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1. Senescent endothelial cells promote pathogenic neutrophil trafficking in inflamed tissues

Author

Rolas, Loïc, Stein, Monja, Barkaway, Anna, Reglero-Real, Natalia, Sciacca, Elisabetta, Yaseen, Mohammed, Wang, Haitao, Vazquez-Martinez, Laura, Golding, Matthew, Blacksell, Isobel A, Giblin, Meredith J, Jaworska, Edyta, Bishop, Cleo L, Voisin, Mathieu-Benoit, Gaston-Massuet, Carles, Fossati-Jimack, Liliane, Pitzalis, Costantino, Cooper, Dianne, Nightingale, Thomas D, Lopez-Otin, Carlos, Lewis, Myles J, and Nourshargh, Sussan

Published
2024
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3. Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response

Author

Corsiero, Elisa, Caliste, Mattia, Jagemann, Lucas, Fossati-Jimack, Liliane, Goldmann, Katriona, Cubuk, Cankut, Ghirardi, Giulia M., Prediletto, Edoardo, Rivellese, Felice, Alessandri, Cristiano, Hopkinson, Mark, Javaheri, Behzad, Pitsillides, Andrew A., Lewis, Myles J., Pitzalis, Costantino, and Bombardieri, Michele

Subjects
Autoimmunity -- Health aspects, Arthritis -- Development and progression -- Complications and side effects, Connective tissue cells -- Health aspects -- Physiological aspects, Monoclonal antibodies -- Health aspects, Autoantigens -- Health aspects, Health care industry
Abstract

Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA- rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA- rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies., Introduction Rheumatoid arthritis (RA) is the most common inflammatory, erosive polyarthritis and affects approximately 0.5%-1.5% of the worldwide population. RA is characterized by breach of self-tolerance and production of several [...]

Published
2024
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5. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Author

Rivellese, Felice, Surace, Anna E. A., Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R., Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E., Hudson, Briana M., Warren, Sarah E., McKeigue, Paul M., Humby, Frances, Bombardieri, Michele, Barnes, Michael R., Lewis, Myles J., and Pitzalis, Costantino

Published
2022
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11. Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

Author

Humby, Frances, primary, Durez, Patrick, additional, Buch, Maya H, additional, Lewis, Myles J, additional, Bombardieri, Michele, additional, John, Christopher, additional, Rizvi, Hasan, additional, Warren, Louise, additional, Peel, Joanna, additional, Fossati-Jimack, Liliane, additional, Hands, Rebecca E, additional, Giorli, Giovanni, additional, Rivellese, Felice, additional, Cañete, Juan D, additional, Taylor, Peter C, additional, Sasieni, Peter, additional, Fonseca, João E, additional, Choy, Ernest, additional, and Pitzalis, Costantino, additional

Published
2022
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12. RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Author

Isaacs, John D., Brockbank, Sarah, Pedersen, Ayako Wakatsuki, Hilkens, Catharien, Anderson, Amy, Stocks, Philip, Lendrem, Dennis, Tarn, Jessica, Smith, Graham R., Allen, Ben, Casement, John, Diboll, Julie, Harry, Rachel, Cooles, Faye A. H., Cope, Andrew P., Simpson, Gemma, Toward, Ruth, Noble, Hayley, Parke, Angela, Wu, Wing, Clarke, Fiona, Scott, David, Scott, Ian C., Galloway, James, Lempp, Heidi, Ibrahim, Fowzia, Schwank, Samana, Molyneux, Gemma, Lazarov, Tomi, Geissmann, Frederic, Goodyear, Carl S., McInnes, Iain B., Donnelly, Iona, Gilmour, Ashley, Virlan, Aysin Tulunay, Porter, Duncan, Ponchel, Frederique, Emery, Paul, El-Jawhari, Jehan, Parmar, Rekha, McDermott, Michael F., Fisher, Benjamin A., Young, Steve P., Jones, Philip, Raza, Karim, Filer, Andrew, Pitzalis, Costantino, Barnes, Michael R., Watson, David S., Henkin, Rafael, Thorborn, Georgina, Fossati-Jimack, Liliane, Kelly, Stephen, Humby, Frances, Bombardieri, Michele, Rana, Sharmila, Jia, Zhilong, Goldmann, Katriona, Lewis, Myles, Ng, Sandra, Barbosa-Silva, Adriano, Tzanis, Evan, Gallagher-Syed, Amaya, John, Christopher R., Ehrenstein, Michael R., Altobelli, Gioia, Martins, Sandra, Nguyen, Dao, Ali, Humayara, Ciurtin, Coziana, Buch, Maya, Symmons, Deborah, Worthington, Jane, Bruce, Ian N., Sergeant, Jamie C., Verstappen, Suzanne M. M., Stirling, Fiona, Hughes-Morley, Adwoa, Tom, Brian, Farewell, Vernon, Zhong, Yujie, Taylor, Peter C., Buckley, Christopher D., Keidel, Sarah, Cuff, Carolyn, Levesque, Marc, Long, Andrew, Liu, Zheng, Lipsky, Samantha, Harvey, Bohdan, Macoritto, Michael, Hong, Feng, Kaymakcalan, Sukru, Tsuji, Wayne, Sabin, Tony, Ward, Neil, Talbot, Susan, Padhji, Desmond, Sleeman, Matthew, Finch, Donna, Herath, Athula, Lindholm, Catharina, Jenkins, Martin, Ho, Meilien, Hollis, Sally, Marshall, Chris, Parker, Gerry, Page, Matt, Edwards, Hannah, Cuza, Alexandru, Gozzard, Neil, Pandis, Ioannis, Rowe, Anthony, Capdevila, Francisco Bonachela, Loza, Matthew J., Curran, Mark, Verbeeck, Denny, Dan Baker, Mela, Christopher M., Vranic, Ivana, Mela, Catherine T., Wright, Stephen, Rowell, Lucy, Vernon, Emma, Joseph, Nina, Payne, Neil, Rao, Ravi, Binks, Michael, Belson, Alexandra, Ludbrook, Valerie, Hicks, Kirsty, Tipney, Hannah, Ellis, Joanne, Hasan, Samiul, Didierlaurent, Arnaud, Burny, Wivine, Haynes, Andrea, Larminie, Chris, Harris, Ray, Dastros-Pitei, Daniela, Carini, Claudio, Kola, Blerina, Jelinsky, Scott, Hodge, Martin, Maciejewski, Mateusz, Ziemek, Daniel, Schulz-Knappe, Peter, Zucht, Hans-Dieter, Budde, Petra, Coles, Mark, Butler, James A., Read, Simon, and Consortium, The RA-MAP

Subjects
Arthritis, Rheumatoid, Proteomics, Statistics and Probability, Vaccines, Humans, Library and Information Sciences, Statistics, Probability and Uncertainty, Monocytes, Autoantibodies, Biological Specimen Banks, Computer Science Applications, Education, Information Systems
Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.

Published
2022

13. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, R4RA collaborative group, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, and R4RA collaborative group

Abstract

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Published
2022

14. Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Bombardieri, Michele, John, Christopher, Rizvi, Hasan, Warren, Louise, Peel, Joanna, Fossati-Jimack, Liliane, Hands, Rebecca E, Giorli, Giovanni, Rivellese, Felice, Cañete, Juan D, Taylor, Peter C, Sasieni, Peter, Fonseca, João E, Choy, Ernest, Pitzalis, Costantino, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Bombardieri, Michele, John, Christopher, Rizvi, Hasan, Warren, Louise, Peel, Joanna, Fossati-Jimack, Liliane, Hands, Rebecca E, Giorli, Giovanni, Rivellese, Felice, Cañete, Juan D, Taylor, Peter C, Sasieni, Peter, Fonseca, João E, Choy, Ernest, and Pitzalis, Costantino

Abstract

Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells).

Published
2022

15. NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment

Author

Pontarini, Elena, primary, Sciacca, Elisabetta, additional, Grigoriadou, Sofia, additional, Rivellese, Felice, additional, Lucchesi, Davide, additional, Fossati-Jimack, Liliane, additional, Coleby, Rachel, additional, Chowdhury, Farzana, additional, Calcaterra, Francesca, additional, Tappuni, Anwar, additional, Lewis, Myles J., additional, Fabris, Martina, additional, Quartuccio, Luca, additional, Bella, Silvia Della, additional, Bowman, Simon, additional, Pitzalis, Costantino, additional, Mavilio, Domenico, additional, De Vita, Salvatore, additional, and Bombardieri, Michele, additional

Published
2021
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17. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Author

Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, R4RA collaborative group, Taylor, PC, group, R4RA collaborative, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie

Subjects
Arthritis, Rheumatoid, Antirheumatic Agents, Biopsy, Antibodies, Monoclonal, Humans, General Medicine, Antibodies, Monoclonal, Humanized, Rituximab, General Biochemistry, Genetics and Molecular Biology, Biomarkers
Abstract

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Published
2021

19. Novel Bispecific Antibody for Synovial-Specific Target Delivery of Anti-TNF Therapy in Rheumatoid Arthritis

Author

Ferrari, Mathieu, primary, Onuoha, Shimobi C., additional, Fossati-Jimack, Liliane, additional, Nerviani, Alessandra, additional, Alves, Pedro L., additional, Pagani, Sara, additional, Deantonio, Cecilia, additional, Colombo, Federico, additional, Santoro, Claudio, additional, Sblattero, Daniele, additional, and Pitzalis, Costantino, additional

Published
2021
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20. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial

Author

Humby, Frances, primary, Durez, Patrick, additional, Buch, Maya H, additional, Lewis, Myles J, additional, Rizvi, Hasan, additional, Rivellese, Felice, additional, Nerviani, Alessandra, additional, Giorli, Giovanni, additional, Mahto, Arti, additional, Montecucco, Carlomaurizio, additional, Lauwerys, Bernard, additional, Ng, Nora, additional, Ho, Pauline, additional, Bombardieri, Michele, additional, Romão, Vasco C, additional, Verschueren, Patrick, additional, Kelly, Stephen, additional, Sainaghi, Pier Paolo, additional, Gendi, Nagui, additional, Dasgupta, Bhaskar, additional, Cauli, Alberto, additional, Reynolds, Piero, additional, Cañete, Juan D, additional, Moots, Robert, additional, Taylor, Peter C, additional, Edwards, Christopher J, additional, Isaacs, John, additional, Sasieni, Peter, additional, Choy, Ernest, additional, Pitzalis, Costantino, additional, Thompson, Charlotte, additional, Bugatti, Serena, additional, Bellan, Mattia, additional, Congia, Mattia, additional, Holroyd, Christopher, additional, Pratt, Arthur, additional, Cabral da Fonseca, João Eurico, additional, White, Laura, additional, Warren, Louise, additional, Peel, Joanna, additional, Hands, Rebecca, additional, Fossati-Jimack, Liliane, additional, Hadfield, Gaye, additional, Thorborn, Georgina, additional, Ramirez, Julio, additional, and Celis, Raquel, additional

Published
2021
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24. Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren’s syndrome with ectopic germinal centres and MALT lymphoma

Author

Pontarini, Elena, primary, Murray-Brown, William James, additional, Croia, Cristina, additional, Lucchesi, Davide, additional, Conway, James, additional, Rivellese, Felice, additional, Fossati-Jimack, Liliane, additional, Astorri, Elisa, additional, Prediletto, Edoardo, additional, Corsiero, Elisa, additional, Romana Delvecchio, Francesca, additional, Coleby, Rachel, additional, Gelbhardt, Eva, additional, Bono, Aurora, additional, Baldini, Chiara, additional, Puxeddu, Ilaria, additional, Ruscitti, Piero, additional, Giacomelli, Roberto, additional, Barone, Francesca, additional, Fisher, Benjamin, additional, Bowman, Simon J, additional, Colafrancesco, Serena, additional, Priori, Roberta, additional, Sutcliffe, Nurhan, additional, Challacombe, Stephen, additional, Carlesso, Gianluca, additional, Tappuni, Anwar, additional, Pitzalis, Costantino, additional, and Bombardieri, Michele, additional

Published
2020
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35. THU0058 B CELL SYNOVITIS AND CLINICAL PHENOTYPES IN RHEUMATOID ARTHRITIS AT DIFFERENT DISEASE STAGES

Author

Rivellese, Felice, primary, Humby, Frances, additional, Bugatti, Serena, additional, Fossati-Jimack, Liliane, additional, Rizvi, Hasan, additional, Lucchesi, Davide, additional, Ribera, Gloria Lliso, additional, Nerviani, Alessandra, additional, Hands, Rebecca, additional, Giorli, Giovanni, additional, Frias, Barbara, additional, Jaworska, Edyta, additional, Goldmann, Katriona, additional, Lewis, Myles, additional, Manzo, Antonio, additional, Bombardieri, Michele, additional, and Pitzalis, Costantino, additional

Published
2019
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36. OP0279 A UNIQUE IL-21 SIGNATURE CHARACTERIZES LESIONAL AND CIRCULATING T-FOLLICULAR HELPER CELLS IN SJÖGREN’S SYNDROME PATIENTS WITH ECTOPIC GERMINAL CENTRES AND MALT LYMPHOMA

Author

Pontarini, Elena, primary, Brown, William Murray, additional, Croia, Cristina, additional, Lucchesi, Davide, additional, Rivellese, Felice, additional, Fossati-Jimack, Liliane, additional, Ruscitti, Piero, additional, Prediletto, Edoardo, additional, Corsiero, Elisa, additional, Barone, Francesca, additional, Fisher, Benjamin, additional, Colafrancesco, Serena, additional, Puxeddu, Ilaria, additional, Giacomelli, Roberto, additional, Priori, Roberta, additional, Baldini, Chiara, additional, Pitzalis, Costantino, additional, and Bombardieri, Michele, additional

Published
2019
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41. Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production

Author

Rivellese, Felice, primary, Mauro, Daniele, additional, Nerviani, Alessandra, additional, Pagani, Sara, additional, Fossati-Jimack, Liliane, additional, Messemaker, Tobias, additional, Kurreeman, Fina A S, additional, Toes, René E M, additional, Ramming, Andreas, additional, Rauber, Simon, additional, Schett, Georg, additional, Jones, Gareth W, additional, Jones, Simon A, additional, Rossi, Francesca Wanda, additional, de Paulis, Amato, additional, Marone, Gianni, additional, El Shikh, Mohey Eldin M, additional, Humby, Frances, additional, and Pitzalis, Costantino, additional

Published
2018
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42. NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation.

Author

Pontarini, Elena, Mavilio, Domenico, Lucchesi, Davide, Fossati‐Jimack, Liliane, Coleby, Rachel, Tentorio, Paolo, Croia, Cristina, and Bombardieri, Michele

Subjects
KILLER cells, SALIVARY glands, TERTIARY structure
Abstract

Salivary glands (SGs) represent a permissive site for several sialotropic viruses whose persistence is linked to the development of autoimmunity. Natural Killer (NK) cells play a key role in viral clearance but their involvement in viral infection control and in tertiary lymphoid structures (TLS) development within SGs is unknown. By using an inducible model of TLS in the SGs of wild‐type C57BL/6 mice, induced by the local delivery of a replication‐defective adenovirus (AdV), we demonstrated that circulating NK cells are rapidly recruited to SGs and highly enrich the early inflammatory infiltrate prior to TLS development. NK cells migrating to SGs in response to AdV infection up‐regulate NKp46, undergo proliferation, acquire cytotoxic potential, produce Granzyme‐B and IFN‐γ, and reduce viral load in the acute phase of the infection. Nonetheless, the selective depletion of both circulating and infiltrating NK cells in AdV‐infected mice neither affect the development and frequency of TLS nor the onset of autoimmunity. These data demonstrate that, upon local viral delivery of AdV, peripheral NK cells homing to SGs can exert an early control of the viral infection but are dispensable for the formation of TLS and breach of immunologic tolerance. Circulating Natural Killer cells migrate to salivary glands after local viral delivery, control infection but are dispensable for the formation of tertiary lymphoid structures. [ABSTRACT FROM AUTHOR]

Published
2019
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45. Identification and characterisation of a lupus suppressor 129 locus on chromosome 31

Author

Carlucci, Francesco, Fossati-Jimack, Liliane, Dumitriu, Ingrid E., Heidari, Yasin, Walport, Mark J., Szajna, Marta, Baruah, Paramita, Garden, Oliver A., Cook, H. Terence, and Botto, Marina

Subjects
B-Lymphocytes, T-Lymphocytes, Fluorescent Antibody Technique, Cell Separation, Flow Cytometry, T-Lymphocytes, Regulatory, Article, Mice, Mice, Congenic, T-Lymphocyte Subsets, Animals, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, Autoantibodies
Abstract

The 129-derived Sle16 is a susceptibility locus for systemic autoimmunity when present on the C57BL/6 (B6) background. Genetic analysis of a (129xB6)F2 cross identified a region from the B6 chromosome 3 (Sle18) with positive linkage to antinuclear Abs. In this study, we have generated a B6 congenic strain harboring the 129 allele of Sle18 and intercrossed this line with the lupus-prone B6.129-Sle16 strain. The presence of the 129-Sle18 allele in the B6.129-Sle16Sle18 double congenic mice suppressed the development of Sle16-mediated autoantibody production and ameliorated the renal pathology. The 129-Sle18 locus rectified the B cell abnormalities detected in the B6.129-Sle16 mice, such as the reduction in the percentage of marginal zone B and B1a cells and the increased number of germinal centers. The B6.129-Sle16Sle18 spleens still displayed an increased percentage of activated T and B cells. However, in the B6.129-Sle16Sle18 strain the percentage of naive T cells was equivalent to that in B6.129-Sle18 and B6 mice and these cells showed a reduced proliferative response to anti-CD3 stimulation compared with B6.129-Sle16 T cells. There was a significant increase in the percentage of CD4(+)FoxP3(+)regulatory T cells in all congenic strains. These cells had normal regulatory function when tested in vitro. Thus, 129-Sle18 represents a novel, non-MHC lupus-suppressor locus probably operating as a functional modifier of B cells that, in combination with other factors, leads to lupus resistance. Further characterization of this locus will help to uncover the immune mechanism(s) conferring protection against lupus.

Published
2010

46. Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum

Author

Banda, Nirmal K, Mehta, Gaurav, Chao, Ying, Wang, Guankui, Inturi, Swetha, Fossati-Jimack, Liliane, Botto, Marina, Wu, Linping, Moghimi, Seyed Moein, Simberg, Dmitri, Banda, Nirmal K, Mehta, Gaurav, Chao, Ying, Wang, Guankui, Inturi, Swetha, Fossati-Jimack, Liliane, Botto, Marina, Wu, Linping, Moghimi, Seyed Moein, and Simberg, Dmitri

Abstract

BACKGROUND: The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex™). In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood.METHODS: 20 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test.RESULTS: In mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. No involvement of the CP was observed. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles.CONCLUSIONS: There were important differences and similarities in the complement a

Published
2014

49. IL-10-producing regulatory B cells induced by IL-33 (BregIL-33) effectively attenuate mucosal inflammatory responses in the gut

Author

Sattler, Susanne, primary, Ling, Guang-Sheng, additional, Xu, Damo, additional, Hussaarts, Leonie, additional, Romaine, Andreas, additional, Zhao, Hongzhi, additional, Fossati-Jimack, Liliane, additional, Malik, Talat, additional, Cook, H. Terence, additional, Botto, Marina, additional, Lau, Yu-Lung, additional, Smits, Hermelijn H., additional, Liew, Foo Y., additional, and Huang, Fang-Ping, additional

Published
2014
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