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Riccardo Dallafavera - One of the best experts on this subject based on the ideXlab platform.

  • the foxo1 transcription factor instructs the Germinal Center dark zone program
    Immunity, 2015
    Co-Authors: David Dominguezsola, Katia Basso, Jennifer Kung, Antony B Holmes, Victoria A Wells, Riccardo Dallafavera
    Abstract:

    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. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression.

  • signatures of murine b cell development implicate yy1 as a regulator of the Germinal Center specific program
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Michael R Green, Marc Schmidtsupprian, Stefano Monti, Riccardo Dallafavera, Laura Pasqualucci, Nicole C Walsh, Jeffery L Kutok, Scott J Rodig, Donna Neuberg, Klaus Rajewsky
    Abstract:

    We utilized gene expression profiling of a comprehensive panel of purified developmentally defined normal murine B cells to identify unique transcriptional signatures for each subset. To elucidate transcription factor activities that function in a stage-specific fashion, we used gene sets that share transcription factor targets and found that Germinal Center B cells had a robust enrichment of up-regulated and down-regulated signatures compared with the other B-cell subsets. Notably, we found Yy1 and its targets to be central regulators of the Germinal Center B (GCB)-specific transcriptional program with binding of Yy1 to select signature genes in GCB cells, and translation of the Yy1 signatures to human GCB cells. We then tested whether our newly generated, stage-specific transcriptional signatures could be used to link murine lymphoma models to stages of normal B-cell development. Although each of the molecularly defined murine lymphoma models conserved certain stage-specific features of normal B-cell development, there was a significant alteration of the normal differentiation signature following malignant transformation. These findings offer important tools and insights for elucidating differences between normal and malignant B cells.

  • bcl6 interacts with the transcription factor miz 1 to suppress the cyclin dependent kinase inhibitor p21 and cell cycle arrest in Germinal Center b cells
    Nature Immunology, 2005
    Co-Authors: Ryan T Phan, Masumichi Saito, Katia Basso, Huifeng Niu, Riccardo Dallafavera
    Abstract:

    The BCL6 proto-oncogene encodes a transcriptional repressor that is required for Germinal Center formation and has been linked to lymphomagenesis. BCL6 functions by directly binding to specific DNA sequences and suppressing the transcription of target genes. Here we report an alternative mechanism by which BCL6 controls the transcription of genes lacking a BCL6 binding site and show that this mechanism was required for the prevention of tumor suppressor p53–independent cell cycle arrest in Germinal Center B cells. BCL6 interacted with the transcriptional activator Miz-1 and, via Miz-1, bound to the promoter and suppressed transcription of the cell cycle arrest gene CDKN1A. Through this mechanism, BCL6 may facilitate the proliferative expansion of Germinal Centers during the normal immune response and, when deregulated, the pathological expansion of B cell lymphomas.

  • transcriptional analysis of the b cell Germinal Center reaction
    Proceedings of the National Academy of Sciences of the United States of America, 2003
    Co-Authors: Ulf Klein, Gustavo Stolovitzky, Jeffrey L Keller, Joseph Haddad, Vladan Miljkovic, Giorgio Cattoretti, Andrea Califano, Riccardo Dallafavera
    Abstract:

    The Germinal Center (GC) reaction is crucial for T cell-dependent immune responses and is targeted by B cell lymphomagenesis. Here we analyzed the transcriptional changes that occur in B cells during GC transit (naive B cells → centroblasts → centrocytes → memory B cells) by gene expression profiling. Naive B cells, characterized by the expression of cell cycle-inhibitory and antiapoptotic genes, become centroblasts by inducing an atypical proliferation program lacking c-Myc expression, switching to a proapoptotic program, and down-regulating cytokine, chemokine, and adhesion receptors. The transition from GC to memory cells is characterized by a return to a phenotype similar to that of naive cells except for an apoptotic program primed for both death and survival and for changes in the expression of cell surface receptors including IL-2 receptor β. These results provide insights into the dynamics of the GC reaction and represent the basis for the analysis of B cell malignancies.

David J Clark - One of the best experts on this subject based on the ideXlab platform.

  • il 6 signaling mediates the Germinal Center response igm production and nociceptive sensitization in male mice after tibia fracture
    Brain Behavior and Immunity, 2021
    Co-Authors: Yang Yang, David J Clark, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Peyman Sahbaie, Qin Guang
    Abstract:

    Abstract Background Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine tibia fracture model of CRPS. Methods Mice deficient in IL-6 expression (IL-6−/−) or B cell deficient (muMT) underwent tibia fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in fractured limbs was followed using Western blotting, and passive serum transfer to muMT fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and Germinal Center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS fracture model. Results Functional IL-6 signaling was required for the post fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6−/− fracture mice into muMT fracture mice caused enhanced allodynia and postural unweighting. IL-6−/− fracture mice displayed reduced popliteal lymphadenopathy after fracture. Germinal Center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6−/− fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after fracture and inhibited lymphadenopathy. Conclusions Collectively, these data support the hypothesis that IL-6 signaling in the fracture limb of mice is required for Germinal Center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb fracture or in the setting of CRPS.

  • Germinal Center formation immunoglobulin production and hindlimb nociceptive sensitization after tibia fracture
    Brain Behavior and Immunity, 2020
    Co-Authors: Yang Yang, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Leonore A. Herzenberg, Qin Guang, David J Clark
    Abstract:

    Abstract Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine tibial fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of Germinal Center formation in lymphoid organs has not been evaluated. Using the murine fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after fracture. We observed that: 1) IgM protein levels in the skin of the fractured mice were elevated at 3 weeks post fracture, but not at earlier time points, 2) serum from fracture mice at 3 weeks, but not 1 and 2 weeks post fracture, had pro-nociceptive effects when passively transferred to fractured muMT mice lacking B cells, 3) fracture induced popliteal lymphadenopathy occurred ipsilateral to fracture beginning at 1 week and peaking at 3 weeks post fracture, 4) a Germinal Center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post fracture but not in other lymphoid tissues, 5) Germinal Center formation was characterized by the induction of T follicular helper cells (Tfh) and Germinal Center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) fracture mice treated with the Tfh signaling inhibitor FK506 had impaired Germinal Center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to fractured muMT mice. Collectively these data demonstrate that tibia fracture induces an adaptive autoimmune response characterized by popliteal lymph node Germinal Center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

Robert C Rickert - One of the best experts on this subject based on the ideXlab platform.

  • cyclin d3 governs clonal expansion of dark zone Germinal Center b cells
    Cell Reports, 2020
    Co-Authors: Parham Ramezanirad, Cindi Chen, Zilu Zhu, Robert C Rickert
    Abstract:

    Germinal Center (GC) B cells surge in their proliferative capacity, which poses a direct risk for B cell malignancies. G1- to S-phase transition is dependent on the expression and stability of D-type cyclins. We show that cyclin D3 expression specifically regulates dark zone (DZ) GC B cell proliferation. B cell receptor (BCR) stimulation of GC B cells downregulates cyclin D3 but induces c-Myc, which subsequently requires cyclin D3 to exert GC expansion. Control of DZ proliferation requires degradation of cyclin D3, which is dependent on phosphorylation of residue Thr283 and can be bypassed by cyclin D3T283A hyperstabilization as observed in B cell lymphoma. Thereby, selected GC B cells in the light zone potentially require disengagement from BCR signaling to accumulate cyclin D3 and undergo clonal expansion in the DZ.

  • cyclin d3 is selectively required for proliferative expansion of Germinal Center b cells
    Molecular and Cellular Biology, 2011
    Co-Authors: Matthew H Cato, Suresh K Chintalapati, Irene W Yau, Sidne A Omori, Robert C Rickert
    Abstract:

    The generation of robust T-cell-dependent humoral immune responses requires the formation and expansion of Germinal Center structures within the follicular regions of the secondary lymphoid tissues. B-cell proliferation in the Germinal Center drives ongoing antigen-dependent selection and the generation of high-affinity class-switched plasma and memory B cells. However, the mechanisms regulating B-cell proliferation within this microenvironment are largely unknown. Here, we report that cyclin D3 is uniquely required for Germinal Center progression. Ccnd3(-/-) mice exhibit a B-cell-intrinsic defect in Germinal Center maturation and fail to generate an affinity-matured IgG response. We determined that the defect resulted from failed proliferative expansion of GL7(+) IgD(-) PNA(+) B cells. Mechanistically, sustained expression of cyclin D3 was found to be regulated at the level of protein stability and controlled by glycogen synthase kinase 3 in a cyclic AMP-protein kinase A-dependent manner. The specific defect in proliferative expansion of GL7(+) IgD(-) PNA(+) B cells in Ccnd3(-/-) mice defines an underappreciated step in Germinal Center progression and solidifies a role for cyclin D3 in the immune response, and as a potential therapeutic target for Germinal Center-derived B-cell malignancies.

Jose Faro - One of the best experts on this subject based on the ideXlab platform.

  • regulation of the Germinal Center reaction by foxp3 follicular regulatory t cells
    Journal of Immunology, 2011
    Co-Authors: Ivonne Wollenberg, Ana Aguadoce, Andrea Hernandez, Catarina F Almeida, Vanessa G Oliveira, Jose Faro
    Abstract:

    Follicular helper T (T(FH)) cells participate in humoral responses providing selection signals to Germinal Center B cells. Recently, expression of CXCR5, PD-1, and the transcription factor Bcl-6 has allowed the identification of T(FH) cells. We found that a proportion of follicular T cells, with phenotypic characteristics of T(FH) cells and expressing Foxp3, are recruited during the course of a Germinal Center (GC) reaction. These Foxp3(+) cells derive from natural regulatory T cells. To establish the in vivo physiologic importance of Foxp3(+) follicular T cells, we used CXCR5-deficient Foxp3(+) cells, which do not have access to the follicular region. Adoptive cell transfers of CXCR5-deficient Foxp3(+) cells have shown that Foxp3(+) follicular T cells are important regulators of the GC reaction following immunization with a thymus-dependent Ag. Our in vivo data show that Foxp3(+) follicular T cells can limit the magnitude of the GC reaction and also the amount of secreted Ag-specific IgM, IgG1, IgG2b, and IgA. Therefore, Foxp3(+) follicular regulatory T cells appear to combine characteristics of T(FH) and regulatory T cells for the control of humoral immune responses.

Christopher D C Allen - One of the best experts on this subject based on the ideXlab platform.

  • the sphingosine 1 phosphate receptor s1p2 maintains the homeostasis of Germinal Center b cells and promotes niche confinement
    Nature Immunology, 2011
    Co-Authors: Jesse A Green, Christopher D C Allen, Kazuhiro Suzuki, Bryan Cho, David L Willison, Daniel Palmer
    Abstract:

    The environmental cues involved in regulating Germinal Center size are not fully understood. Cyster and colleagues show that the sphingosine 1-phosphate receptor S1P2 controls the survival and localization of B cells in Germinal Centers by antagonizing signaling by the kinase Akt and follicular chemoattractants.

  • imaging of Germinal Center selection events during affinity maturation
    Science, 2007
    Co-Authors: Christopher D C Allen, Takaharu Okada, Lucy H Tang, Jason G Cyster
    Abstract:

    The Germinal Center (GC) is an important site for the generation and selection of B cells bearing high-affinity antibodies, yet GC cell migration and interaction dynamics have not been directly observed. Using two-photon microscopy of mouse lymph nodes, we revealed that GC B cells are highly motile and extend long cell processes. They transited between GC dark and light zones and divided in both regions, although these B cells resided for only several hours in the light zone where antigen is displayed. GC B cells formed few stable contacts with GC T cells despite frequent encounters, and T cells were seen to carry dead B cell blebs. On the basis of these observations, we propose a model in which competition for T cell help plays a more dominant role in the selection of GC B cells than previously appreciated.

  • Germinal Center dark and light zone organization is mediated by cxcr4 and cxcr5
    Nature Immunology, 2004
    Co-Authors: Christopher D C Allen, Robin Lesley, Mark K Ansel, Hirokazu Tamamura, Nobutaka Fujii, Jason G Cyster
    Abstract:

    Germinal Center (GC) dark and light zones segregate cells undergoing somatic hypermutation and antigen-driven selection, respectively, yet the factors guiding this organization are unknown. We report here that GC organization was absent from mice deficient in the chemokine receptor CXCR4. Centroblasts had high expression of CXCR4 and GC B cells migrated toward the CXCR4 ligand SDF-1 (CXCL12), which was more abundant in the dark zone than in the light zone. CXCR4-deficient cells were excluded from the dark zone in the context of a wild-type GC. These findings establish that GC organization depends on sorting of centroblasts by CXCR4 into the dark zone. In contrast, CXCR5 helped direct cells to the light zone and deficiency in CXCL13 was associated with aberrant light zone localization.