and suggest that epithelial adhesion is an important contributor to airway remodelling and lung function in asthma. These effects are modified by the use of inhaled corticosteroids.

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“…Similar changes occur after deletion of other adherens junction components, such as p120 and afadin Ikeda et al, 1999;Smalley-Freed et al, 2010;Tanaka-Okamoto et al, 2011). Although the functional impact is not well defined, it is also worth noting that E-cadherin (CDH1) polymorphisms are linked to inflammatory bowel disease (Barrett et al, 2009;Muise et al, 2009), and both gastric (Guilford et al, 1998) and colonic adenocarcinoma (Houlston et al, 2008).…”

Section: Adherens Junctions Contribute To Epithelial Barrier Functionmentioning

confidence: 93%

The mucosal barrier at a glance

Turner

2017

Journal of Cell Science

214

183

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Mucosal barriers separate self from non-self and are essential for life. These barriers, which are the first line of defense against external pathogens, are formed by epithelial cells and the substances they secrete. Rather than an absolute barrier, epithelia at mucosal surfaces must allow selective paracellular flux that discriminates between solutes and water while preventing the passage of bacteria and toxins. In vertebrates, tight junctions seal the paracellular space; flux across the tight junction can occur through two distinct routes that differ in selectivity, capacity, molecular composition and regulation. Dysregulation of either pathway can accompany disease. A third, tight-junction-independent route that reflects epithelial damage can also contribute to barrier loss during disease. In this Cell Science at a Glance article and accompanying poster, we present current knowledge on the molecular components and pathways that establish this selectively permeable barrier and the interactions that lead to barrier dysfunction during disease.

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Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease

Abstract: The mis-localisation of E-cadherin and beta-catenin may explain the increased permeability seen in some patients with Crohn's disease. Thus, the polymorphisms identified in CDH1 are important for understanding the pathogenesis of Crohn's disease and point to a defect in barrier defence.

Cited by 123 publications

References 55 publications

Crohn's disease-derived monocytes fail to induce Paneth cell defensins

Crohn's disease-derived monocytes fail to induce Paneth cell defensins

E-cadherin gene polymorphisms in asthma patients using inhaled corticosteroids

The mucosal barrier at a glance

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