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1. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.

Author

Thomas, Tom, Friedrich, Matthias, Rich-Griffin, Charlotte, Pohin, Mathilde, Agarwal, Devika, Pakpoor, Julia, Lee, Carl, Tandon, Ruchi, Rendek, Aniko, Aschenbrenner, Dominik, Jainarayanan, Ashwin, Voda, Alexandru, Siu, Jacqueline, Sanches-Peres, Raphael, Nee, Eloise, Sathananthan, Dharshan, Kotliar, Dylan, Todd, Peter, Kiourlappou, Maria, Gartner, Lisa, Ilott, Nicholas, Issa, Fadi, Hester, Joanna, Turner, Jason, Nayar, Saba, Mackerodt, Jonas, Zhang, Fan, Jonsson, Anna, Brenner, Michael, Raychaudhuri, Soumya, Kulicke, Ruth, Ramsdell, Danielle, Stransky, Nicolas, Pagliarini, Ray, Bielecki, Piotr, Spies, Noah, Marsden, Brian, Taylor, Stephen, Wagner, Allon, Klenerman, Paul, Walsh, Alissa, Coles, Mark, Jostins-Dean, Luke, Powrie, Fiona, Filer, Andrew, Travis, Simon, Uhlig, Holm, Dendrou, Calliope, and Buckley, Christopher

Subjects
Humans, Single-Cell Analysis, Adalimumab, Inflammatory Bowel Diseases, Crohn Disease, Longitudinal Studies, Colitis, Ulcerative, Tumor Necrosis Factor-alpha, Transcriptome, Female, Adult, Male, Interferons, Signal Transduction, Arthritis, Rheumatoid
Abstract

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas represents the largest cellular census of perturbation with the most common biologic treatment, anti-TNF, across multiple inflammatory diseases.

Published
2024

2. Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue

Author

Bell, Richard D., Brendel, Matthew, Konnaris, Maxwell A., Xiang, Justin, Otero, Miguel, Fontana, Mark A., Bai, Zilong, Krenitsky, Daria M., Meednu, Nida, Rangel-Moreno, Javier, Scheel-Toellner, Dagmar, Carr, Hayley, Nayar, Saba, McMurray, Jack, DiCarlo, Edward, Anolik, Jennifer H., Donlin, Laura T., Orange, Dana E., Kenney, H. Mark, Schwarz, Edward M., Filer, Andrew, Ivashkiv, Lionel B., and Wang, Fei

Published
2024
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3. Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Author

Dunlap, Garrett, Wagner, Aaron, Meednu, Nida, Wang, Ruoqiao, Zhang, Fan, Ekabe, Jabea Cyril, Jonsson, Anna Helena, Wei, Kevin, Sakaue, Saori, Nathan, Aparna, Bykerk, Vivian P., Donlin, Laura T., Goodman, Susan M., Firestein, Gary S., Boyle, David L., Holers, V. Michael, Moreland, Larry W., Tabechian, Darren, Pitzalis, Costantino, Filer, Andrew, Raychaudhuri, Soumya, Brenner, Michael B., Thakar, Juilee, McDavid, Andrew, Rao, Deepak A., and Anolik, Jennifer H.

Published
2024
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4. Predictors of quality of life, functional status, depression and fatigue in early arthritis: comparison between clinically suspect arthralgia, unclassified arthritis and rheumatoid arthritis

Author

Torlinska, Barbara, Raza, Karim, Filer, Andrew, Jutley, Gurpreet, Sahbudin, Ilfita, Singh, Ruchir, de Pablo, Paola, Rankin, Elizabeth, Rhodes, Benjamin, Amft, Nicole, Justice, Elizabeth, McGrath, Catherine, Baskar, Sangeetha, Trickey, Jeanette, Calvert, Melanie, and Falahee, Marie

Published
2024
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5. Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Author

Zhang, Fan, Jonsson, Anna, Nathan, Aparna, Millard, Nghia, Curtis, Michelle, Xiao, Qian, Gutierrez-Arcelus, Maria, Apruzzese, William, Watts, Gerald, Weisenfeld, Dana, Nayar, Saba, Rangel-Moreno, Javier, Meednu, Nida, Marks, Kathryne, Mantel, Ian, Kang, Joyce, Rumker, Laurie, Mears, Joseph, Slowikowski, Kamil, Weinand, Kathryn, Orange, Dana, Geraldino-Pardilla, Laura, Deane, Kevin, Tabechian, Darren, Ceponis, Arnoldas, Firestein, Gary, Maybury, Mark, Sahbudin, Ilfita, Ben-Artzi, Ami, Mandelin, Arthur, Nerviani, Alessandra, Lewis, Myles, Rivellese, Felice, Pitzalis, Costantino, Hughes, Laura, Horowitz, Diane, DiCarlo, Edward, Gravallese, Ellen, Boyce, Brendan, Moreland, Larry, Goodman, Susan, Perlman, Harris, Holers, V, Liao, Katherine, Filer, Andrew, Bykerk, Vivian, Wei, Kevin, Rao, Deepak, Donlin, Laura, Anolik, Jennifer, Brenner, Michael, and Raychaudhuri, Soumya

Subjects
Humans, Arthritis, Rheumatoid, Cytokines, Inflammation, Synovial Membrane, T-Lymphocytes, B-Lymphocytes, Genetic Predisposition to Disease, Phenotype, Single-Cell Gene Expression Analysis
Abstract

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

Published
2023

6. High incidence of proliferative and membranous nephritis in SLE patients with low proteinuria in the Accelerating Medicines Partnership.

Author

Carlucci, Philip M, Li, Jessica, Fava, Andrea, Deonaraine, Kristina K, Wofsy, David, James, Judith A, Putterman, Chaim, Diamond, Betty, Davidson, Anne, Fine, Derek M, Monroy-Trujillo, Jose, Atta, Mohamed G, DeJager, Wade, Guthridge, Joel M, Haag, Kristin, Rao, Deepak A, Brenner, Michael B, Lederer, James A, Apruzzese, William, Belmont, H Michael, Izmirly, Peter M, Zaminski, Devyn, Wu, Ming, Connery, Sean, Payan-Schober, Fernanda, Furie, Richard, Dall’Era, Maria, Cho, Kerry, Kamen, Diane, Kalunian, Kenneth, Anolik, Jennifer, Barnas, Jennifer, Ishimori, Mariko, Weisman, Michael H, Goff, Jennifer, Dunn, Patrick J, Raychaudhuri, Soumya, Zhang, Fan, Korsunsky, Ilya, Nathan, Aparna, Mears, Joseph, Ishigaki, Kazuyoshi, Xiao, Qian, Millard, Nghia, Weinand, Kathryn, Sakaue, Saori, Utz, PJ, Mao, Rong, Robinson, Bill, Maecker, Holden, Macwana, Susan, Bridges, S Louis, Bykerk, Vivian, Donlin, Laura, Goodman, Susan, DiCarlo, Edward, Smith, Melanie, Lakhanpal, Amit, Sherman, Heather, Singaraju, Anvita, Shakib, Lorien, Ritchlin, Christopher, Boyce, Brendan, Tabechian, Darren, McDavid, Andrew, Rangel-Moreno, Javier, Meednu, Nida, Albrecht, Jen, Wei, Kevin, Helena Jonsson, A, Simmons, Daimon, Keras, Gregory, Keegan, Joshua, Watts, Gerald, Li Zhu, Yuhong, Chicoine, Adam, Jian Li, Zhihan, Gravallese, Ellen M, Howard, Kaitlyn, McGeachy, Mandy, Firestein, Gary S, Boyle, David L, Ceponis, Arnold, Gregersen, Peter K, Horowitz, Diane, Perlman, Harris, Dominguez, Salina, Cuda, Carla M, Mandolin, Arthur M, Thakrar, Anjali, Bathon, Joan M, Hughes, Laura, Michael Holers, V, Seifert, Jennifer, Deane, Kevin, Moreland, Larry W, Filer, Andrew, Raza, Karim, Sahbudin, Ilfita, and Pitzalis, Costantino

Subjects
Clinical Research, Kidney Disease, Lupus, Autoimmune Disease, Humans, Lupus Nephritis, Prospective Studies, Incidence, Proteinuria, Kidney Function Tests, Kidney, systemic lupus erythematosus, lupus nephritis, diagnosis, Accelerating Medicines Partnership (AMP) RA/SLE Network, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectiveDelayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1.MethodsA total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year.ResultsAt biopsy, 54 patients had UPCR

Published
2022

8. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Author

Norton, Sam, Lempp, Heidi, Opena, Maria, Subesinghe, Sujith, Garrood, Toby, Menon, Bina, Ng, Nora, Douglas, Karen, Koutsianas, Christos, Cooles, Faye, Falahee, Marie, Echavez-Naguicnic, Irene, Bharadwaj, Anurag, Villaruel, Michael, Pande, Ira, Collins, David, Pegler, Suzannah, Raizada, Sabrina, Siebert, Stefan, Fragoulis, George, Guinto, Jesusa, Galloway, James, Rutherford, Andrew, Barnes, Theresa, Jeffrey, Helen, Patel, Yusuf, Batley, Michael, O'Reilly, Brendan, Venkatachalam, Srivinisan, Sheeran, Thomas, Gorman, Claire, Reynolds, Piero, Khan, Asad, Gullick, Nicola, Banerjee, Siwalik, Mankia, Kulveer, Jordan, Deepak, Rowlands, Jane, Starmans-Kool, Mirian, Taylor, James, Nandi, Pradip, Sahbudin, Ilfita, Maybury, Mark, Hider, Samantha, Barcroft, Ann, McNally, Jeremy, Kitchen, Jo, Nisar, Muhammad, Quick, Vanessa, Cope, Andrew P, Jasenecova, Marianna, Vasconcelos, Joana C, Filer, Andrew, Raza, Karim, Qureshi, Sumera, D'Agostino, Maria Antonietta, McInnes, Iain B, Isaacs, John D, Pratt, Arthur G, Fisher, Benjamin A, Buckley, Christopher D, Emery, Paul, Ho, Pauline, Buch, Maya H, Ciurtin, Coziana, van Schaardenburg, Dirkjan, Huizinga, Thomas, Toes, René, Georgiou, Evangelos, Kelly, Joanna, Murphy, Caroline, and Prevost, A Toby

Published
2024
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9. Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Author

Deonaraine, Kristina K, Carlucci, Philip M, Fava, Andrea, Li, Jessica, Wofsy, David, James, Judith A, Putterman, Chaim, Diamond, Betty, Davidson, Anne, Fine, Derek M, Monroy-Trujillo, Jose, Atta, Mohamed G, Haag, Kristin, Rao, Deepak A, Apruzzese, William, Belmont, H Michael, Izmirly, Peter M, Wu, Ming, Connery, Sean, Payan-Schober, Fernanda, Furie, Richard A, Berthier, Celine C, Dall'Era, Maria, Cho, Kerry, Kamen, Diane L, Kalunian, Kenneth, Anolik, Jennifer, Ishimori, Mariko, Weisman, Michael H, Petri, Michelle A, Buyon, Jill P, Goff, Jennifer, Dunn, Patrick, Raychaudhuri, Soumya, Zhang, Fan, Korsunsky, Ilya, Nathan, Aparna, Mears, Joseph, Ishigaki, Kazuyoshi, Xiao, Qian, Millard, Nghia, Weinand, Kathryn, Sakaue, Saori, Utz, PJ, Mao, Rong, Robinson, Bill, Maecker, Holden, Guthridge, Joel, DeJager, Wade, Macwana, Susan, Bridges, Louis, Bykerk, Vivian, Donlin, Laura, Goodman, Susan, DiCarlo, Edward, Smith, Melanie, Lakhanpal, Amit, Sherman, Heather, Singaraju, Anvita, Shakib, Lorien, Ritchlin, Christopher, Boyce, Brendan, Tabechian, Darren, McDavid, Andrew, Rangel-Moreno, Javier, Meednu, Nida, Albrecht, Jen, Brenner, Michael, Lederer, James, Wei, Kevin, Jonsson, A Helena, Simmons, Daimon, Keras, Gregory, Keegan, Joshua, Watts, Gerald, Li, Yuhong, Zhu, Zhu, Chicoine, Adam, Li, Zhihan Jian, McGeachy, Mandy, Firestein, Gary, Boyle, David, Ceponis, Arnold, Gregersen, Peter, Horowitz, Diane, Perlman, Harris, Dominguez, Salina, Cuda, Carla, Mandelin, Arthur, Thakrar, Anjali, Bathon, Joan, Hughes, Laura, Holers, Mike, Seifert, Jennifer, Deane, Kevin, Moreland, Larry, Filer, Andrew, Raza, Karim, Sahbudin, Ilfita, and Pitzalis, Constanino

Subjects
Autoimmune Disease, Patient Safety, Kidney Disease, Lupus, Clinical Research, Renal and urogenital, Arteriovenous Fistula, Biopsy, Hematoma, Humans, Kidney, Lupus Nephritis, United States, lupus nephritis, lupus erythematosus, systemic, autoimmunity, Accelerating Medicines Partnership RA/SLE network
Abstract

In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis. 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines. 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved. Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

Published
2021

10. Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Author

Zayat, Ahmed, Machado, Ana Rita, Cuervo, Andrea, Mahto, Arti, Cubuk, Cankut, Rawlings, Charlotte, Mosanya, Chijioke, Buckley, Chris, Holroyd, Chris, Maskall, Debbie, Carlucci, Francesco, Thorborn, Georgina, Tan, Gina, Lliso-Ribera, Gloria, Rizvi, Hasan, Peel, Joanna, Fonseca, João Eurico, Isaacs, John, Ramírez, Julio, Meric de Bellefon, Laurent, Fossati-Jimak, Liliane, Githinji, Mary, Congia, Mattia, Millar, Neal, Purkayastha, Nirupam, Celis, Raquel, Seth, Rakhi, Hands-Greenwood, Rebecca, Landewé, Robert, Perniola, Simone, Alivernini, Stefano, Marcia, Stefano, Marini, Stefano, Kelly, Stephen, Romão, Vasco, Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Warren, Louise, Jaworska, Edyta, Bombardieri, Michele, Lewis, Myles J, Humby, Frances, Pratt, Arthur G, Filer, Andrew, Gendi, Nagui, Cauli, Alberto, Choy, Ernest, McInnes, Iain, Durez, Patrick, Edwards, Christopher J, Buch, Maya H, Gremese, Elisa, Taylor, Peter C, Ng, Nora, Cañete, Juan D, Raizada, Sabrina, McKay, Neil D, Jadon, Deepak, Sainaghi, Pier Paolo, Stratton, Richard, Ehrenstein, Michael R, Ho, Pauline, Pereira, Joaquim P, Dasgupta, Bhaskar, Gorman, Claire, Galloway, James, Chinoy, Hector, van der Heijde, Désirée, Sasieni, Peter, Barton, Anne, and Pitzalis, Costantino

Published
2023
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11. Tissue-resident, extravascular Ly6c− monocytes are critical for inflammation in the synovium

Author

Montgomery, Anna B., Chen, Shang Yang, Wang, Yidan, Gadhvi, Gaurav, Mayr, Maximilian G., Cuda, Carla M., Dominguez, Salina, Moradeke Makinde, Hadijat-Kubura, Gurra, Miranda G., Misharin, Alexander V., Mandelin, Arthur M., Ruderman, Eric M., Thakrar, Anjali, Brar, Simran, Carns, Mary, Aren, Kathleen, Akbarpour, Mahzad, Filer, Andrew, Nayar, Saba, Teososio, Ana, Major, Triin, Bharat, Ankit, Budinger, G.R. Scott, Winter, Deborah R., and Perlman, Harris

Published
2023
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12. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry

Author

Zhang, Fan, Wei, Kevin, Slowikowski, Kamil, Fonseka, Chamith Y, Rao, Deepak A, Kelly, Stephen, Goodman, Susan M, Tabechian, Darren, Hughes, Laura B, Salomon-Escoto, Karen, Watts, Gerald FM, Jonsson, A Helena, Rangel-Moreno, Javier, Meednu, Nida, Rozo, Cristina, Apruzzese, William, Eisenhaure, Thomas M, Lieb, David J, Boyle, David L, Mandelin, Arthur M, Boyce, Brendan F, DiCarlo, Edward, Gravallese, Ellen M, Gregersen, Peter K, Moreland, Larry, Firestein, Gary S, Hacohen, Nir, Nusbaum, Chad, Lederer, James A, Perlman, Harris, Pitzalis, Costantino, Filer, Andrew, Holers, V Michael, Bykerk, Vivian P, Donlin, Laura T, Anolik, Jennifer H, Brenner, Michael B, and Raychaudhuri, Soumya

Subjects
Clinical Research, Autoimmune Disease, Arthritis, Human Genome, Rheumatoid Arthritis, Genetics, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Arthritis, Rheumatoid, Autoimmunity, Biomarkers, Computational Biology, Cross-Sectional Studies, Cytokines, Fibroblasts, Flow Cytometry, Gene Expression, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Histocompatibility Antigens Class II, Humans, Leukocytes, Monocytes, Signal Transduction, Single-Cell Analysis, Synovial Membrane, T-Lymphocyte Subsets, Transcriptome, Workflow, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Immunology
Abstract

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Published
2019

13. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

Author

Korsunsky, Ilya, Wei, Kevin, Pohin, Mathilde, Kim, Edy Y., Barone, Francesca, Major, Triin, Taylor, Emily, Ravindran, Rahul, Kemble, Samuel, Watts, Gerald F.M., Jonsson, A. Helena, Jeong, Yunju, Athar, Humra, Windell, Dylan, Kang, Joyce B., Friedrich, Matthias, Turner, Jason, Nayar, Saba, Fisher, Benjamin A., Raza, Karim, Marshall, Jennifer L., Croft, Adam P., Tamura, Tomoyoshi, Sholl, Lynette M., Vivero, Marina, Rosas, Ivan O., Bowman, Simon J., Coles, Mark, Frei, Andreas P., Lassen, Kara, Filer, Andrew, Powrie, Fiona, Buckley, Christopher D., Brenner, Michael B., and Raychaudhuri, Soumya

Published
2022
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14. Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue

Author

Donlin, Laura T, Rao, Deepak A, Wei, Kevin, Slowikowski, Kamil, McGeachy, Mandy J, Turner, Jason D, Meednu, Nida, Mizoguchi, Fumitaka, Gutierrez-Arcelus, Maria, Lieb, David J, Keegan, Joshua, Muskat, Kaylin, Hillman, Joshua, Rozo, Cristina, Ricker, Edd, Eisenhaure, Thomas M, Li, Shuqiang, Browne, Edward P, Chicoine, Adam, Sutherby, Danielle, Noma, Akiko, Accelerating Medicines Partnership RA/SLE Network, Nusbaum, Chad, Kelly, Stephen, Pernis, Alessandra B, Ivashkiv, Lionel B, Goodman, Susan M, Robinson, William H, Utz, Paul J, Lederer, James A, Gravallese, Ellen M, Boyce, Brendan F, Hacohen, Nir, Pitzalis, Costantino, Gregersen, Peter K, Firestein, Gary S, Raychaudhuri, Soumya, Moreland, Larry W, Holers, V Michael, Bykerk, Vivian P, Filer, Andrew, Boyle, David L, Brenner, Michael B, and Anolik, Jennifer H

Subjects
Accelerating Medicines Partnership RA/SLE Network, Synovial Membrane, Humans, Arthritis, Rheumatoid, Cryopreservation, Flow Cytometry, High-Throughput Screening Assays, Accelerating Medicines Partnership, Arthroplasty, CyTOF, Mass cytometry, RNA sequencing, Rheumatoid arthritis, Synovial biopsy, Synovial tissue, Arthritis, Autoimmune Disease, Biotechnology, Human Genome, Clinical Research, Genetics, Bioengineering, 2.1 Biological and endogenous factors, Inflammatory and immune system, Arthritis & Rheumatology, Clinical Sciences, Immunology, Public Health and Health Services
Abstract

BackgroundDetailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples.MethodsMultiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA-seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single-cell CEL-Seq2 RNA-seq.ResultsUpon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 μg/ml of Liberase™ TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4+ and CD8+ T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified.ConclusionsWe have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers.

Published
2018

16. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Author

Cope, Andrew P, Jasenecova, Marianna, Vasconcelos, Joana C, Filer, Andrew, Raza, Karim, Qureshi, Sumera, D'Agostino, Maria Antonietta, Mcinnes, Iain B, Isaacs, John D, Pratt, Arthur G, Fisher, Benjamin A, Buckley, Christopher D, Emery, Paul, Ho, Pauline, Buch, Maya H, Ciurtin, Coziana, van Schaardenburg, Dirkjan, Huizinga, Thoma, Toes, René, Georgiou, Evangelo, Kelly, Joanna, Murphy, Caroline, Prevost, A Toby, Norton, Sam, Lempp, Heidi, Opena, Maria, Subesinghe, Sujith, Garrood, Toby, Menon, Bina, Ng, Nora, Douglas, Karen, Koutsianas, Christo, Cooles, Faye, Falahee, Marie, Echavez-Naguicnic, Irene, Bharadwaj, Anurag, Villaruel, Michael, Pande, Ira, Collins, David, Pegler, Suzannah, Raizada, Sabrina, Siebert, Stefan, Fragoulis, George, Guinto, Jesusa, Galloway, Jame, Rutherford, Andrew, Barnes, Theresa, Jeffrey, Helen, Patel, Yusuf, Batley, Michael, O'Reilly, Brendan, Venkatachalam, Srivinisan, Sheeran, Thoma, Gorman, Claire, Reynolds, Piero, Khan, Asad, Gullick, Nicola, Banerjee, Siwalik, Mankia, Kulveer, Jordan, Deepak, Rowlands, Jane, Starmans-Kool, Mirian, Taylor, Jame, Nandi, Pradip, Sahbudin, Ilfita, Maybury, Mark, Hider, Samantha, Barcroft, Ann, Mcnally, Jeremy, Kitchen, Jo, Nisar, Muhammad, Quick, Vanessa, D'Agostino, Maria Antonietta (ORCID:0000-0002-5347-0060), Cope, Andrew P, Jasenecova, Marianna, Vasconcelos, Joana C, Filer, Andrew, Raza, Karim, Qureshi, Sumera, D'Agostino, Maria Antonietta, Mcinnes, Iain B, Isaacs, John D, Pratt, Arthur G, Fisher, Benjamin A, Buckley, Christopher D, Emery, Paul, Ho, Pauline, Buch, Maya H, Ciurtin, Coziana, van Schaardenburg, Dirkjan, Huizinga, Thoma, Toes, René, Georgiou, Evangelo, Kelly, Joanna, Murphy, Caroline, Prevost, A Toby, Norton, Sam, Lempp, Heidi, Opena, Maria, Subesinghe, Sujith, Garrood, Toby, Menon, Bina, Ng, Nora, Douglas, Karen, Koutsianas, Christo, Cooles, Faye, Falahee, Marie, Echavez-Naguicnic, Irene, Bharadwaj, Anurag, Villaruel, Michael, Pande, Ira, Collins, David, Pegler, Suzannah, Raizada, Sabrina, Siebert, Stefan, Fragoulis, George, Guinto, Jesusa, Galloway, Jame, Rutherford, Andrew, Barnes, Theresa, Jeffrey, Helen, Patel, Yusuf, Batley, Michael, O'Reilly, Brendan, Venkatachalam, Srivinisan, Sheeran, Thoma, Gorman, Claire, Reynolds, Piero, Khan, Asad, Gullick, Nicola, Banerjee, Siwalik, Mankia, Kulveer, Jordan, Deepak, Rowlands, Jane, Starmans-Kool, Mirian, Taylor, Jame, Nandi, Pradip, Sahbudin, Ilfita, Maybury, Mark, Hider, Samantha, Barcroft, Ann, Mcnally, Jeremy, Kitchen, Jo, Nisar, Muhammad, Quick, Vanessa, and D'Agostino, Maria Antonietta (ORCID:0000-0002-5347-0060)

Abstract

Background: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. Methods: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). Findings: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for el

Published
2024

17. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Author

Cope, Andrew P, primary, Jasenecova, Marianna, additional, Vasconcelos, Joana C, additional, Filer, Andrew, additional, Raza, Karim, additional, Qureshi, Sumera, additional, D'Agostino, Maria Antonietta, additional, McInnes, Iain B, additional, Isaacs, John D, additional, Pratt, Arthur G, additional, Fisher, Benjamin A, additional, Buckley, Christopher D, additional, Emery, Paul, additional, Ho, Pauline, additional, Buch, Maya H, additional, Ciurtin, Coziana, additional, van Schaardenburg, Dirkjan, additional, Huizinga, Thomas, additional, Toes, René, additional, Georgiou, Evangelos, additional, Kelly, Joanna, additional, Murphy, Caroline, additional, Prevost, A Toby, additional, Norton, Sam, additional, Lempp, Heidi, additional, Opena, Maria, additional, Subesinghe, Sujith, additional, Garrood, Toby, additional, Menon, Bina, additional, Ng, Nora, additional, Douglas, Karen, additional, Koutsianas, Christos, additional, Cooles, Faye, additional, Falahee, Marie, additional, Echavez-Naguicnic, Irene, additional, Bharadwaj, Anurag, additional, Villaruel, Michael, additional, Pande, Ira, additional, Collins, David, additional, Pegler, Suzannah, additional, Raizada, Sabrina, additional, Siebert, Stefan, additional, Fragoulis, George, additional, Guinto, Jesusa, additional, Galloway, James, additional, Rutherford, Andrew, additional, Barnes, Theresa, additional, Jeffrey, Helen, additional, Patel, Yusuf, additional, Batley, Michael, additional, O'Reilly, Brendan, additional, Venkatachalam, Srivinisan, additional, Sheeran, Thomas, additional, Gorman, Claire, additional, Reynolds, Piero, additional, Khan, Asad, additional, Gullick, Nicola, additional, Banerjee, Siwalik, additional, Mankia, Kulveer, additional, Jordan, Deepak, additional, Rowlands, Jane, additional, Starmans-Kool, Mirian, additional, Taylor, James, additional, Nandi, Pradip, additional, Sahbudin, Ilfita, additional, Maybury, Mark, additional, Hider, Samantha, additional, Barcroft, Ann, additional, McNally, Jeremy, additional, Kitchen, Jo, additional, Nisar, Muhammad, additional, and Quick, Vanessa, additional

Published
2024
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18. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology

Author

Nayar, Saba, Campos, Joana, Smith, Charlotte G., Iannizzotto, Valentina, Gardner, David H., Mourcin, Frédéric, Roulois, David, Turner, Jason, Sylvestre, Marvin, Asam, Saba, Glaysher, Bridget, Bowman, Simon J., Fearon, Douglas T., Filer, Andrew, Tarte, Karin, Luther, Sanjiv A., Fisher, Benjamin A., Buckley, Christopher D., Coles, Mark C., and Barone, Francesca

Published
2019

19. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis

Author

Alivernini, Stefano, MacDonald, Lucy, Elmesmari, Aziza, Finlay, Samuel, Tolusso, Barbara, Gigante, Maria Rita, Petricca, Luca, Di Mario, Clara, Bui, Laura, Perniola, Simone, Attar, Moustafa, Gessi, Marco, Fedele, Anna Laura, Chilaka, Sabarinadh, Somma, Domenico, Sansom, Stephen N., Filer, Andrew, McSharry, Charles, Millar, Neal L., Kirschner, Kristina, Nerviani, Alessandra, Lewis, Myles J., Pitzalis, Costantino, Clark, Andrew R., Ferraccioli, Gianfranco, Udalova, Irina, Buckley, Christopher D., Gremese, Elisa, McInnes, Iain B., Otto, Thomas D., and Kurowska-Stolarska, Mariola

Published
2020
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21. Fibroblasts and Osteoblasts in Inflammation and Bone Damage

Author

Turner, Jason D., Naylor, Amy J., Buckley, Christopher, Filer, Andrew, Tak, Paul-Peter, COHEN, IRUN R., Series Editor, LAJTHA, ABEL, Series Editor, LAMBRIS, JOHN D., Series Editor, PAOLETTI, RODOLFO, Series Editor, REZAEI, NIMA, Series Editor, Owens, Benjamin M.J, editor, and Lakins, Matthew A., editor

Published
2018
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23. BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study

Author

Rayner, Fiona, Anderson, Amy E., Baker, Kenneth F., Buckley, Christopher D., Dyke, Bernard, Fenton, Sally, Filer, Andrew, Goodyear, Carl S., Hilkens, Catharien M. U., Hiu, Shaun, Kerrigan, Sean, Kurowska-Stolarska, Mariola, Matthews, Fiona, McInnes, Iain, Ng, Wan-Fai, Pratt, Arthur G., Prichard, Jonathan, Raza, Karim, Siebert, Stefan, Stocken, Deborah, Teare, M. Dawn, Young, Stephen, and Isaacs, John D.

Published
2021
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27. Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Author

Rivellese, Felice, primary, Nerviani, Alessandra, additional, Giorli, Giovanni, additional, Warren, Louise, additional, Jaworska, Edyta, additional, Bombardieri, Michele, additional, Lewis, Myles J, additional, Humby, Frances, additional, Pratt, Arthur G, additional, Filer, Andrew, additional, Gendi, Nagui, additional, Cauli, Alberto, additional, Choy, Ernest, additional, McInnes, Iain, additional, Durez, Patrick, additional, Edwards, Christopher J, additional, Buch, Maya H, additional, Gremese, Elisa, additional, Taylor, Peter C, additional, Ng, Nora, additional, Cañete, Juan D, additional, Raizada, Sabrina, additional, McKay, Neil D, additional, Jadon, Deepak, additional, Sainaghi, Pier Paolo, additional, Stratton, Richard, additional, Ehrenstein, Michael R, additional, Ho, Pauline, additional, Pereira, Joaquim P, additional, Dasgupta, Bhaskar, additional, Gorman, Claire, additional, Galloway, James, additional, Chinoy, Hector, additional, van der Heijde, Désirée, additional, Sasieni, Peter, additional, Barton, Anne, additional, Pitzalis, Costantino, additional, Zayat, Ahmed, additional, Machado, Ana Rita, additional, Cuervo, Andrea, additional, Mahto, Arti, additional, Cubuk, Cankut, additional, Rawlings, Charlotte, additional, Mosanya, Chijioke, additional, Buckley, Chris, additional, Holroyd, Chris, additional, Maskall, Debbie, additional, Carlucci, Francesco, additional, Thorborn, Georgina, additional, Tan, Gina, additional, Lliso-Ribera, Gloria, additional, Rizvi, Hasan, additional, Peel, Joanna, additional, Fonseca, João Eurico, additional, Isaacs, John, additional, Ramírez, Julio, additional, Meric de Bellefon, Laurent, additional, Fossati-Jimak, Liliane, additional, Githinji, Mary, additional, Congia, Mattia, additional, Millar, Neal, additional, Purkayastha, Nirupam, additional, Celis, Raquel, additional, Seth, Rakhi, additional, Hands-Greenwood, Rebecca, additional, Landewé, Robert, additional, Perniola, Simone, additional, Alivernini, Stefano, additional, Marcia, Stefano, additional, Marini, Stefano, additional, Kelly, Stephen, additional, and Romão, Vasco, additional

Published
2023
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30. Distinct fibroblast subsets drive inflammation and damage in arthritis

Author

Croft, Adam P., Campos, Joana, Jansen, Kathrin, Turner, Jason D., Marshall, Jennifer, Attar, Moustafa, Savary, Loriane, Wehmeyer, Corinna, Naylor, Amy J., Kemble, Samuel, Begum, Jenefa, Dürholz, Kerstin, Perlman, Harris, Barone, Francesca, McGettrick, Helen M., Fearon, Douglas T., Wei, Kevin, Raychaudhuri, Soumya, Korsunsky, Ilya, Brenner, Michael B., Coles, Mark, Sansom, Stephen N., Filer, Andrew, and Buckley, Christopher D.

Published
2019
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31. Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells

Author

Ahasan, Mohammad M, Hardy, Rowan, Jones, Christopher, Kaur, Kirren, Nanus, Dominika, Juarez, Maria, Morgan, Stuart A, Hassan‐Smith, Zaki, Bénézech, Cécile, Caamaño, Jorge H, Hewison, Martin, Lavery, Gareth, Rabbitt, Elizabeth H, Clark, Andrew R, Filer, Andrew, Buckley, Christopher D, Raza, Karim, Stewart, Paul M, and Cooper, Mark S

Subjects
Genetics, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aetiology, Inflammatory and immune system, Cancer, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Animals, Arthritis, Rheumatoid, Cells, Cultured, Cytokines, Fibroblasts, Glucocorticoids, Humans, Inflammation, Interleukin-1beta, Mesenchymal Stem Cells, Mice, NF-kappa B, Osteoarthritis, Synovial Membrane, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectiveTissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation.MethodsGene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression.ResultsGene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression.ConclusionThe mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.

Published
2012

32. New biologic (Ab-IPL-IL-17) for IL-17-mediated diseases: identification of the bioactive sequence (nIL-17) for IL-17A/F function

Author

Saviano, Anella, primary, Manosour, Adel Abo, additional, Raucci, Federica, additional, Merlino, Francesco, additional, Marigliano, Noemi, additional, Schettino, Anna, additional, Wahid, Mussarat, additional, Begum, Jenefa, additional, Filer, Andrew, additional, Manning, Julia E, additional, Casillo, Gian Marco, additional, Piccolo, Marialuisa, additional, Ferraro, Maria Grazia, additional, Marzano, Simona, additional, Russomanno, Pasquale, additional, Bellavita, Rosa, additional, Irace, Carlo, additional, Amato, Jussara, additional, Alfaifi, Mohammed, additional, Rimmer, Peter, additional, Iqbal, Tariq, additional, Pieretti, Stefano, additional, Vellecco, Valentina, additional, Caso, Francesco, additional, Costa, Luisa, additional, Giacomelli, Roberto, additional, Scarpa, Raffaele, additional, Cirino, Giuseppe, additional, Bucci, Mariarosaria, additional, McGettrick, Helen M, additional, Grieco, Paolo, additional, Iqbal, Asif Jilani, additional, and Maione, Francesco, additional

Published
2023
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33. LAT1 enables T cell activation under inflammatory conditions

Author

Ogbechi, Joy, primary, Wright, Helen L., additional, Balint, Stefan, additional, Topping, Louise M., additional, Kristina, Zec, additional, Huang, Yi-Shu, additional, Pantazi, Eirini, additional, Swart, Maarten, additional, Windell, Dylan, additional, Marin, Eros, additional, Wempe, Michael F., additional, Endou, Hitoshi, additional, Thomas, Andrew M., additional, Filer, Andrew, additional, Stone, Trevor W., additional, Clarke, Alexander J., additional, Dustin, Michael L., additional, and Williams, Richard O., additional

Published
2023
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35. Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

Author

Penkava, Frank, Velasco-Herrera, Martin Del Castillo, Young, Matthew D., Yager, Nicole, Nwosu, Lilian N., Pratt, Arthur G., Lara, Alicia Lledo, Guzzo, Charlotte, Maroof, Ash, Mamanova, Lira, Cole, Suzanne, Efremova, Mirjana, Simone, Davide, Filer, Andrew, Brown, Chrysothemis C., Croxford, Andrew L., Isaacs, John D., Teichmann, Sarah, Bowness, Paul, Behjati, Sam, and Hussein Al-Mossawi, M.

Published
2020
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38. Differential expression, function and response to inflammatory stimuli of 11beta-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation.

Author

Hardy, Rowan S, Filer, Andrew, Cooper, Mark S, Parsonage, Greg, Raza, Karim, Hardie, Debbie L, Rabbitt, Elizabeth H, Stewart, Paul M, Buckley, Christopher D, and Hewison, Martin

Subjects
Synovial Membrane, Cells, Cultured, Fibroblasts, Bone Marrow, Skin, Humans, Arthritis, Rheumatoid, Osteoarthritis, Cortisone, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Tumor Necrosis Factor-alpha, RNA, Messenger, Interleukin-6, Glucocorticoids, Interleukin-1beta, Cells, Cultured, Arthritis, Rheumatoid, RNA, Messenger, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.

Published
2006

41. A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Author

Thomas, Tom, primary, Rich-Griffin, Charlotte, additional, Pohin, Mathilde, additional, Friedrich, Matthias, additional, Aschenbrenner, Dominik, additional, Pakpoor, Julia, additional, Jainarayanan, Ashwin, additional, Voda, Alexandru-Ioan, additional, Sanches Peres, Raphael, additional, Nee, Eloise, additional, Sathananthan, Dharshan, additional, Kotliar, Dylan, additional, Turner, Jason, additional, Nayar, Saba, additional, Zhang, Fan, additional, Jonsson, Anna, additional, Brenner, Michael, additional, Raychaudhuri, Soumya, additional, Kulicke, Ruth, additional, Ramsdell, Danielle, additional, Stransky, Nicolas, additional, Pagliarini, Ray, additional, Belecki, Piotr, additional, Spies, Noah, additional, Wagner, Allon, additional, Walsh, Alissa, additional, Coles, Mark, additional, Jostins-Dean, Luke, additional, Powrie, Fiona, additional, Filer, Andrew, additional, Travis, Simon, additional, Uhlig, Holm, additional, Dendrou, Calliope, additional, and Buckley, Christopher, additional

Published
2023
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43. Supplementary Data from CD151 Regulates Tumorigenesis by Modulating the Communication between Tumor Cells and Endothelium

Author

Sadej, Rafal, primary, Romanska, Hanna, primary, Baldwin, Gouri, primary, Gkirtzimanaki, Katerina, primary, Novitskaya, Vera, primary, Filer, Andrew D., primary, Krcova, Zuzana, primary, Kusinska, Renata, primary, Ehrmann, Jiri, primary, Buckley, Christopher D., primary, Kordek, Radzisław, primary, Potemski, Piotr, primary, Eliopoulos, Aristides G., primary, Lalani, El-Nasir, primary, and Berditchevski, Fedor, primary

Published
2023
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44. OA04 Association of clinical and demographic factors with quality of life, functional status, depression, and fatigue in patients presenting with, and at risk of, rheumatoid arthritis

Author

Torlinska, Barbara, primary, Raza, Karim, additional, Filer, Andrew, additional, Jutley, Gurpreet, additional, Sahbudin, Ilfita, additional, Singh, Ruchir, additional, de Pablo, Paola, additional, Rankin, Elizabeth, additional, Rhodes, Benjamin, additional, Amft, Nicole, additional, Justice, Elizabeth, additional, McGrath, Catherine, additional, Baskar, Sangeetha, additional, Trickey, Jeanette, additional, Calvert, Melanie, additional, and Falahee, Marie, additional

Published
2023
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45. 3D Articulated Registration of the Mouse Hind Limb for Bone Morphometric Analysis in Rheumatoid Arthritis

Author

Brown, James M., Naylor, Amy, Buckley, Chris, Filer, Andrew, Claridge, Ela, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Kobsa, Alfred, editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Weikum, Gerhard, editor, Ourselin, Sébastien, editor, and Modat, Marc, editor

Published
2014
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47. Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol

Author

Al-Laith, Mariam, Jasenecova, Marianna, Abraham, Sonya, Bosworth, Aisla, Bruce, Ian N., Buckley, Christopher D., Ciurtin, Coziana, D’Agostino, Maria-Antonietta, Emery, Paul, Gaston, Hill, Isaacs, John D., Filer, Andrew, Fisher, Benjamin A., Huizinga, Thomas W. J., Ho, Pauline, Jacklin, Clare, Lempp, Heidi, McInnes, Iain B., Pratt, Arthur G., Östor, Andrew, Raza, Karim, Taylor, Peter C., van Schaardenburg, Dirkjan, Shivapatham, Dharshene, Wright, Alison J., Vasconcelos, Joana C., Kelly, Joanna, Murphy, Caroline, Prevost, A. Toby, and Cope, Andrew P.

Published
2019
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48. Clonal associations of lymphocyte subsets and functional states revealed by single cell antigen receptor profiling of T and B cells in rheumatoid arthritis synovium

Author

Dunlap, Garrett, Wagner, Aaron, Meednu, Nida, Zhang, Fan, Jonsson, A. Helena, Wei, Kevin, Sakaue, Saori, Nathan, Aparna, Bykerk, Vivian P., Donlin, Laura T., Goodman, Susan M., Firestein, Gary S., Boyle, David L., Holers, V. Michael, Moreland, Larry W., Tabechian, Darren, Pitzalis, Costantino, Filer, Andrew, Raychaudhuri, Soumya, Brenner, Michael B., McDavid, Andrew, Rao, Deepak A., and Anolik, Jennifer H.

Subjects
Article
Abstract

Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched in GZMK + cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC), NR4A1+ activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.

Published
2023

49. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis

Author

Rao, Deepak A., Gurish, Michael F., Marshall, Jennifer L., Slowikowski, Kamil, Fonseka, Chamith Y., Liu, Yanyan, Donlin, Laura T., Henderson, Lauren A., Wei, Kevin, Mizoguchi, Fumitaka, Teslovich, Nikola C., Weinblatt, Michael E., Massarotti, Elena M., Coblyn, Jonathan S., Helfgott, Simon M., Lee, Yvonne C., Todd, Derrick J., Bykerk, Vivian P., Goodman, Susan M., Pernis, Alessandra B., Ivashkiv, Lionel B., Karlson, Elizabeth W., Nigrovic, Peter A., Filer, Andrew, Buckley, Christopher D., Lederer, James A., Raychaudhuri, Soumya, and Brenner, Michael B.

Subjects
Rheumatoid arthritis -- Development and progression, B cells -- Health aspects, T cells -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Deepak A. Rao (corresponding author) [1]; Michael F. Gurish [1]; Jennifer L. Marshall [2]; Kamil Slowikowski [1, 3, 4, 5, 6]; Chamith Y. Fonseka [1, 3, 4, 6, 7]; [...]

Published
2017
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50. LAT1 enables T cell activation under inflammatory conditions: a new therapeutic target for rheumatoid arthritis

Author

Ogbechi, Joy, primary, Wright, Helen L., additional, Balint, Stefan, additional, Topping, Louise M., additional, Kristina, Zec, additional, Huang, Yi-Shu, additional, Pantazi, Eirini, additional, Swart, Maarten, additional, Windell, Dylan, additional, Marin, Eros, additional, Wempe, Michael F., additional, Endou, Hitoshi, additional, Thomas, Andrew M., additional, Filer, Andrew, additional, Stone, Trevor W., additional, Clarke, Alexander J., additional, Dustin, Michael L., additional, and Williams, Richard O., additional

Published
2022
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