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3. Understanding repertoire sequencing data through a multiscale computational model of the germinal center

Author

García-Valiente, Rodrigo, Merino Tejero, Elena, Stratigopoulou, Maria, Balashova, Daria, Jongejan, Aldo, Lashgari, Danial, Pélissier, Aurélien, Caniels, Tom G., Claireaux, Mathieu A. F., Musters, Anne, van Gils, Marit J., Rodríguez Martínez, María, de Vries, Niek, Meyer-Hermann, Michael, Guikema, Jeroen E. J., Hoefsloot, Huub, and van Kampen, Antoine H. C.

Published
2023
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4. Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

Author

Merino-Vico, Ana, van Hamburg, Jan Piet, Tuijnenburg, Paul, Frazzei, Giulia, Al-Soudi, Aram, Bonasia, Carlo G., Helder, Boy, Rutgers, Abraham, Abdulahad, Wayel H., Stegeman, Coen A., Sanders, Jan-Stephan, Bergamaschi, Laura, Lyons, Paul A., Bijma, Theo, van Keep, Laura, Wesenhagen, Kirsten, Jongejan, Aldo, Olsson, Henric, de Vries, Niek, Kuijpers, Taco W., Heeringa, Peter, and Tas, Sander W.

Published
2024
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6. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis

Author

Ishigaki, Kazuyoshi, Sakaue, Saori, Terao, Chikashi, Luo, Yang, Sonehara, Kyuto, Yamaguchi, Kensuke, Amariuta, Tiffany, Too, Chun Lai, Laufer, Vincent A., Scott, Ian C., Viatte, Sebastien, Takahashi, Meiko, Ohmura, Koichiro, Murasawa, Akira, Hashimoto, Motomu, Ito, Hiromu, Hammoudeh, Mohammed, Emadi, Samar Al, Masri, Basel K., Halabi, Hussein, Badsha, Humeira, Uthman, Imad W., Wu, Xin, Lin, Li, Li, Ting, Plant, Darren, Barton, Anne, Orozco, Gisela, Verstappen, Suzanne M. M., Bowes, John, MacGregor, Alexander J., Honda, Suguru, Koido, Masaru, Tomizuka, Kohei, Kamatani, Yoichiro, Tanaka, Hiroaki, Tanaka, Eiichi, Suzuki, Akari, Maeda, Yuichi, Yamamoto, Kenichi, Miyawaki, Satoru, Xie, Gang, Zhang, Jinyi, Amos, Christopher I., Keystone, Edward, Wolbink, Gertjan, van der Horst-Bruinsma, Irene, Cui, Jing, Liao, Katherine P., Carroll, Robert J., Lee, Hye-Soon, Bang, So-Young, Siminovitch, Katherine A., de Vries, Niek, Alfredsson, Lars, Rantapää-Dahlqvist, Solbritt, Karlson, Elizabeth W., Bae, Sang-Cheol, Kimberly, Robert P., Edberg, Jeffrey C., Mariette, Xavier, Huizinga, Tom, Dieudé, Philippe, Schneider, Matthias, Kerick, Martin, Denny, Joshua C., Matsuda, Koichi, Matsuo, Keitaro, Mimori, Tsuneyo, Matsuda, Fumihiko, Fujio, Keishi, Tanaka, Yoshiya, Kumanogoh, Atsushi, Traylor, Matthew, Lewis, Cathryn M., Eyre, Stephen, Xu, Huji, Saxena, Richa, Arayssi, Thurayya, Kochi, Yuta, Ikari, Katsunori, Harigai, Masayoshi, Gregersen, Peter K., Yamamoto, Kazuhiko, Louis Bridges, Jr, S., Padyukov, Leonid, Martin, Javier, Klareskog, Lars, Okada, Yukinori, and Raychaudhuri, Soumya

Published
2022
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7. Longitudinal analysis of anti-drug antibody development in multiple sclerosis patients treated with interferon beta-1a (Rebif™) using B cell receptor repertoire analysis

Author

van der Weele, Linda, Pollastro, Sabrina, van Schaik, Barbera D.C., van Kampen, Antoine H.C., Niewold, Ilse T.G., Kuijpers, Taco W., Warnke, Clemens, Jensen, Poul Erik H., Kramer, Daniel, Ryner, Malin, Hermanrud, Christina, Dönnes, Pierre, Pallardy, Marc, Spindeldreher, Sebastian, Deisenhammer, Florian, Fogdell-Hahn, Anna, and de Vries, Niek

Published
2022
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9. Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis

Author

Quistrebert, Jocelyn, Hässler, Signe, Bachelet, Delphine, Mbogning, Cyprien, Musters, Anne, Tak, Paul Peter, Wijbrandts, Carla Ann, Herenius, Marieke, Bergstra, Sytske Anne, Akdemir, Gülşah, Johannesson, Martina, Combe, Bernard, Fautrel, Bruno, Chollet-Martin, Sylvie, Gleizes, Aude, Donnellan, Naoimh, Deisenhammer, Florian, Davidson, Julie, Hincelin-Mery, Agnès, Dönnes, Pierre, Fogdell-Hahn, Anna, De Vries, Niek, Huizinga, Tom, Abugessaisa, Imad, Saevarsdottir, Saedis, Hacein-Bey-Abina, Salima, Pallardy, Marc, Broët, Philippe, and Mariette, Xavier

Published
2019
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10. Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life

Author

Schreurs, Renée R.C.E., Baumdick, Martin E., Sagebiel, Adrian F., Kaufmann, Max, Mokry, Michal, Klarenbeek, Paul L., Schaltenberg, Nicola, Steinert, Fenja L., van Rijn, Jorik M., Drewniak, Agata, The, Sarah-May M.L., Bakx, Roel, Derikx, Joep P.M., de Vries, Niek, Corpeleijn, Willemijn E., Pals, Steven T., Gagliani, Nicola, Friese, Manuel A., Middendorp, Sabine, Nieuwenhuis, Edward E.S., Reinshagen, Konrad, Geijtenbeek, Teunis B.H., van Goudoever, Johannes B., and Bunders, Madeleine J.

Published
2019
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11. New Susceptibility Locus for Rheumatoid Arthritis Suggested by a Genome-Wide Linkage Study

Author

Cornelis, Francois, Faure, Sabine, Martinez, Maria, Fritz, Pierre, Dib, Colette, Alves, Helena, Barrera, Pilar, De Vries, Niek, Balsa, Alejandro, Pascual-Salcedo, Dora, Maenaut, Kristin, Westhovens, Rene, Migliorini, Paola, Tran, Tuyet-Hoa, Delaye, Arnaud, Prince, Nathalie, Lefevre, Caroline, Thomas, Gaelle, Poirier, Murielle, Soubigou, Stephane, Alibert, Olivier, Lasbleiz, Sandra, Fouix, Sylvaine, Bouchier, Christiane, Liote, Frederic, Loste, Marie-Noelle, Lepage, Virginia, Charron, Dominique, Gyapay, Gabor, Lopes-Vaz, Antonio, Kuntz, Daniel, Bardin, Thomas, and Weissenbach, Jean

Published
1998

13. TCRβ clones in muscle tissue share structural features in patients with idiopathic inflammatory myopathy and are associated with disease activity.

Author

Anang, Dornatien C., Walter, Hannah A. W., Lim, Johan, Niewold, Ilse T. G., van der Weele, Linda, Aronica, Eleonora, Eftimov, Filip, Raaphorst, Joost, van Schaik, Barbera D. C., van Kampen, Antoine H. C., van der Kooi, Anneke J., and de Vries, Niek

Subjects
T cell receptors, TISSUE expansion, MYOSITIS, MUSCLE diseases, MUSCLE strength, T cells, DERMATOMYOSITIS
Abstract

Objectives: To characterize the T cell receptor (TCRβ) repertoire in peripheral blood and muscle tissues of treatment naïve patients with newly diagnosed idiopathic inflammatory myopathies (IIMs). Methods: High throughput RNA sequencing of the TCRβ chain was performed in peripheral blood and muscle tissue in twenty newly-diagnosed treatment-naïve IIM patients (9 DM, 5 NM/OM, 5 IMNM and 1 ASyS) and healthy controls. Results thereof were correlated with markers of disease activity. Results: Muscle tissue of IIM patients shows more expansion of TCRb clones and decreased diversity when compared to peripheral blood of IIM as well as healthy controls (both p=0.0001). Several expanded TCRb clones in muscle are tissue restricted and cannot be retrieved in peripheral blood. These clones have significantly longer CDR3 regions when compared to clones (also) found in circulation (p=0.0002), while their CDR3 region is more hydrophobic (p<0.01). Network analysis shows that clonal TCRβ signatures are shared between patients. Increased clonal expansion in muscle tissue is significantly correlated with increased CK levels (p=0.03), while it tends to correlate with decreased muscle strength (p=0.08). Conclusion: Network analysis of clones in muscle of IIM patients shows shared clusters of sequences across patients. Muscle-restricted CDR3 TCRβ clones show specific structural features in their T cell receptor. Our results indicate that clonal TCRβ expansion in muscle tissue might be associated with disease activity. Collectively, these findings support a role for specific clonal T cell responses in muscle tissue in the pathogenesis of the IIM subtypes studied. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Latitude gradient influences the age of onset of rheumatoid arthritis: a worldwide survey

Author

Ramos-Remus, Cesar, Ramirez-Gomez, Andrea, Brambila-Barba, Victor, Barajas-Ochoa, Aldo, Castillo-Ortiz, Jose D., Adebajo, Adewale O., Espinoza, Luis R., Aceves-Avila, Francisco J., Sánchez-González, Jorge M., Boudersa, Nadia, Slimani, Samy, Ladjouze-Rezig, Aicha, Diaz, Mónica P., Kirmayr, Karin I., Asnal, Cecilia A., Catoggio, Luis J., Citera, Gustavo, Casado, Gustavo C., Alvarez, Analia P., Pisoni, Cecilia N., Benavente, Emilio, Lopez-Cabanillas, Adriana, Baez, Roberto M., Pons-Estel, Bernardo A., Sacnún, Mónica P., Cavallasca, Javier A., Paniego, Raúl H., Proudman, Susanna M., Thomas, Ranjeny, Major, Gabor, Mathers, David M., Schrieber, Leslie, Haq, Syed A., Islam, Nazrul, Dessein, Patrick H., von Muhlen, Carlos A., Bianchi, Washington A., da R. Castelar-Pinheiro, Geraldo, Feldman-Pollak, Daniel, Cossermelli, Waldenise, Bonfiglioli, Karina R., Giorgi, Rina D., Zabsonre-Tiendrebeogo, Wendlassida J., Russell, Anthony S., Olaru, Lilia, Karsh, Jacob, Fuentealba, Carlos, Aguilera, Sergio, Castro-Esparza, Irene H., Burgos, Paula I., Neira, Oscar, Li, Zhan-guo, Tam, Lai-Shan, Mok, Mo Y., Medina, Yimy F., Moreno-Alvarez, Mario J., Zúñiga-Vera, Andrés E., Vera, Claudia, Quezada, Ivonne, Moreno, Iván M., Calapaqui, Wendy, El-Mardenly, Ghada, Salama, M. Salah, Ragab, Gaafar, Hadidi, Tahsin, Gado, Kamel, Leirisalo-Repo, Marjatta, Tuompo, Riitta, Koivuniemi, Riitta, Berenbaum, Francis, Allanore, Yannick, Constantin, Arnaud, Buttgereit, Frank, Schulze-Koops, Hendrik, Liz, Myriam, Dey, Dzifa, Alonzo-Borjas, Hugo D., Santiago-Pastelín, Carlos B., Cuéllar-Cruz, Víctor, Dharmanand, Balebail G., Yathish, G. C., Akerkar, Shashank M., Malaviya, Anand N., Ahmadzadeh, Arman, Hasunuma, Tomoko, Owino, Benard O., Pacheco-Tena, César, Frausto-Arenas, Aaron, De la Madrid-Cernas, Adrián A., Cardona-Cabrera, Román, Centeno-Valadez, Juan D., Rodríguez-Torres, Isaura M., Vaidya, Binit, Gupta, Arun K., Harrison, Andrew A., Grainger, Rebecca, Nwankwo, Henry M., Diamantopoulos, Andreas P., Mæland, Elisabeth, Besada, Emilio, Gorriz, Luis, Duarte, Margarita, Albrecht, Maria T. Romero-de, Cabrera-Villalba, Sonia, Segami, María I., García-Poma, Augusto, Pérez-Medina, Wilkerson, Ramos, María P., Navarra, Sandra V., Racaza, Geraldine Z., Penserga, Ester G., Manapat-Reyes, Bernadette H., Dianongco, Maria L., Lichauco, Juan J., Torralba, Tito P., Al-Emadi, Samar, Hammoudeh, Mohammed, Botchkova, Anna G., AlSaeedi, Sabri H., Almoallim, Hani, Al-Arfaj, Hussein F., Koh, Wei H., Leung, Ying Y., Whitelaw, David A., Hodkinson, Bridget, García-Miguel, Javier, Duro, Juan C., Andreu, José L., Martin-Mola, Emilio, Ahijón-Lana, María, Finckh, Axel, Alpízar-Rodríguez, Deshiré, Osiri, Manathip, Kasitanon, Nuntana, Louthrenoo, Worawit, de Vries, Niek, van Denderen, Christiaan, Gerritsen, Martjin, van Vollenhoven, Ronald F., Jansen, Tim L., van Riel, Piet, Núñez-Sotelo, Concepción M., Villegas-Morales, Sol, and GEO-RA Group

Published
2017
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15. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

Author

Hässler, Signe, Bachelet, Delphine, Duhaze, Julianne, Szely, Natacha, Gleizes, Aude, Hacein-Bey Abina, Salima, Aktas, Orhan, Auer, Michael, Avouac, Jerôme, Birchler, Mary, Bouhnik, Yoram, Brocq, Olivier, Buck-Martin, Dorothea, Cadiot, Guillaume, Carbonnel, Franck, Chowers, Yehuda, Comabella, Manuel, Derfuss, Tobias, De Vries, Niek, Donnellan, Naoimh, Doukani, Abiba, Guger, Michael, Hartung, Hans-Peter, Kubala Havrdova, Eva, Hemmer, Bernhard, Huizinga, Tom, Ingenhoven, Kathleen, Hyldgaard-Jensen, Poul Erik, Jury, Elizabeth C., Khalil, Michael, Kieseier, Bernd, Laurén, Anna, Lindberg, Raija, Loercher, Amy, Maggi, Enrico, Manson, Jessica, Mauri, Claudia, Mohand Oumoussa, Badreddine, Montalban, Xavier, Nachury, Maria, Nytrova, Petra, Richez, Christophe, Ryner, Malin, Sellebjerg, Finn, Sievers, Claudia, Sikkema, Dan, Soubrier, Martin, Tourdot, Sophie, Trang, Caroline, Vultaggio, Alessandra, Warnke, Clemens, Spindeldreher, Sebastian, Dönnes, Pierre, Hickling, Timothy P., Hincelin Mery, Agnès, Allez, Matthieu, Deisenhammer, Florian, Fogdell-Hahn, Anna, Mariette, Xavier, Pallardy, Marc, and Broët, Philippe

Subjects
Drug therapy, Usage, Complications and side effects, Genetic aspects, Health aspects, Autoimmune diseases -- Drug therapy -- Genetic aspects, Biopharmaceuticals -- Usage -- Complications and side effects, Immune response -- Genetic aspects -- Health aspects
Abstract

Author(s): Signe Hässler 1,2,3,*, Delphine Bachelet 1,4, Julianne Duhaze 1,5, Natacha Szely 6, Aude Gleizes 6,7, Salima Hacein-Bey Abina 7,8, Orhan Aktas 9, Michael Auer 10, Jerôme Avouac 11,12, Mary [...], Background Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. Methods and findings The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn&apos;s disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 x 10.sup.-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. Conclusion In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Published
2020
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19. IgG4-Associated Cholangitis: A Comprehensive Review

Author

Hubers, Lowiek M., Maillette de Buy Wenniger, Lucas J., Doorenspleet, Marieke E., Klarenbeek, Paul L., Verheij, Joanne, Rauws, Erik A., van Gulik, Thomas M., Oude Elferink, Ronald P. J., van de Graaf, Stan F. J., de Vries, Niek, and Beuers, Ulrich

Published
2015
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23. Improving naive B cell isolation by absence of CD45RB glycosylation and CD27 expression in combination with BCR isotype.

Author

Koers, Jana, Pollastro, Sabrina, Tol, Simon, Niewold, Ilse T.G., van Schouwenburg, Pauline A., de Vries, Niek, and Rispens, Theo

Subjects
B cells, CELL separation, B cell differentiation, B cell receptors, GLYCOSYLATION
Abstract

In past years ex vivo and in vivo experimental approaches involving human naive B cells have proven fundamental for elucidation of mechanisms promoting B cell differentiation in both health and disease. For such studies, it is paramount that isolation strategies yield a population of bona fide naive B cells, i.e., B cells that are phenotypically and functionally naive, clonally non‐expanded, and have non‐mutated BCR variable regions. In this study different combinations of common as well as recently identified B cell markers were compared to isolate naive B cells from human peripheral blood. High‐throughput BCR sequencing was performed to analyze levels of somatic hypermutation and clonal expansion. Additionally, contamination from mature mutated B cells intrinsic to each cell‐sorting strategy was evaluated and how this impacts the purity of obtained populations. Our results show that current naive B cell isolation strategies harbor contamination from non‐naive B cells, and use of CD27‐IgD+ is adequate but can be improved by including markers for CD45RB glycosylation and IgM. The finetuning of naive B cell classification provided herein will harmonize research lines using naive B cells, and will improve B cell profiling during health and disease, e.g. during diagnosis, treatment, and vaccination strategies. [ABSTRACT FROM AUTHOR]

Published
2022
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24. Genetics of rheumatoid arthritis contributes to biology and drug discovery

Author

Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R., Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C., Carroll, Robert J., Eyler, Anne E., Greenberg, Jeffrey D., Kremer, Joel M., Pappas, Dimitrios A., Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tõnu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A., Diogo, Dorothée, Cui, Jing, Liao, Katherine, Guo, Michael H., Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke J. H., van Riel, Piet L. C. M., van de Laar, Mart A. F. J., Guchelaar, Henk-Jan, Huizinga, Tom W. J., Dieudé, Philippe, Mariette, Xavier, Bridges, Louis S., Jr, Zhernakova, Alexandra, Toes, Rene E. M., Tak, Paul P., Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A., Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K., Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry W., Criswell, Lindsey A., Karlson, Elizabeth W., Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun S., Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter K., Raychaudhuri, Soumya, Stranger, Barbara E., De Jager, Philip L., Franke, Lude, Visscher, Peter M., Brown, Matthew A., Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W., Siminovitch, Katherine A., Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, and Plenge, Robert M.

Published
2014
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25. Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis

Author

Umiċeviċ Mirkov, Maša, Cui, Jing, Vermeulen, Sita H, Stahl, Eli A, Toonen, Erik J M, Makkinje, Remco R, Lee, Annette T, Huizinga, Tom W J, Allaart, Renee, Barton, Anne, Mariette, Xavier, Miceli, Corinne Richard, Criswell, Lindsey A, Tak, Paul P, de Vries, Niek, Saevarsdottir, Saedis, Padyukov, Leonid, Bridges, S Louis, van Schaardenburg, Dirk-Jan, Jansen, Tim L, Dutmer, Ellen A J, van de Laar, Mart A F J, Barrera, Pilar, Radstake, Timothy R D J, van Riel, Piet L C M, Scheffer, Hans, Franke, Barbara, Brunner, Han G, Plenge, Robert M, Gregersen, Peter K, Guchelaar, Henk-Jan, and Coenen, Marieke J H

Published
2013
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27. In rheumatoid arthritis inflamed joints share dominant patientspecific B-cell clones.

Author

Musters, Anne, Balzaretti, Giulia, van Schaik, Barbera D. C., Jongejan, Aldo, van der Weele, Linda, Tas, Sander W., van Kampen, Antoine H. C., and de Vries, Niek

Subjects
RHEUMATOID arthritis, SYNOVIAL fluid, ANTIGEN receptors, B cells, INFLAMMATION
Abstract

Background: In patients with rheumatoid arthritis (RA) different joints were shown to share the same dominant T-cell clones, suggesting shared characteristics of the inflammatory process and indicating that strategies to selectively target the antigen receptor might be feasible. Since T- and Blymphocytes closely interact in adaptive responses, we analysed to what extent different joints also share dominant B-cell clones. Methods: In 11 RA patients, quantitative B-cell receptor (BCR) repertoire analysis was performed in simultaneously obtained samples from inflamed synovial tissue (ST) from distinct locations within one joint, from multiple joints, from synovial fluid (SF) and peripheral blood (PB). Results: ST biopsies from different locations in the same joint showed clear overlap in the top-25 dominant BCR clones (16.7%, SD 12.5), in the same range as the overlap between ST and SF in the same joint (8.0%, SD 8.8) and the overlap between ST-ST between different joints (9.1%, SD 8.2), but clearly higher than the overlap between ST and PB (1.7%, SD 2.4; p<0.05) and SF and PB (2.7%, SD 4.1; p<0.05). Interestingly, these figures were substantially lower than the overlap observed in previous T-cell clonality studies. Conclusions: We conclude that in RA BCR clonal responses may be more localized than TCR clonal responses, pointing to antigen-selective influx, proliferation and/or maturation of B-cells. B lineage cells in the SF may adequately represent the dominant BCR clones of the ST, which is in contrast to T-cells. Collectively, the presence of shared B- and especially T-cells in different joints from the same patient suggests that approaches might be feasible that aim to develop antigen-receptor specific targeting of lymphocyte clones in RA as an alternative tomore generalized immunosuppressive strategies. [ABSTRACT FROM AUTHOR]

Published
2022
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32. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti–tumor necrosis factor α therapy

Author

Cui, Jing, Saevarsdottir, Saedis, Thomson, Brian, Padyukov, Leonid, van der Helm-Van Mil, Annette H. M., Nititham, Joanne, Hughes, Laura B., de Vries, Niek, Raychaudhuri, Soumya, Alfredsson, Lars, Askling, Johan, Wedrén, Sara, Ding, Bo, Guiducci, Candace, Wolbink, Gert Jan, Crusius, J. Bart A., van der Horst-Bruinsma, Irene E., Herenius, Marieke, Weinblatt, Michael E., Shadick, Nancy A., Worthington, Jane, Batliwalla, Franak, Kern, Marlena, Morgan, Ann W., Wilson, Anthony G., Isaacs, John D., Hyrich, Kimme, Seldin, Michael F., Moreland, Larry W., Behrens, Timothy W., Allaart, Cornelia F., Criswell, Lindsey A., Huizinga, Tom W. J., Tak, Paul P., Bridges, S. Louis, Jr., Toes, Rene E. M., Barton, Anne, Klareskog, Lars, Gregersen, Peter K., Karlson, Elizabeth W., and Plenge, Robert M.

Published
2010
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35. Proteogenomic analysis of the autoreactive B cell repertoire in blood and tissues of patients with Sjögren's syndrome.

Author

Broeren, Mathijs G. A., Wang, Jing J., Balzaretti, Giulia, Groenen, Patricia J. T. A., van Schaik, Barbera D. C., Chataway, Tim, Kaffa, Charlotte, Bervoets, Sander, Hebeda, Konnie M., Bounova, Gergana, Pruijn, Ger J. M., Gordon, Thomas P., De Vries, Niek, and Thurlings, Rogier M.

Abstract

Objective: To comparatively analyse the aberrant affinity maturation of the antinuclear and rheumatoid factor (RF) B cell repertoires in blood and tissues of patients with Sjögren's syndrome (SjS) using an integrated omics workflow.Methods: Peptide sequencing of anti-Ro60, anti-Ro52, anti-La and RF was combined with B cell repertoire analysis at the DNA, RNA and single cell level in blood B cell subsets, affected salivary gland and extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) of patients with SjS.Results: Affected tissues contained anti-Ro60, anti-Ro52, anti-La and RF clones as a small part of a polyclonal infiltrate. Anti-Ro60, anti-La and anti-Ro52 clones outnumbered RF clones. MALT lymphoma tissues contained monoclonal RF expansions. Autoreactive clones were not selected from a restricted repertoire in a circulating B cell subset. The antinuclear antibody (ANA) repertoires displayed similar antigen-dependent and immunoglobulin (Ig) G1-directed affinity maturation. RF clones displayed antigen-dependent, IgM-directed and more B cell receptor integrity-dependent affinity maturation. This coincided with extensive intra-clonal diversification in RF-derived lymphomas. Regeneration of clinical disease manifestations after rituximab coincided with large RF clones, which not necessarily belonged to the lymphoma clone, that displayed continuous affinity maturation and intra-clonal diversification.Conclusion: The ANA and RF repertoires in patients with SjS display tissue-restricted, antigen-dependent and divergent affinity maturation. Affinity maturation of RF clones deviates further during RF clone derived lymphomagenesis and during regeneration of the autoreactive repertoire after temporary disruption by rituximab. These data give insight into the molecular mechanisms of autoreactive inflammation in SjS, assist MALT lymphoma diagnosis and allow tracking its response to rituximab. [ABSTRACT FROM AUTHOR]

Published
2022
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36. Identification and Characterization of Circulating Naïve CD4+ and CD8+ T Cells Recognizing Nickel

Author

Bechara, Rami, Pollastro, Sabrina, Azoury, Marie Eliane, Szely, Natacha, Maillère, Bernard, de Vries, Niek, Pallardy, Marc, Clinical Immunology and Rheumatology, Graduate School, and AII - Inflammatory diseases

Subjects
CD4-Positive T-Lymphocytes, inorganic chemicals, lcsh:Immunologic diseases. Allergy, Enzyme-Linked Immunospot Assay, Immunology, T-Cell Antigen Receptor Specificity, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Immunophenotyping, Interferon-gamma, Nickel, otorhinolaryngologic diseases, Humans, Cells, Cultured, Original Research, T-cell assay, repertoire, High-Throughput Nucleotide Sequencing, Clone Cells, naive T cells, allergy and immunology, in vitro tests, metals hapten, Blood Circulation, Dermatitis, Allergic Contact, Genes, T-Cell Receptor beta, allergic contact dermatitis, lcsh:RC581-607
Abstract

Allergic contact dermatitis caused by contact sensitizers is a T-cell-mediated inflammatory skin disease. The most prevalent contact allergens is nickel. Whereas, memory T cells from nickel-allergic patients are well-characterized, little is known concerning nickel-specific naïve T-cell repertoire. The purpose of this study was to identify and quantify naïve CD4+ and CD8+ T cells recognizing nickel in the general population. Using a T-cell priming in vitro assay based on autologous co-cultures between naïve T cells and dendritic cells loaded with nickel, we were able to detect a naïve CD4+ and CD8+ T-cell repertoire for nickel in 10/11 and 7/8 of the tested donors. We calculated a mean frequency of 0.49 nickel-specific naïve CD4+ T cells and 0.37 nickel-specific naïve CD8+ T cells per million of circulating naïve T cells. The activation of these specific T cells requires MHC molecules and alongside IFN-γ production, some nickel-specific T-cells were able to produce granzyme-B. Interestingly, nickel-specific naïve CD4+ and CD8+ T cells showed a low rate of cross-reactivity with cobalt, another metallic hapten, frequently mixed with nickel in many alloys. Moreover, naïve CD4+ T cells showed a polyclonal TCRβ composition and the presence of highly expanded clones with an enrichment and/or preferentially expansion of some TRBV genes that was donor and T-cell specific. Our results contribute to a better understanding of the mechanism of immunization to nickel and propose the T-cell priming assay as a useful tool to identify antigen-specific naïve T cells.

Published
2019
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38. Restoration of Default Blood Monocyte-Derived Macrophage Polarization With Adalimumab But Not Etanercept in Rheumatoid Arthritis.

Author

Paoletti, Audrey, Ly, Bineta, Bitoun, Samuel, Nocturne, Gaëtane, Rivière, Elodie, Manson, Jessica J., Matucci, Andrea, Pallardy, Marc, De Vries, Niek, and Mariette, Xavier

Subjects
RHEUMATOID arthritis, TUMOR necrosis factors, MACROPHAGES, ADALIMUMAB, ETANERCEPT
Abstract

Introduction: We previously reported a specific defect of rheumatoid arthritis (RA) monocyte polarization to anti-inflammatory M2-like macrophages related to increased miR-155 expression in all RA patients except those receiving adalimumab (ADA). In this longitudinal study, we examined whether different tumor necrosis factor inhibitors were able to restore monocyte polarization to M2-like macrophages and their effect on the transcriptomic signature. Methods: M2-like polarization induced by human serum AB was studied in 7 healthy donors and 20 RA patients included in the ABIRA cohort before and 3 months after starting ADA or etanercept (ETA). The differential gene expression of M2- and M1-related transcripts was studied in macrophage-derived monocytes after differentiation. Results: At baseline, RA monocytes showed a defect of polarization to M2-like macrophages as compared with healthy donor monocytes, which was negatively correlated with disease activity. M2-like polarization from circulating monocytes was restored only with ADA and not ETA treatment. The transcriptomic signature demonstrated downregulation of M2-related transcripts and upregulation of M1-related transcripts in active RA. In patients receiving ADA, the transcriptomic signature of M2-related transcripts was restored. Conclusion: This longitudinal study demonstrates that ADA but not ETA is able to restore the M2-like polarization of monocytes that is defective in RA. [ABSTRACT FROM AUTHOR]

Published
2022
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44. Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

Author

Sieberts, Solveig K., Zhu, Fan, García-García, Javier, Stahl, Eli, Pratap, Abhishek, Pandey, Gaurav, Pappas, Dimitrios, Aguilar, Daniel, Anton, Bernat, Bonet, Jaume, Eksi, Ridvan, Fornés, Oriol, Guney, Emre, Li, Hongdong, Marín, Manuel Alejandro, Panwar, Bharat, Planas-Iglesias, Joan, Poglayen, Daniel, Cui, Jing, Falcao, Andre O., Suver, Christine, Hoff, Bruce, Balagurusamy, Venkat S. K., Dillenberger, Donna, Neto, Elias Chaibub, Norman, Thea, Aittokallio, Tero, Ammad-ud-din, Muhammad, Azencott, Chloe-Agathe, Bellón, Víctor, Boeva, Valentina, Bunte, Kerstin, Chheda, Himanshu, Cheng, Lu, Corander, Jukka, Dumontier, Michel, Goldenberg, Anna, Gopalacharyulu, Peddinti, Hajiloo, Mohsen, Hidru, Daniel, Jaiswal, Alok, Kaski, Samuel, Khalfaoui, Beyrem, Khan, Suleiman Ali, Kramer, Eric R., Marttinen, Pekka, Mezlini, Aziz M., Molparia, Bhuvan, Pirinen, Matti, Saarela, Janna, Samwald, Matthias, Stoven, Véronique, Tang, Hao, Tang, Jing, Torkamani, Ali, Vert, Jean-Phillipe, Wang, Bo, Wang, Tao, Wennerberg, Krister, Wineinger, Nathan E., Xiao, Guanghua, Xie, Yang, Yeung, Rae, Zhan, Xiaowei, Zhao, Cheng, Calaza, Manuel, Elmarakeby, Haitham, Heath, Lenwood S., Long, Quan, Moore, Jonathan D., Opiyo, Stephen Obol, Savage, Richard S., Zhu, Jun, Greenberg, Jeff, Kremer, Joel, Michaud, Kaleb, Barton, Anne, Coenen, Marieke, Mariette, Xavier, Miceli, Corinne, Shadick, Nancy, Weinblatt, Michael, de Vries, Niek, Tak, Paul P., Gerlag, Danielle, Huizinga, Tom W. J., Kurreeman, Fina, Allaart, Cornelia F., Louis Bridges Jr., S., Criswell, Lindsey, Moreland, Larry, Klareskog, Lars, Saevarsdottir, Saedis, Padyukov, Leonid, Gregersen, Peter K., Friend, Stephen, Plenge, Robert, Stolovitzky, Gustavo, Oliva, Baldo, Guan, Yuanfang, Mangravite, Lara M., Bridges, S. Louis, Intelligent Systems, Institute for Molecular Medicine Finland, Department of Mathematics and Statistics, Helsinki Institute for Information Technology, Jukka Corander / Principal Investigator, Department of Computer Science, Janna Saarela / Principal Investigator, Krister Wennerberg / Principal Investigator, Biostatistics Helsinki, Statistical and population genetics, AII - Amsterdam institute for Infection and Immunity, Clinical Immunology and Rheumatology, Zhejiang University, Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), DYNBIO LEGOS, Laboratoire d'études en Géophysique et océanographie spatiales (LEGOS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institut d'Ecologia Aquàtica, Universitat de Girona (UdG), Department of Medical Genetics, Faculty of Medicine-Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia (UBC), China Agricultural University (CAU), Computational Intelligence Research Group (CA3), Centre of Technology and Systems (CTS), Faculdade de Ciências e Tecnologia = School of Science & Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Faculdade de Ciências e Tecnologia = School of Science & Technology (FCT NOVA), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Hefei University of Technology (HFUT), Stanford Center for BioMedical Informatics Research (BMIR), Stanford University, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Technical Research Centre of Finland, VTT Technical Research Centre of Finland (VTT), U.S. Food and Drug Administration (FDA), Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Profium Oy [Helsinki], Chinese Academy of Agricultural Sciences (CAAS), Business School [Hohai University], Hohai University, Institute of Industrial Economics [Hohai University], State Key Laboratory of Medical Genetics of China, Hunan Medical College, State Key Laboratory of Advanced Special Steel, Shanghai University, Quantitative Biomedical Research Center (QBRC), University of Texas Southwestern Medical Center [Dallas], Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), China National Research Center of Intelligent Equipment for Agriculture [Beijing] (NRCIEA), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Gregor Mendel Institute of Molecular Plant Biology (GMI), Austrian Academy of Sciences (OeAW), Department of Mechanical and Aerospace Engineering [Univ California Davis] (MAE - UC Davis), University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Tongji University, Laboratory for Measles and Rubella, Laboratoire National de Santé [Luxembourg] (LNS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], INSERM U1012, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), School of biosciences and biotechnology, University of Camerino, Università degli Studi di Camerino = University of Camerino (UNICAM), Division of Rheumatology, Immunology and Allergy and Partners Asthma Center, Brigham and Women's Hospital [Boston], Department of Health Education and Promotion, Maastricht University [Maastricht], University of Amsterdam [Amsterdam] (UvA), Department of rheumatology, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Rheumatology Unit, Department of Medicine, University of California [San Francisco] (UC San Francisco), University of California (UC), Rheumatology Unit, Karolinska Institutet [Stockholm], Merck & Co. Inc, Structural Bioinformatics Group (GRIB), Barcelona Research Park of Biomedicine (PRBB), Universitat Pompeu Fabra [Barcelona] (UPF), Capital Normal University [Beijing], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), MINES ParisTech - École nationale supérieure des mines de Paris, California Institute of Technology (CALTECH)-NASA, Department of Mechanical and Aerospace Engineering [Davis], University of California-University of California, Università degli Studi di Camerino (UNICAM), University of California [San Francisco] (UCSF), University of California, Sage Bionetworks, University of Michigan, Ann Arbor, Pompeu Fabra University, Icahn School of Medicine at Mount Sinai, Corrona LLC, Northeastern University, Harvard University, University of Lisbon, IBM, INSERM U900, University of Helsinki, University of Toronto, Scripps Research Institute, Medical University of Vienna, University of Texas at Dallas, New York University, Albany Medical College, Arthritis Research Center Foundation, Radboud University Nijmegen, INSERM U1184, University of Amsterdam, Glaxo Smith Kline, Leiden University, University of Alabama at Birmingham, University of California San Francisco, University of Pittsburgh, Karolinska Institutet, North Shore-Long Island Jewish Health System, Merck, Aalto-yliopisto, and Aalto University

Subjects
Male, 0301 basic medicine, General Physics and Astronomy, Arthritis, Genome-wide association study, Bioinformatics, DISEASE, Arthritis, Rheumatoid, Cohort Studies, Missing heritability problem, MISSING HERITABILITY, Medicine, Certolizumab pegol, RISK, Multidisciplinary, Antibodies, Monoclonal, Middle Aged, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, STACKED GENERALIZATION, Treatment Outcome, Antirheumatic Agents, Crowdsourcing, Biomarker (medicine), Female, Erratum, medicine.drug, Adult, Science, Context (language use), Antibodies, Monoclonal, Humanized, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, INFLIXIMAB, Journal Article, Humans, SNP, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Aged, ta113, Tumor Necrosis Factor-alpha, business.industry, NETWORK INFERENCE, COMPLEX TRAITS, Artritis reumatoide -- Tractament, CLINICAL-RESPONSE, General Chemistry, 113 Computer and information sciences, medicine.disease, Infliximab, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Certolizumab Pegol, business, RC
Abstract

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data., Rheumatoid arthritis patients respond differently to anti-TNF treatment. Using community-based challenge, the authors show that currently available data does not reveal meaningful genetic predictors of response to anti-TNF therapy, thus confirming clinical observations.

Published
2016
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46. Characterization and Monitoring of Antigen-Responsive T Cell Clones Using T Cell Receptor Gene Expression Analysis.

Author

Pollastro, Sabrina, de Bourayne, Marie, Balzaretti, Giulia, Jongejan, Aldo, van Schaik, Barbera D. C., Niewold, Ilse T. G., van Kampen, Antoine H. C., Maillère, Bernard, and de Vries, Niek

Subjects
T cell receptors, T cells, CLONE cells, GENE expression, PHENOTYPES
Abstract

High-throughput T-cell receptor repertoire sequencing constitutes a powerful tool to study T cell responses at the clonal level. However, it does not give information on the functional phenotype of the responding clones and lacks a statistical framework for quantitative evaluation. To overcome this, we combined datasets from different experiments, all starting from the same blood samples. We used a novel, sensitive, UMI-based protocol to perform repertoire analysis on experimental replicates. Applying established bioinformatic routines for transcriptomic expression analysis we explored the dynamics of antigen-induced clonal expansion after in vitro stimulation, identified antigen-responsive clones, and confirmed their activation status using the expression of activation markers upon antigen re-challenge. We demonstrate that the addition of IL-4 after antigen stimulation drives the expansion of T cell clones encoding unique receptor sequences. We show that our approach represents a scalable, high-throughput immunological tool, which can be used to identify and characterize antigen-responsive T cells at clonal level. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity.

Author

Kavazović, Inga, Han, Hongya, Balzaretti, Giulia, Slinger, Erik, Lemmermann, Niels A. W., ten Brinke, Anja, Merkler, Doron, Koster, Jan, Bryceson, Yenan T., de Vries, Niek, Jonjić, Stipan, Klarenbeek, Paul L., Polić, Bojan, Eldering, Eric, and Wensveen, Felix M.

Subjects
BCL-2 proteins, MEMORY, TRANSCRIPTION factors, EPITOPES
Abstract

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection. This study shows that the diversity of the memory CD8 T-cell pool is regulated by the transcription factor Eomes, which drives transcription of the pro-survival protein Bcl-2. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool. [ABSTRACT FROM AUTHOR]

Published
2020
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48. Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay

Author

Schultz, Heidi S., Reedtz-Runge, Stine Louise, Bäckström, B. Thomas, Lamberth, Kasper, Pedersen, Christian R., Kvarnhammar, Anne M., de Vries, Niek, et al, AII - Inflammatory diseases, Clinical Immunology and Rheumatology, and Amsterdam institute for Infection and Immunity

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, Physiology, lcsh:Medicine, Pathology and Laboratory Medicine, Biochemistry, White Blood Cells, 0302 clinical medicine, Natalizumab, HLA Antigens, Animal Cells, Immune Physiology, Medicine and Health Sciences, Medicine, Enzyme-Linked Immunoassays, lcsh:Science, Immune Response, Multidisciplinary, Immune System Proteins, biology, T Cells, Immunogenicity, ELISPOT, Tissue Donors, 3. Good health, medicine.anatomical_structure, Medical Microbiology, Viral Pathogens, Viruses, Human Cytomegalovirus, Rituximab, Antibody, Cellular Types, Pathogens, medicine.drug, Research Article, Herpesviruses, T cell, Immune Cells, Immunology, Antigen-Presenting Cells, Enzyme-Linked Immunosorbent Assay, Cytotoxic T cells, chemical and pharmacologic phenomena, Human leukocyte antigen, Research and Analysis Methods, Microbiology, complex mixtures, Antibodies, 03 medical and health sciences, Humans, Antigens, Immunoassays, Microbial Pathogens, Secretion, 030203 arthritis & rheumatology, Blood Cells, business.industry, lcsh:R, Organisms, Biology and Life Sciences, Proteins, Cell Biology, 030104 developmental biology, Haplotypes, biology.protein, Immunologic Techniques, lcsh:Q, business, Physiological Processes, DNA viruses, Keyhole limpet hemocyanin
Abstract

Many biopharmaceuticals (BPs) are known to be immunogenic in the clinic, which can result in modified pharmacokinetics, reduced efficacy, allergic reactions and anaphylaxis. During recent years, several technologies to predict immunogenicity have been introduced, but the predictive value is still considered low. Thus, there is an unmet medical need for optimization of such technologies. The generation of T cell dependent high affinity anti-drug antibodies plays a key role in clinical immunogenicity. This study aimed at developing and evaluating a novel in vitro T cell:PBMC assay for prediction of the immunogenicity potential of BPs. To this end, we assessed the ability of infliximab (anti-TNF-α), rituximab (anti-CD20), adalimumab (anti-TNF-α) and natalizumab (anti-α4-integrin), all showing immunogenicity in the clinic, to induce a CD4+ T cells response. Keyhole limpet hemocyanin (KLH) and cytomegalovirus pp65 protein (CMV) were included as neo-antigen and recall antigen positive controls, respectively. By analyzing 26 healthy donors having HLA-DRB1 alleles matching the European population, we calculated the frequency of responding donors, the magnitude of the response, and the frequency of BP-specific T cells, as measured by 3[H]-thymidine incorporation and ELISpot IL-2 secretion. KLH and CMV demonstrated a strong T cell response in all the donors analyzed. The frequency of responding donors to the BPs was 4% for infliximab, 8% for adalimumab, 19% for rituximab and 27% for natalizumab, which is compared to and discussed with their respective observed clinical immunogenicity. This study further complements predictive immunogenicity testing by quantifying the in vitro CD4+ T cell responses to different BPs. Even though the data generated using this modified method does not directly translate to the clinical situation, a high sensitivity and immunogenic potential of most BPs is demonstrated.

Published
2017

49. The role of rare protein-coding variants to anti-TNF treatment response in rheumatoid arthritis

Author

Cui, Jing, Diogo, Dorothee, Stahl, Eli A, Canhao, Helena, Mariette, Xavier, Greenberg, Jeffrey D, Okada, Yukinori, Pappas, Dimitrios A, Fulton, Robert S, Tak, Paul P, Nurmohamed, Michael T, Lee, Annette, Larson, David E, Kurreeman, Fina, Deluca, Tracie L, O'Laughlin, Michelle, Fronick, Catrina C, Fulton, Lucinda L, Mardis, Elaine R, van der Horst-Bruinsma, Irene E, Wolbink, Gert-Jan, Gregersen, Peter K, Kremer, Joel M, Crusius, J Bart A, de Vries, Niek, Huizinga, Tom W J, Fonseca, João Eurico, Miceli-Richard, Corinne, Karlson, Elizabeth W, Coenen, Marieke Jh, Barton, Anne, Plenge, Robert M, Raychaudhuri, Soumya, AII - Inflammatory diseases, Rheumatology, and ICaR - Circulation and metabolism

Abstract

Objective Many rheumatoid arthritis (RA) patients have their disease controlled with anti-tumor necrosis factor alpha (anti-TNF) biologic therapies. However, a significant number of RA patients fail to respond to anti-TNF therapy. Here, we hypothesized that rare and low-frequency variants might influence anti-TNF treatment response. Methods We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry treated with anti-TNF medications. After quality control, we included 690 genes in the analysis. We applied single variants association and gene-based association tests to identify variants associated with anti-TNF treatment response. We also performed gene set analyses of 27 TNF pathway genes, considering TNF's key mechanistic role. Results We identified 14,420 functional variants, of which 6,934 were predicted as non-synonymous where 2,136 were further predicted to be damaging. Despite being a well-powered study, no single variant or gene showed study-wide significant association with change in disease activity outcome or EULAR response outcome. Intriguingly, we observed 3 genes, out of 27 with nominal signals of association (P

Published
2017
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