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102. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies

Author

Ouahed, Jodie, Spencer, Elizabeth, Kotlarz, Daniel, Shouval, Dror S, Kowalik, Matthew, Peng, Kaiyue, Field, Michael, Grushkin-Lerner, Leslie, Pai, Sung-Yun, Bousvaros, Athos, Cho, Judy, Argmann, Carmen, Schadt, Eric, Mcgovern, Dermot P B, Mokry, Michal, Nieuwenhuis, Edward, Clevers, Hans, Powrie, Fiona, Uhlig, Holm, Klein, Christoph, Muise, Aleixo, Dubinsky, Marla, Snapper, Scott B, Ouahed, Jodie, Spencer, Elizabeth, Kotlarz, Daniel, Shouval, Dror S, Kowalik, Matthew, Peng, Kaiyue, Field, Michael, Grushkin-Lerner, Leslie, Pai, Sung-Yun, Bousvaros, Athos, Cho, Judy, Argmann, Carmen, Schadt, Eric, Mcgovern, Dermot P B, Mokry, Michal, Nieuwenhuis, Edward, Clevers, Hans, Powrie, Fiona, Uhlig, Holm, Klein, Christoph, Muise, Aleixo, Dubinsky, Marla, and Snapper, Scott B

Abstract

Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

Published
2019

103. Correction: Defining the microbial transcriptional response to colitis through integrated host and microbiome profiling

Author

Ilott, Nicholas E., Bollrath, Julia, Danne, Camille, Schiering, Chris, Shale, Matthew, Adelmann, Krista, Krausgruber, Thomas, Heger, Andreas, Sims, David, Powrie, Fiona, Ilott, Nicholas E., Bollrath, Julia, Danne, Camille, Schiering, Chris, Shale, Matthew, Adelmann, Krista, Krausgruber, Thomas, Heger, Andreas, Sims, David, and Powrie, Fiona

Abstract

Correction to: The ISME Journal https://doi.org/10.1038/ismej.2016.40 Since publication of the original paper the authors realised the following funding body was missing from the article’s Acknowledgements: "FP and this work was also supported by the European Research Council (ERC, Advanced Grant Ares(2013)3687660)". The authors apologise for any inconvenience caused.

Published
2019

105. Malnutrition promotes rogue bacteria: dietary lack of a single amino acid impairs intestinal immunity in mice, altering the gut's microbial community and leaving it vulnerable to damage. The finding helps to explain how malnutrition favours gut inflammation

Author

Izcue, Ana and Powrie, Fiona

Subjects
Inflammation -- Physiological aspects -- Development and progression, Malnutrition -- Physiological aspects -- Development and progression, Microbial colonies -- Physiological aspects -- Health aspects, Amino acids -- Physiological aspects -- Health aspects, Disease susceptibility -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Malnutrition enhances the susceptibility to and the severity of gastrointestinal infections and diarrhoeal diseases (1). Although this effect has been observed for decades, the underlying mechanisms linking diet and immunodeficiency [...]

Published
2012

108. Cytokine regulation of T-cell function: potential for therapeutic intervention

Author

Powrie, Fiona and Coffman, Robert L.

Subjects
CD4 lymphocytes -- Health aspects, Immune response -- Regulation, Cytokines -- Health aspects, Biological sciences, Chemistry, Pharmaceuticals and cosmetics industries
Abstract

CD4+ T cells, via the cytokines that they produce, play a pivotal role in the induction and regulation of cell-mediated and humoral immunity. Recently it has become clear that the CD4+ T-cell population is heterogeneous and that distinct CD4+ T-cell subsets, defined by their cytokine repertoire, regulate cell-mediated and humoral immune responses. Protective responses to pathogens are dependent on activation of the appropriate T(sub H) subset accompanied by its characteristic set of immune effector functions. Evidence to date suggests that the cytokines produced by the T(sub H) cells themselves are important regulators of T(sub H) subset activation and differentiation. Fiona Powrie and Robert Coffman discuss how manipulation of the levels of these cytokines can be used to alter the balance of T(sub H)-cell subsets and illustrate some clinical situations where this may be beneficial.

Published
1993

112. Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.

Author

Aschenbrenner, Dominik, Quaranta, Maria, Banerjee, Soumya, Ilott, Nicholas, Jansen, Joanneke, Steere, Boyd, Yin-Huai Chen, Stephen Ho, Cox, Karen, Arancibia-Cárcamo, Carolina V., Coles, Mark, Gaffney, Eamonn, Travis, Simon PL, Denson, Lee, Kugathasan, Subra, Schmitz, Jochen, Powrie, Fiona, Sansom, Stephen N., and Uhlig, Holm H.

Subjects
INFLAMMATORY bowel diseases, INTESTINAL diseases, MONONUCLEAR leukocytes, INFLAMMATION, MACROPHAGES
Published
2021
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116. TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions

Author

Leng, Tianqi, Akther, Hossain Delowar, Hackstein, Carl-Philipp, King, Thomas, Friedrich, Matthias, Christoforidou, Zoe, McCuaig, Sarah, Neyazi, Mastura, Arancibia-Cárcamo, Carolina V., Powrie, Fiona, Marchi, Emanuele, Peres, Raphael Sanches, Millar, Val, Ebner, Danie, Willberg, Chris, and Klenerman, Paul

Subjects
0303 health sciences, education.field_of_study, Effector, medicine.medical_treatment, T cell, Population, T-cell receptor, Biology, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Cytokine, medicine.anatomical_structure, In vivo, Gene expression, medicine, education, Tissue homeostasis, 030304 developmental biology, 030215 immunology
Abstract

SUMMARYMAIT cells are an abundant T-cell population enriched in peripheral tissues such as the liver. They are activated both through TCR-dependent and - independent mechanisms. However, the different specific functional responses of MAIT cells to these distinct signals remain elusive. We examined the impact of combinations of TCR-dependent and -independent signals in blood and tissue-derived human MAIT cells. TCR-independent activation of MAIT cells from blood and gut was maximised by extending the panel of cytokines to including TNF-superfamily member TL1A. RNAseq experiments revealed that TCR-dependent and -independent signals drive MAIT cells to exert overlapping and unique effector functions, impacting both host defence and tissue homeostasis. While TCR-triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells did show specific enrichment of tissue-repair functions at the level of gene expression, protein production and in in vitro assays and these functions were amplified by cytokine costimulation. Taken together, these data indicate the blend of TCR-dependent and -independent signalling to MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.

Published
2018
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117. Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I–driven CD8+ T cell response

Author

Stockenhuber, Krista, Hegazy, Ahmed N., West, Nathaniel R., Ilott, Nicholas E., Stockenhuber, Alexander, Bullers, Samuel J., Thornton, Emily E., Arnold, Isabelle C., Tucci, Andrea, Waldmann, Herman, Ogg, Graham S., and Powrie, Fiona

Subjects
Inflammation, Phagocytes, integumentary system, Brief Definitive Report, Forkhead Transcription Factors, CD8-Positive T-Lymphocytes, Severity of Illness Index, T-Lymphocytes, Regulatory, Mice, Inbred C57BL, Interferon Type I, Animals, Psoriasis, Research Articles, Skin
Abstract

Stockenhuber et al. demonstrate that Foxp3+ regulatory T cells control psoriasiform skin inflammation by restraining a type I interferon (IFN-I)–driven CD8+ T cell response. The absence of T reg cells led to exacerbated inflammation, infiltration of CD8+ T cells to the epidermis, and an IFN-I gene signature in the tissue., Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell–depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP–IFN-I–driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease., Graphical Abstract

Published
2018

119. TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions

Author

Leng, Tianqi, primary, Akther, Hossain Delowar, additional, Hackstein, Carl-Philipp, additional, Powell, Kate, additional, King, Thomas, additional, Friedrich, Matthias, additional, Christoforidou, Zoe, additional, McCuaig, Sarah, additional, Neyazi, Mastura, additional, Arancibia-Cárcamo, Carolina V., additional, Hagel, Joachim, additional, Powrie, Fiona, additional, Peres, Raphael Sanches, additional, Millar, Val, additional, Ebner, Daniel, additional, Lamichhane, Rajesh, additional, Ussher, James, additional, Hinks, Timothy S.C., additional, Marchi, Emanuele, additional, Willberg, Chris, additional, and Klenerman, Paul, additional

Published
2019
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123. The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages

Author

Schulthess, Julie, primary, Pandey, Sumeet, additional, Capitani, Melania, additional, Rue-Albrecht, Kevin C., additional, Arnold, Isabelle, additional, Franchini, Fanny, additional, Chomka, Agnieszka, additional, Ilott, Nicholas E., additional, Johnston, Daniel G.W., additional, Pires, Elisabete, additional, McCullagh, James, additional, Sansom, Stephen N., additional, Arancibia-Cárcamo, Carolina V., additional, Uhlig, Holm H., additional, and Powrie, Fiona, additional

Published
2019
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124. Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation

Author

Miragaia, Ricardo J., primary, Gomes, Tomás, additional, Chomka, Agnieszka, additional, Jardine, Laura, additional, Riedel, Angela, additional, Hegazy, Ahmed N., additional, Whibley, Natasha, additional, Tucci, Andrea, additional, Chen, Xi, additional, Lindeman, Ida, additional, Emerton, Guy, additional, Krausgruber, Thomas, additional, Shields, Jacqueline, additional, Haniffa, Muzlifah, additional, Powrie, Fiona, additional, and Teichmann, Sarah A., additional

Published
2019
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127. Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation

Author

Hegazy, Ahmed N, West, Nathaniel R, Stubbington, Michael JT, Wendt, Emily, Suijker, Kim IM, Datsi, Angeliki, This, Sebastien, Danne, Camille, Campion, Suzanne, Duncan, Sylvia H, Owens, Benjamin MJ, Uhlig, Holm H, McMichael, Andrew, Oxford IBD Cohort Investigators, Bergthaler, Andreas, Teichmann, Sarah A, Keshav, Satish, Powrie, Fiona, Teichmann, Sarah [0000-0002-6294-6366], and Apollo - University of Cambridge Repository

Subjects
CD4-Positive T-Lymphocytes, Bacteria, Microbiota, Receptors, Antigen, T-Cell, alpha-beta, Interleukin-17, CD4 Lymphocyte Count, Cell Line, Gastrointestinal Microbiome, Immune Regulation, Tissue-resident Memory T cells, Intestines, Phenotype, Crohn Disease, Case-Control Studies, Host-Pathogen Interactions, Cytokines, Humans, Th17 Cells, Colitis, Ulcerative, Immunity, Mucosal, Immunologic Memory
Abstract

BACKGROUND & AIMS: Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4+ T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. METHODS: We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4+ T cells. We sequenced T-cell receptor Vβ genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4+ T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. RESULTS: Circulating and gut-resident CD4+ T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4+ T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vβ repertoire. These cells were functionally heterogeneous, produced barrier-protective cytokines, and stimulated intestinal stromal and epithelial cells via interleukin 17A, interferon gamma, and tumor necrosis factor. In patients with inflammatory bowel diseases, microbiota-reactive CD4+ T cells were reduced in the blood compared with intestine; T-cell responses that we detected had an increased frequency of interleukin 17A production compared with responses of T cells from blood or intestinal tissues of controls. CONCLUSIONS: In an analysis of peripheral blood mononuclear cells and intestinal tissues from patients with inflammatory bowel diseases vs controls, we found that reactivity to intestinal bacteria is a normal property of the human CD4+ T-cell repertoire, and does not necessarily indicate disrupted interactions between immune cells and the commensal microbiota. T-cell responses to commensals might support intestinal homeostasis, by producing barrier-protective cytokines and providing a large pool of T cells that react to pathogens.

Published
2017

128. IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation.

Author

Corbin, Alastair L., Gomez-Vazquez, Maria, Berthold, Dorothée L., Attar, Moustafa, Arnold, Isabelle C., Powrie, Fiona M., Sansom, Stephen N., and Udalova, Irina A.

Abstract

Targeting overzealous macrophages: Intestinal homeostasis relies on maintenance of a complex set of interactions between intestinal microbiota and the intestinal immune system. Pathogens that colonize the gut invariably disrupt these interactions and promote intestinal inflammation. Here, Corbin et al. have used a mouse pathobiont, Helicobacter hepaticus, that causes inflammation akin to human inflammatory bowel disease (IBD) to study the role of intestinal macrophages in driving inflammation. Using this model, they found the transcription factor IRF5 to be a critical regulator of macrophage inflammatory potential and that deletion of IRF5 rendered mice resistant to H. hepaticus–driven intestinal inflammation. Their studies propose IRF5 and molecules upstream of IRF5 to be potential drug targets in the treatment of human IBD. Mononuclear phagocytes (MNPs) are vital for maintaining intestinal homeostasis but, in response to acute microbial stimulation, can also trigger immunopathology, accelerating recruitment of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon regulatory factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here, we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state but ameliorates immunopathology during Helicobacter hepaticus–induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single-cell RNA-sequencing approaches, we examined the intrinsic role of IRF5 in controlling colonic MNP development. We demonstrate that IRF5 promotes differentiation of Ly6Chi monocytes into CD11c+ macrophages and controls the production of antimicrobial and inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional regulator of the colonic MNP system during intestinal inflammation. [ABSTRACT FROM AUTHOR]

Published
2020
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131. Innate Lymphoid Cells: 10 Years On

Author

Vivier, Eric, primary, Artis, David, additional, Colonna, Marco, additional, Diefenbach, Andreas, additional, Di Santo, James P., additional, Eberl, Gérard, additional, Koyasu, Shigeo, additional, Locksley, Richard M., additional, McKenzie, Andrew N.J., additional, Mebius, Reina E., additional, Powrie, Fiona, additional, and Spits, Hergen, additional

Published
2018
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136. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease

Author

Schwerd, Tobias, Pandey, Sumeet, Yang, Huei-Ting, Bagola, Katrin, Jameson, Elisabeth, Jung, Jonathan, Lachmann, Robin H, Shah, Neil, Patel, Smita Y, Booth, Claire, Runz, Heiko, Düker, Gesche, Bettels, Ruth, Rohrbach, Marianne, Kugathasan, Subra, Chapel, Helen, Keshav, Satish, Elkadri, Abdul, Platt, Nick, Muise, Alexio M, Koletzko, Sibylle, Xavier, Ramnik J, Marquardt, Thorsten, Powrie, Fiona, Wraith, James E, Gyrd-Hansen, Mads, Platt, Frances M, Uhlig, Holm H, Schwerd, Tobias, Pandey, Sumeet, Yang, Huei-Ting, Bagola, Katrin, Jameson, Elisabeth, Jung, Jonathan, Lachmann, Robin H, Shah, Neil, Patel, Smita Y, Booth, Claire, Runz, Heiko, Düker, Gesche, Bettels, Ruth, Rohrbach, Marianne, Kugathasan, Subra, Chapel, Helen, Keshav, Satish, Elkadri, Abdul, Platt, Nick, Muise, Alexio M, Koletzko, Sibylle, Xavier, Ramnik J, Marquardt, Thorsten, Powrie, Fiona, Wraith, James E, Gyrd-Hansen, Mads, Platt, Frances M, and Uhlig, Holm H

Abstract

OBJECTIVE: Patients with Niemann-Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1. DESIGN: We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP). RESULTS: Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1. CONCLUSIONS: NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.

Published
2017

137. Defining the microbial transcriptional response to colitis through integrated host and microbiome profiling

Author

Ilott, Nicholas Edward, Bollrath, Julia, Danne, Camille, Schiering, Chris, Shale, Matthew, Adelmann, Krista, Krausgruber, Thomas, Heger, Andreas, Sims, David, and Powrie, Fiona

Subjects
05 Environmental Sciences, Environmental Sciences & Ecology, SUSCEPTIBILITY, Microbiology, GUT MICROBIOME, Mice, MICROARRAY, Bacterial Proteins, 10 Technology, Animals, Humans, ddc:610, OXIDATIVE STRESS, Science & Technology, Ecology, Bacteria, Gene Expression Profiling, Correction, CELL-DEPENDENT COLITIS, 06 Biological Sciences, Colitis, CROHNS-DISEASE, Gastrointestinal Microbiome, Mice, Inbred C57BL, ULCERATIVE-COLITIS, ESCHERICHIA-COLI, DNA-BINDING PROTEIN, Original Article, Female, Metagenomics, Life Sciences & Biomedicine, INFLAMMATORY-BOWEL-DISEASE
Abstract

The gut microbiome is significantly altered in inflammatory bowel diseases, but the basis of these changes is not well understood. We have combined metagenomic and metatranscriptomic profiling of the gut microbiome to assess modifications to both bacterial community structure and transcriptional activity in a mouse model of colitis. By using transcriptomic analysis of colonic tissue and luminal RNA derived from the host, we have also characterised how host transcription relates to the microbial transcriptional response in inflammation. In colitis, increased abundance and transcription of diverse microbial gene families involved in responses to nutrient deprivation, antimicrobial peptide production and oxidative stress support an adaptation of multiple commensal genera to withstand a diverse set of environmental stressors in the inflammatory environment. These data are supported by a transcriptional signature of activated macrophages and granulocytes in the gut lumen during colitis, a signature that includes the transcription of the key antimicrobial genes S100a8 and S100a9 (calprotectin). Genes involved in microbial resistance to oxidative stress, including Dps/ferritin, Fe-dependent peroxidase and glutathione S-transferase were identified as changing to a greater extent at the level of transcription than would be predicted by DNA abundance changes, implicating a role for increased oxygen tension and/or host-derived reactive oxygen species in driving transcriptional changes in commensal microbes.

Published
2016

138. Erratum: Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease

Author

West, Nathaniel R, Hegazy, Ahmed N, Owens, Benjamin M J, Bullers, Samuel J, Linggi, Bryan, Buonocore, Sofia, Coccia, Margherita, Görtz, Dieter, This, Sébastien, Stockenhuber, Krista, Pott, Johanna, Friedrich, Matthias, Ryzhakov, Grigory, Baribaud, Frédéric, Brodmerkel, Carrie, Cieluch, Constanze, Rahman, Nahid, Müller-Newen, Gerhard, Owens, Raymond J, Kühl, Anja A, Maloy, Kevin J, Plevy, Scott E, Keshav, Satish, Travis, Simon P L, and Powrie, Fiona

Subjects
Biological sciences, Health
Abstract

Author(s): Nathaniel R West; Ahmed N Hegazy; Benjamin M J Owens; Samuel J Bullers; Bryan Linggi; Sofia Buonocore; Margherita Coccia; Dieter Görtz; Sébastien This; Krista Stockenhuber; Johanna Pott; Matthias Friedrich; [...]

Published
2017
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139. Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation

Author

Miragaia, Ricardo J, primary, Gomes, Tomás, additional, Chomka, Agnieszka, additional, Jardine, Laura, additional, Riedel, Angela, additional, Hegazy, Ahmed N., additional, Lindeman, Ida, additional, Emerton, Guy, additional, Krausgruber, Thomas, additional, Shields, Jacqueline, additional, Haniffa, Muzlifah, additional, Powrie, Fiona, additional, and Teichmann, Sarah A., additional

Published
2017
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140. Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation

Author

Hegazy, Ahmed N., primary, West, Nathaniel R., additional, Stubbington, Michael J.T., additional, Wendt, Emily, additional, Suijker, Kim I.M., additional, Datsi, Angeliki, additional, This, Sebastien, additional, Danne, Camille, additional, Campion, Suzanne, additional, Duncan, Sylvia H., additional, Owens, Benjamin M.J., additional, Uhlig, Holm H., additional, McMichael, Andrew, additional, Bergthaler, Andreas, additional, Teichmann, Sarah A., additional, Keshav, Satish, additional, and Powrie, Fiona, additional

Published
2017
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142. Defining the microbial transcriptional response to colitis through integrated host and microbiome profiling

Author

Ilott, Nicholas E., Bollrath, Julia, Danne, Camille, Schiering, Chris, Shale, Matthew, Adelmann, Krista, Krausgruber, Thomas, Heger, Andreas, Sims, David, Powrie, Fiona, Ilott, Nicholas E., Bollrath, Julia, Danne, Camille, Schiering, Chris, Shale, Matthew, Adelmann, Krista, Krausgruber, Thomas, Heger, Andreas, Sims, David, and Powrie, Fiona

Abstract

The gut microbiome is significantly altered in inflammatory bowel diseases, but the basis of these changes is not well understood. We have combined metagenomic and metatranscriptomic profiling of the gut microbiome to assess modifications to both bacterial community structure and transcriptional activity in a mouse model of colitis. By using transcriptomic analysis of colonic tissue and luminal RNA derived from the host, we have also characterised how host transcription relates to the microbial transcriptional response in inflammation. In colitis, increased abundance and transcription of diverse microbial gene families involved in responses to nutrient deprivation, antimicrobial peptide production and oxidative stress support an adaptation of multiple commensal genera to withstand a diverse set of environmental stressors in the inflammatory environment. These data are supported by a transcriptional signature of activated macrophages and granulocytes in the gut lumen during colitis, a signature that includes the transcription of the key antimicrobial genes S100a8 and S100a9 (calprotectin). Genes involved in microbial resistance to oxidative stress, including Dps/ferritin, Fe-dependent peroxidase and glutathione S-transferase were identified as changing to a greater extent at the level of transcription than would be predicted by DNA abundance changes, implicating a role for increased oxygen tension and/or host-derived reactive oxygen species in driving transcriptional changes in commensal microbes.

Published
2016

146. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann–Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease

Author

Schwerd, Tobias, primary, Pandey, Sumeet, additional, Yang, Huei-Ting, additional, Bagola, Katrin, additional, Jameson, Elisabeth, additional, Jung, Jonathan, additional, Lachmann, Robin H, additional, Shah, Neil, additional, Patel, Smita Y, additional, Booth, Claire, additional, Runz, Heiko, additional, Düker, Gesche, additional, Bettels, Ruth, additional, Rohrbach, Marianne, additional, Kugathasan, Subra, additional, Chapel, Helen, additional, Keshav, Satish, additional, Elkadri, Abdul, additional, Platt, Nick, additional, Muise, Alexio M, additional, Koletzko, Sibylle, additional, Xavier, Ramnik J, additional, Marquardt, Thorsten, additional, Powrie, Fiona, additional, Wraith, James E, additional, Gyrd-Hansen, Mads, additional, Platt, Frances M, additional, and Uhlig, Holm H, additional

Published
2016
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148. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, Wright, Ben, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, McVean, Gilean, Taylor, Jenny C., Martin, Hilary C., Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A. Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J., Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R., Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E., Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L., Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D., Goriely, Anne, Green, Angie, Greger, Ingo H., Grocock, Russell, Gruszczyk, Anja V., Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C., Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J., McMullin, Mary Frances, Miller, Kerry A., Murray, Lisa, Németh, Andrea H., Nesbit, M. Andrew, Nutt, David, Ormondroyd, Elizabeth, Bang Oturai, Annette, Pagnamenta, Alistair, Patel, Smita Y., Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E., Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A., Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, Van Schouwenburg, Pauline A., Schuh, Anna, Silverman, Earl, Simmons, Alison, Sorensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V., Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R. F., Uhlig, Holm H., Vyas, Paresh, Vyse, Tim, Wall, Steven A., Watkins, Hugh, Whyte, Michael P., Witty, Lorna, and Wright, Ben

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

149. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

Author

Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, McVean, Gilean, Taylor, Jenny C, Martin, Hilary C, Lise, Stefano, Broxholme, John, Cazier, Jean-Baptiste, Rimmer, Andy, Kanapin, Alexander, Lunter, Gerton, Fiddy, Simon, Allan, Chris, Aricescu, A Radu, Attar, Moustafa, Babbs, Christian, Becq, Jennifer, Beeson, David, Bento, Celeste, Bignell, Patricia, Blair, Edward, Buckle, Veronica J, Bull, Katherine, Cais, Ondrej, Cario, Holger, Chapel, Helen, Copley, Richard R, Cornall, Richard, Craft, Jude, Dahan, Karin, Davenport, Emma E, Dendrou, Calliope, Devuyst, Olivier, Fenwick, Aimée L, Flint, Jonathan, Fugger, Lars, Gilbert, Rodney D, Goriely, Anne, Green, Angie, Greger, Ingo H, Grocock, Russell, Gruszczyk, Anja V, Hastings, Robert, Hatton, Edouard, Higgs, Doug, Hill, Adrian, Holmes, Chris, Howard, Malcolm, Hughes, Linda, Humburg, Peter, Johnson, David, Karpe, Fredrik, Kingsbury, Zoya, Kini, Usha, Knight, Julian C, Krohn, Jonathan, Lamble, Sarah, Langman, Craig, Lonie, Lorne, Luck, Joshua, McCarthy, Davis, McGowan, Simon J, McMullin, Mary Frances, Miller, Kerry A, Murray, Lisa, Németh, Andrea H, Nesbit, M Andrew, Nutt, David, Ormondroyd, Elizabeth, Oturai, Annette Bang, Pagnamenta, Alistair, Patel, Smita Y, Percy, Melanie, Petousi, Nayia, Piazza, Paolo, Piret, Sian E, Polanco-Echeverry, Guadalupe, Popitsch, Niko, Powrie, Fiona, Pugh, Chris, Quek, Lynn, Robbins, Peter A, Robson, Kathryn, Russo, Alexandra, Sahgal, Natasha, van Schouwenburg, Pauline A, Schuh, Anna, Silverman, Earl, Simmons, Alison, Sørensen, Per Soelberg, Sweeney, Elizabeth, Taylor, John, Thakker, Rajesh V, Tomlinson, Ian, Trebes, Amy, Twigg, Stephen R F, Uhlig, Holm H, Vyas, Paresh, Vyse, Tim, Wall, Steven A, Watkins, Hugh, Whyte, Michael P, Witty, Lorna, Wright, Ben, Yau, Chris, Buck, David, Humphray, Sean, Ratcliffe, Peter J, Bell, John I, Wilkie, Andrew O M, Bentley, David, Donnelly, Peter, and McVean, Gilean

Abstract

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Published
2015

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