Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Martin, Jérôme C.; Boschetti, Gilles; Chang, Christie; Ungaro, Ryan C.; Giri, Mamta; Chuang, Ling-Shiang; Nayar, Shikha; Greenstein, Alexander J.; Dubinsky, Marla; Walker, Laura; Leader, Andrew M.; Fine, Jay S.; Whitehurst, Charles E.; Mbow, Lamine; Kugathasan, Subra; Denson, Lee A.; Hyams, Jeffrey S.; Friedman, Joshua R.; Desai, Prerak; Ko, Mabel; Laface, Ilaria; Aktürk, Güray; Schadt, Eric E.; Gnjatic, Sacha; Rahman, Adeeb; Mérad, Miriam; Cho, Judy H.; Kenigsberg, Ephraim

doi:10.1101/503102

Cited by 106 publications

(233 citation statements)

References 97 publications

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“…The majority receptors for coronavirus entry were highly expressed in enterocytes in epithelial cells and mononuclear phagocytes, stromal cells and glial cells in immune cells ( Fig. 1b) [8]. In the complete view of ileum cells, we summarized here that the majority of coronavirus are likely to infect enterocytes that highly expressed specific receptors for coronavirus binding.…”

Section: The Potential Target Cells Of Coronaviruses Are Conserved Inmentioning

confidence: 83%

The Small Intestine, an Underestimated Site of SARS-CoV-2 Infection: From Red Queen Effect to Probiotics

Zhan¹,

Wang²,

Wu³

2020

Preprint

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Understanding how the coronaviruses invade our body is an essential point, and the expression profile of coronaviruses receptor may help us to find where the coronavirus infects our body. We found that the coronavirus receptors, including angiotensin-converting enzyme 2 (ACE2) for SARS-CoV and SARS-Cov-2, are digestion-related enzymes in human enterocytes. Coronaviruses are continually altering the binding receptor and binding modes during their evolution, but the potential target cell in the small intestine is constant when in the lung is inconstant. Enterocytes may act as a conserved cell reservoir for coronaviruses, which may be partially explained by the Red Queen hypothesis. We also found that coronaviruses receptors could be elevated in the presence of both invasive bacteria and their counterpart, probiotics. We demonstrated here that enterocytes act as a conserved cell reservoir for coronaviruses during their evolutions, which should not be ignored in the investigation of coronavirus diagnosis and treatment strategies.

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Section: The Potential Target Cells Of Coronaviruses Are Conserved Inmentioning

confidence: 83%

The Small Intestine, an Underestimated Site of SARS-CoV-2 Infection: From Red Queen Effect to Probiotics

Zhan¹,

Wang²,

Wu³

2020

Preprint

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“…This study also identified a gene signature that associates with anti-TNF and anti-integrin therapy response 123 . In CD, a recent study investigating cellular subsets in ileal CD identified a unique cellular module in inflamed tissue that includes IgG plasma cells, mononuclear phagocytes, activated T cells and stromal cells (GIMATS module) 125 . The presence of this module in patients at diagnosis was associated with a failure to achieve durable corticosteroid remission with anti-TNF therapy 125 .…”

Section: Personalising Therapies In Inflammatory Bowel Diseasementioning

confidence: 99%

Precision medicine in inflammatory bowel disease: concept, progress and challenges

et al. 2020

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Crohn’s disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from “reactive” management driven by disease complications to “proactive” care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.

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“…Next, we analyzed data set from a publicly available single-cell RNA-sequencing experiment 23 of inflamed and uninflamed ileal tissue (biopsies) obtained from CD patients. Unsupervised clustering analysis identified 22 cluster blocks ( Fig.…”

Section: Elevated Sp140 Expression In Inflammatory Diseases and Mucosmentioning

confidence: 99%

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

Ghiboub

Köster

Craggs

et al. 2020

Preprint

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SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD68+ CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation. SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-bound genes. GSK761 inhibited the spontaneous expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal-mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

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Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Cited by 106 publications

References 97 publications

The Small Intestine, an Underestimated Site of SARS-CoV-2 Infection: From Red Queen Effect to Probiotics

The Small Intestine, an Underestimated Site of SARS-CoV-2 Infection: From Red Queen Effect to Probiotics

Precision medicine in inflammatory bowel disease: concept, progress and challenges

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

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