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Germinal center reaction

Haotian Mao, Mengying Chen, Yanqiu Su, Nan Wu, Ming Yuan, Shu Yuan, Marian Brestic, Marek Zivcak, Huaiyu Zhang, Yanger Chen
To investigate the evolutionary differences of wheat with different ploidy levels and octoploid Triticale, photosynthetic capacity, and antioxidant defenses system were compared within and between diploid, tetraploid and hexaploid wheat, and octoploid Triticale seedlings. The results showed that seed germination rate, chlorophyll content, and photochemical activity of photosystems, and the activities of antioxidative enzymes in hexaploid wheat and octoploid Triticale were significantly higher than in diploid and tetraploid wheat...
October 2, 2018: International Journal of Molecular Sciences
Katelyn Paz, Ryan Flynn, Jing Du, Jun Qi, Leo Luznik, Ivan Maillard, Kelli P MacDonald, Geoffrey R Hill, Jonathan S Serody, William J Murphy, Peter T Sage, Arlene H Sharpe, David Miklos, Corey S Culter, John Koreth, Joseph H Antin, Robert J Soiffer, Jerome Ritz, James E Bradner, Ari M Melnick, Bruce Blazar
Patient outcomes for steroid-dependent or -refractory cGVHD are poor and only ibrutinib has been FDA approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B-cells to produce antibodies that are associated with disease pathogenesis. The transcriptional co-repressor BCL6 is a member of the BTB/POZ transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T-cells and B-cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target...
October 2, 2018: Blood
Carlos G Briseño, Ansuman T Satpathy, Jesse T Davidson, Stephen T Ferris, Vivek Durai, Prachi Bagadia, Kevin W O'Connor, Derek J Theisen, Theresa L Murphy, Kenneth M Murphy
CD4+ T follicular helper (TFH ) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2 -dependent cDC2s, but not Batf3 -dependent cDC1s or Klf4 -dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes This effect was mediated independent of Il2ra and several Notch2 -dependent genes expressed in cDC2s, including Stat4 and Havcr2 Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation...
October 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
Pilar M Dominguez, Hussein Ghamlouch, Wojciech Rosikiewicz, Parveen Kumar, Wendy Béguelin, Lorena Fontan, Martín A Rivas, Patrycja Pawlikowska, Marine Armand, Enguerran Mouly, Miguel Torres-Martin, Ashley S Doane, Maria Teresa Calvo Fernandez, Matt Durant, Veronique Della-Valle, Matt Teater, Luisa Cimmino, Nathalie Droin, Saber Tadros, Samaneh Motanagh, Alan H Shih, Mark A Rubin, Wayne Tam, Iannis Aifantis, Ross L Levine, Olivier Elemento, Giorgio Inghirami, Michael R Green, Maria E Figueroa, Olivier A Bernard, Said Aoufouchi, Sheng Li, Rita Shaknovich, Ari M Melnick
TET2 somatic mutations occur in ~10% of DLBCLs but are of unknown significance. Herein we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B-cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation and a pre-neoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit such as PRDM1...
October 1, 2018: Cancer Discovery
Kati Kiil, Julia Bein, Bianca Schuhmacher, Lorenz Thurner, Markus Schneider, Martin-Leo Hansmann, Sylvia Hartmann
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma that frequently shows a nodal growth pattern with abundant reactive B cells in the microenvironment. Early NLPHL cases can be particularly difficult to differentiate from progressively transformed germinal centers (PTGC). Since PTGC have been described to be IgG4 associated in a relatively high proportion of cases, the aim of the present study was to determine if IgG4 immunostaining can be helpful in the differential diagnosis between NLPHL and PTGC...
September 26, 2018: Virchows Archiv: An International Journal of Pathology
Carolyn E Rydyznski, Stacey A Cranert, Julian Q Zhou, Heping Xu, Steven H Kleinstein, Harinder Singh, Stephen N Waggoner
Somatic hypermutation of immunoglobulin sequences in germinal center (GC) reactions must be optimized to elicit high-affinity, protective antibodies after vaccination. We expose natural killer (NK) cells as robust negative regulators of somatic hypermutation in antigen-reactive B cells. NK cells restrict follicular helper T cell (TFH ) and GC B cell frequencies and titers of antigen-specific immunoglobulin after administration of alum-adjuvanted hapten-protein conjugate vaccines. This inhibition is perforin dependent, suggesting that NK cells kill one or more cells critical for GC development...
September 25, 2018: Cell Reports
John L Snider, Nuengsap Thangthong, Cristiane Pilon, Gurpreet Virk, Viktor Tishchenko
Vigorous seedling growth in cotton is desirable because it minimizes the negative impact of multiple early season stresses, and seedling vigor can be impacted by early season growth temperature or cultivar. OJIP fluorescence provides rapid information on a broad range of photosynthetic component processes and may be a useful surrogate for seeding vigor, but this possibility has not been evaluated previously in cotton. To this end, a controlled environment study was conducted with six cultivars selected based on seed characteristics that are widely indicative of vigor and under two growth temperature regimes (sub-optimal = 20/15 °C day/night temperature; optimal = 30/20 °C) for the first two weeks after seed germination...
September 12, 2018: Plant Physiology and Biochemistry: PPB
Shuang Song, Patrick D Matthias
Germinal centers (GCs) are essential structures of the humoral immune response, which form in the periphery in response to T cell dependent antigens. During the GC reaction, B cells undergo critical differentiation steps, which ultimately lead to the generation of antibodies with altered effector function and higher affinity for the selected antigen. Remarkably, many of the B cell tumors have their origin in the GCs; thus, understanding how the formation of these structures is regulated or deregulated is of high medical importance...
2018: Frontiers in Immunology
Lei Qin, Tayab C Waseem, Anupama Sahoo, Shayahati Bieerkehazhi, Hong Zhou, Elena V Galkina, Roza Nurieva
T follicular helper (Tfh) cells play key role in providing help to B cells during germinal center (GC) reactions. Generation of protective antibodies against various infections is an important aspect of Tfh-mediated immune responses and the dysregulation of Tfh cell responses has been implicated in various autoimmune disorders, inflammation, and malignancy. Thus, their differentiation and maintenance must be closely regulated to ensure appropriate help to B cells. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs...
2018: Frontiers in Immunology
Nicolas Fazilleau, Meryem Aloulou
An efficient B cell immunity requires a dynamic equilibrium between positive and negative signals. In germinal centers (GCs), T follicular helper cells are supposed to be the positive regulator while T follicular regulatory (Tfr) cells were assigned to be the negative regulators. Indeed, Tfr cells are considered as a homogenous cell population dedicated to dampen the GC extent. Moreover, Tfr cells prevent autoimmunity since their dysregulation leads to production of self-reactive antibodies (Ab). However, a growing corpus of evidence has revealed additional and unexpected functions for Tfr cells in the regulation of B cell responses...
2018: Frontiers in Immunology
Karīna Siliņa, Chiara Burkhardt, Ruben Casanova, Alex Solterman, Maries van den Broek
Tertiary lymphoid structures (TLS) develop in the human tumor microenvironment and correlate with prolonged survival in most cancer types. We recently demonstrated that TLS development follows sequential maturation stages and culminates in the generation of a germinal center (GC) reaction. This maturation process is crucial for the prognostic relevance of TLS in lung and colorectal cancer patients.The mechanisms underlying TLS development in various inflammatory conditions or their functional relevance in tumor immunity are not fully understood...
2018: Methods in Molecular Biology
Vinod Krishna, Kurtis E Bachman
A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the Germinal Center reaction...
2018: PloS One
Jeremy S Leventhal
T cell-dependent germinal center (GC) reactions are the pinnacle of adaptive immune responses, with profound effects on human health and disease. It has long been known that ligands of an innate immune pattern recognition receptor subgroup, TLRs, amplify antibody responses; however, the mechanisms regulating this phenomenon are poorly understood. In this issue of the JCI, Raso et al. demonstrate that αvβ3 integrins regulate the magnitude and speed of TLR-augmented GC reactions, limiting both short- and long-term humoral immunity...
August 31, 2018: Journal of Clinical Investigation
Giuseppe Lofano, Matthew J Gorman, Ashraf S Yousif, Wen-Han Yu, Julie M Fox, Anne-Sophie Dugast, Margaret E Ackerman, Todd J Suscovich, Joshua Weiner, Dan Barouch, Hendrik Streeck, Susan Little, Davey Smith, Douglas Richman, Douglas Lauffenburger, Bruce D Walker, Michael S Diamond, Galit Alter
HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC...
August 17, 2018: Science Immunology
Wandi Zhu, Song Li, Chao Wang, Guoying Yu, Mark R Prausnitz, Bao-Zhong Wang
Skin vaccination using biodegradable microneedle patch (MNP) technology in vaccine delivery is a promising strategy showing significant advantages over conventional flu shots. In this study, we developed an MNP encapsulating a 4M2e-tFliC fusion protein and two types of whole inactivated influenza virus vaccines (H1N1 and H3N2) as a universal vaccine candidate. We demonstrated that mice receiving this tri-component influenza vaccine via MNP acquired improved IgG1 antibody responses with more balanced IgG1/IgG2a antibody responses and enhanced cellular immune responses, including increased populations of IL-4 and IFN-γ producing cells and higher frequencies of antigen-specific plasma cells compared with intramuscular injection...
2018: Frontiers in Immunology
Pierre Milpied, Iñaki Cervera-Marzal, Marie-Laure Mollichella, Bruno Tesson, Gabriel Brisou, Alexandra Traverse-Glehen, Gilles Salles, Lionel Spinelli, Bertrand Nadel
Most adult B cell lymphomas originate from germinal center (GC) B cells, but it is unclear to what extent B cells in overt lymphoma retain the functional dynamics of GC B cells or are blocked at a particular stage of the GC reaction. Here we used integrative single-cell analysis of phenotype, gene expression and variable-region sequence of the immunoglobulin heavy-chain locus to track the characteristic human GC B cell program in follicular lymphoma B cells. By modeling the cyclic continuum of GC B cell transitional states, we identified characteristic patterns of synchronously expressed gene clusters...
September 2018: Nature Immunology
Lan He, Wangpeng Gu, Meng Wang, Xiaoyan Chang, Xiaoyu Sun, Yuan Zhang, Xuan Lin, Chenghua Yan, Weiguo Fan, Pan Su, Yanming Wang, Chunyan Yi, Guomei Lin, Li Li, Yu Jiang, Junxia Lu, Chen Dong, Haikun Wang, Bing Sun
T-follicular helper (TFH ) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model...
August 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
Andreas Hutloff
T and B cell cooperation normally takes place in secondary lymphoid organs (SLO). However, both cell types are also frequently found in inflamed non-lymphoid tissues. Under certain conditions, these infiltrates develop into ectopic lymphoid structures, also known as tertiary lymphoid tissues, which structurally and functionally fully resemble germinal centers (GCs) in SLO. However, tertiary lymphoid tissue is uncommon in most human autoimmune conditions; instead, relatively unstructured T and B cell infiltrates are found...
2018: Frontiers in Immunology
Xiaoqing Lu, Tharu Fernando, Chen Lossos, Nevin Yusufova, Fan Liu, Lorena Fontán, Matthew Durant, Huimin Geng, Jacob Melnick, Yuan Luo, Francisco Vega, Vincent Moy, Giorgio Inghirami, Stephen Nimer, Ari M Melnick, Izidore S Lossos
The Germinal Center (GC) reaction plays an important role in generating humoral immunity and is believed to give rise to most B-cell lymphomas. GC entry and exit are tightly regulated processes, controlled by the actions of transcription factors such as BCL6. Herein we demonstrate that PRMT5, a symmetric dimethyl arginine methyltransferase, is also necessary for GC formation and affinity maturation. PRMT5 contributes to GC formation and affinity maturation at least in part through its direct interaction with and methylation of BCL6 at arginine 305 (R305), a modification necessary for the full transcriptional repressive effects of BCL6...
August 6, 2018: Blood
Noémie Gensous, Manon Charrier, Dorothée Duluc, Cécile Contin-Bordes, Marie-Elise Truchetet, Estibaliz Lazaro, Pierre Duffau, Patrick Blanco, Christophe Richez
T follicular helper (Tfh) cells are a distinct subset of CD4+ T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity...
2018: Frontiers in Immunology
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