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Germinal center dark zone

Chun Chou, Daniel J Verbaro, Elena Tonc, Melanie Holmgren, Marina Cella, Marco Colonna, Deepta Bhattacharya, Takeshi Egawa
B cells diversify and affinity mature their antigen receptor repertoire in germinal centers (GCs). GC B cells receive help signals during transient interaction with T cells, yet it remains unknown how these transient T-B interactions in the light zone sustain the subsequent proliferative program of selected B cells that occurs in the anatomically distant dark zone. Here, we show that the transcription factor AP4 was required for sustained GC B cell proliferation and subsequent establishment of a diverse and protective antibody repertoire...
September 20, 2016: Immunity
Elisa Ferretti, Maurilio Ponzoni, Claudio Doglioni, Vito Pistoia
The germinal center (GC) is a dynamic structure formed by proliferating B cells in the follicles of secondary lymphoid organs during T cell-dependent antibody responses to exogenous antigens. GC is composed by a dark zone, enriched in proliferating centroblasts (CBs), and a light zone where CBs migrate and transform into centrocytes (CCs), a minority of which is selected to survive, undergoes Ig class-switch recombination, and differentiates into memory B cells or long-lived plasma cells. CBs express CXCR4 and are attracted to the dark zone by stromal cell-derived CXCL12, whereas CCs express CXCR5 and are recruited to the light zone along a gradient of CXCL13 produced by follicular dendritic cells (FDCs)...
August 26, 2016: Journal of Leukocyte Biology
Sally E Trabucco, Rachel M Gerstein, Hong Zhang
The germinal center (GC) reaction produces high-affinity Abs for a robust adaptive immune response. When dysregulated, the same processes cause GC B cells to become susceptible to lymphomagenesis. It is important to understand how the GC reaction is regulated. In this study, we show that transcription factor YY1 is required to maintain a robust GC reaction in mice. Selective ablation of YY1 significantly decreased in the frequency and number of GC B cells during the GC reaction. This decrease of GC B cells was accompanied by increased apoptosis in these cells...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Christof Schneider, Ning Kon, Letizia Amadori, Qiong Shen, Friederike H Schwartz, Benjamin Tischler, Marion Bossennec, David Dominguez-Sola, Govind Bhagat, Wei Gu, Katia Basso, Riccardo Dalla-Favera
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for the germinal center (GC) reaction and is implicated in lymphomagenesis. BCL6 protein stability is regulated by F-box protein 11 (FBXO11)-mediated ubiquitination and degradation, which is impaired in ∼6% of diffuse large B-cell lymphomas that carry inactivating genetic alterations targeting the FBXO11 gene. In order to investigate the role of FBXO11 in vivo, we analyzed GC-specific FBXO11 knockout mice. FBXO11 reduction or loss led to an increased number of GC B cells, to an altered ratio of GC dark zone to light zone cells, and to higher levels of BCL6 protein in GC B cells...
August 4, 2016: Blood
Jane A Healy, Adrienne Nugent, Rachel E Rempel, Andrea B Moffitt, Nicholas S Davis, Xiaoyu Jiang, Jennifer R Shingleton, Jenny Zhang, Cassandra Love, Jyotishka Datta, Matthew E McKinney, Tiffany J Tzeng, Nina Wettschureck, Stefan Offermanns, Katelyn A Walzer, Jen-Tsan Chi, Suhail A K Rasheed, Patrick J Casey, Izidore S Lossos, Sandeep S Dave
GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro...
June 2, 2016: Blood
Lena Krzyzak, Christine Seitz, Anne Urbat, Stefan Hutzler, Christian Ostalecki, Joachim Gläsner, Andreas Hiergeist, André Gessner, Thomas H Winkler, Alexander Steinkasserer, Lars Nitschke
CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli...
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Alba Llibre, Constantino López-Macías, Teresa Marafioti, Hema Mehta, Amy Partridge, Carina Kanzig, Felice Rivellese, Jacob D Galson, Lucy J Walker, Paul Milne, Rodney E Phillips, Dominic F Kelly, Gordon J Freeman, Mohey Eldin El Shikh, Paul Klenerman, Christian B Willberg
Germinal centers (GCs) are microanatomical structures critical for the development of high-affinity Abs and B cell memory. They are organized into two zones, light and dark, with coordinated roles, controlled by local signaling. The innate lectin-like transcript 1 (LLT1) is known to be expressed on B cells, but its functional role in the GC reaction has not been explored. In this study, we report high expression of LLT1 on GC-associated B cells, early plasmablasts, and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40, and CpG stimulation on B cells...
March 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jason G Cyster
Germinal center B cells exist in two conditions, a dark zone state and a light zone state. Two studies in this issue (Dominguez-Sola et al., 2015; Sander et al., 2015) report that Foxo1 deficiency causes an almost complete loss of dark zone cells and an inability to undergo robust antibody affinity maturation.
December 15, 2015: Immunity
Sandrine Sander, Van Trung Chu, Tomoharu Yasuda, Andrew Franklin, Robin Graf, Dinis Pedro Calado, Shuang Li, Koshi Imami, Matthias Selbach, Michela Di Virgilio, Lars Bullinger, Klaus Rajewsky
Phosphatidylinositol 3' OH kinase (PI3K) signaling and FOXO transcription factors play opposing roles at several B cell developmental stages. We show here abundant nuclear FOXO1 expression in the proliferative compartment of the germinal center (GC), its dark zone (DZ), and PI3K activity, downregulating FOXO1, in the light zone (LZ), where cells are selected for further differentiation. In the LZ, however, FOXO1 was expressed in a fraction of cells destined for DZ reentry. Upon FOXO1 ablation or induction of PI3K activity, GCs lost their DZ, owing at least partly to downregulation of the chemokine receptor CXCR4...
December 15, 2015: Immunity
David Dominguez-Sola, Jennifer Kung, Antony B Holmes, Victoria A Wells, Tongwei Mo, Katia Basso, Riccardo Dalla-Favera
The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation...
December 15, 2015: Immunity
Lauren B Rodda, Oliver Bannard, Burkhard Ludewig, Takashi Nagasawa, Jason G Cyster
The germinal center (GC) is divided into a dark zone (DZ) and a light zone (LZ). GC B cells must cycle between these zones to achieve efficient Ab affinity maturation. Follicular dendritic cells (FDCs) are well characterized for their role in supporting B cell Ag encounter in primary follicles and in the GC LZ. However, the properties of stromal cells supporting B cells in the DZ are relatively unexplored. Recent work identified a novel stromal population of Cxcl12-expressing reticular cells (CRCs) in murine GC DZs...
November 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Helene Kretzmer, Stephan H Bernhart, Wei Wang, Andrea Haake, Marc A Weniger, Anke K Bergmann, Matthew J Betts, Enrique Carrillo-de-Santa-Pau, Gero Doose, Jana Gutwein, Julia Richter, Volker Hovestadt, Bingding Huang, Daniel Rico, Frank Jühling, Julia Kolarova, Qianhao Lu, Christian Otto, Rabea Wagener, Judith Arnolds, Birgit Burkhardt, Alexander Claviez, Hans G Drexler, Sonja Eberth, Roland Eils, Paul Flicek, Siegfried Haas, Michael Hummel, Dennis Karsch, Hinrik H D Kerstens, Wolfram Klapper, Markus Kreuz, Chris Lawerenz, Dido Lenze, Markus Loeffler, Cristina López, Roderick A F MacLeod, Joost H A Martens, Marta Kulis, José Ignacio Martín-Subero, Peter Möller, Inga Nagel, Simone Picelli, Inga Vater, Marius Rohde, Philip Rosenstiel, Maciej Rosolowski, Robert B Russell, Markus Schilhabel, Matthias Schlesner, Peter F Stadler, Monika Szczepanowski, Lorenz Trümper, Hendrik G Stunnenberg, Ralf Küppers, Ole Ammerpohl, Peter Lichter, Reiner Siebert, Steve Hoffmann, Bernhard Radlwimmer
Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells...
November 2015: Nature Genetics
Lydia Hopp, Henry Löffler-Wirth, Hans Binder
Mature B-cell lymphoma is a clinically and biologically highly diverse disease. Its diagnosis and prognosis is a challenge due to its molecular heterogeneity and diverse regimes of biological dysfunctions, which are partly driven by epigenetic mechanisms. We here present an integrative analysis of DNA methylation and gene expression data of several lymphoma subtypes. Our study confirms previous results about the role of stemness genes during development and maturation of B-cells and their dysfunction in lymphoma locking in more proliferative or immune-reactive states referring to B-cell functionalities in the dark and light zone of the germinal center and also in plasma cells...
September 7, 2015: Genes
Silvia Preite, Dirk Baumjohann, Mathilde Foglierini, Camilla Basso, Francesca Ronchi, Blanca M Fernandez Rodriguez, Davide Corti, Antonio Lanzavecchia, Federica Sallusto
We previously reported that Cd3e-deficient mice adoptively transferred with CD4(+) T cells generate high numbers of T follicular helper (Tfh) cells, which go on to induce a strong B-cell and germinal center (GC) reaction. Here, we show that in this system, GC B cells display an altered distribution between the dark and light zones, and express low levels of activation-induced cytidine deaminase. Furthermore, GC B cells from Cd3e(-/-) mice accumulate fewer somatic mutations as compared with GC B cells from wild-type mice, and exhibit impaired affinity maturation and reduced differentiation into long-lived plasma cells...
November 2015: European Journal of Immunology
Megan Woods, Yong-Rui Zou, Anne Davidson
Germinal centers (GCs) are the primary site at which clonal expansion and affinity maturation of B cells occur. B cells encounter antigen and receive T cell help in the GC light zone (LZ) and then migrate to the dark zone where they proliferate and undergo somatic mutation before cycling back to the LZ for further rounds of selection. Tolerance to autoantigens is frequently lost de novo as GC B cells undergo class switching and somatic mutation. This loss of tolerance is regulated by a variety of mechanisms including cell death, failure to compete for T cell help, and failure to differentiate into effector cells...
2015: Frontiers in Immunology
Alexander D Gitlin, Christian T Mayer, Thiago Y Oliveira, Ziv Shulman, Mathew J K Jones, Amnon Koren, Michel C Nussenzweig
The germinal center (GC) is a microanatomical compartment wherein high-affinity antibody-producing B cells are selectively expanded. B cells proliferate and mutate their antibody genes in the dark zone (DZ) of the GC and are then selected by T cells in the light zone (LZ) on the basis of affinity. Here, we show that T cell help regulates the speed of cell cycle phase transitions and DNA replication of GC B cells. Genome sequencing and single-molecule analyses revealed that T cell help shortens S phase by regulating replication fork progression, while preserving the relative order of replication origin activation...
August 7, 2015: Science
Alexis Boneparth, Weiqing Huang, Ramalingam Bethunaickan, Megan Woods, Ranjit Sahu, Shitij Arora, Meredith Akerman, Martin Lesser, Anne Davidson
TLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain transgene 3H9 that encodes for the TLR7 regulated anti-CL response. To create a physiologic setting in which autoreactive B cells compete for survival with non-autoreactive B cells, we generated bone marrow chimeras in which disease onset occurred with similar kinetics and the transferred 3H9+ female non-Yaa, male Yaa or male TLR7(-/Yaa) cells could be easily identified by positivity for GFP...
2015: PloS One
Shi-Kang Zhai, Veronica V Volgina, Periannan Sethupathi, Katherine L Knight, Dennis K Lanning
Microbial and host cell interactions stimulate rabbit B cells to diversify the primary Ab repertoire in GALT. B cells at the base of appendix follicles begin proliferating and diversifying their V-(D)-J genes around 1 wk of age, ∼5 d after B cells first begin entering appendix follicles. To gain insight into the microbial and host cell interactions that stimulate B cells to diversify the primary Ab repertoire, we analyzed B cell trafficking within follicles during the first week of life. We visualized B cells, as well as chemokines that mediate B cell homing in lymphoid tissues, by in situ hybridization, and we examined B cell chemokine receptor expression by flow cytometry...
December 15, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Nicole Heise, Nilushi S De Silva, Kathryn Silva, Amanda Carette, Giorgia Simonetti, Manolis Pasparakis, Ulf Klein
Germinal centers (GCs) are the sites where memory B cells and plasma cells producing high-affinity antibodies are generated during T cell-dependent immune responses. The molecular control of GC B cell maintenance and differentiation remains incompletely understood. Activation of the NF-κB signaling pathway has been implicated; however, the distinct roles of the individual NF-κB transcription factor subunits are unknown. We report that GC B cell-specific deletion of the NF-κB subunits c-REL or RELA, which are both activated by the canonical NF-κB pathway, abolished the generation of high-affinity B cells via different mechanisms acting at distinct stages during the GC reaction...
September 22, 2014: Journal of Experimental Medicine
Yuanyuan Zheng, Xiaoge Zhou, Jianlan Xie, Hong Zhu, Shuhong Zhang, Yanning Zhang, Xuejing Wei, Bing Yue
The trapping of IgM-containing immune complexes (ICs) by follicular dendritic cells (FDCs) serves as an important step in promoting germinal center (GC) formation. Thus, the deposition of IgM-containing ICs on FDCs can be detected by antibodies recognizing IgM. The present investigation provides the first comprehensive report on the IgM staining pattern in follicular lymphoma (FL, n = 60), with comparisons to reactive follicular hyperplasias (RFH, n = 25), demonstrating that immunohistochemical staining for IgM in paraffin-embedded sections seems to be an additional tool for differentiating between FL and RFH...
2014: International Journal of Clinical and Experimental Pathology
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