We determined that, as compared with human naïve B cells, human GC B cells have a higher intrinsic affinity threshold for antigen. We observed that independently of other extrinsic factors, such as competition among B cells for antigen, the intrinsic affinity of GC B cells for an antigen dictated each subsequent step in B cell activation from the magnitude of BCR signaling to the receptivity of BCR-stimulated GC B cells to Tfh cell signals that drive IRF-4 expression and PC differentiation. We provided evidence that BCRs on LZ GC B cells are concentrated in distinct, highly dynamic, ezrin- and actin-rich pod-like structures through which the BCRs engage antigen, signal, exert pulling forces, and extract antigen from membranes. In contrast, the BCRs on naïve B cells function in flat, stable membrane contacts, with antigen-containing surfaces displaying the well-described features of immune synapses and cSMACs. The role of these pod-like structures in establishing high-affinity thresholds for GC ...
Follicular helper CD4 T cells (Tfh) are the specialized providers of B cell help and are essential for germinal centers and most antibody responses. Germinal centers are the engines of rapid B cell evolution and have exquisitely complex cellular dynamics. Tfh differentiation is a multistage, multifactorial process. Tfh have recently emerged as major players in protective immunity to pathogens, generation of high-affinity and long-term antibody responses to vaccines, autoimmune diseases, allergies and even cancer. However, there are major gaps in our understanding of Tfh differentiation, Tfh function, germinal center function and the biological selection of high-affinity antibody responses in vivo in a variety of relevant anti-pathogen and autoimmune contexts. This conference will bring together scientists and physicians from a range of disciplines and disease models to elaborate the complex biology of Tfh cells and germinal centers and discuss emerging avenues to manipulate them in clinical settings.
Previous work established that a TLR ligand attached to a haptenated protein Ag or contained within a virus particle can promote the magnitude and quality of the GC reaction and, moreover, that TLR signaling within the Ag-specific B cell is an important contributor to that enhancement (7, 13). In this study, we used mRNA sequencing and GSEA to identify the intracellular transcriptional programs that were enhanced by coupled Ag and TLR9/MyD88 signaling in GC B cells. Especially enhanced were the transcriptional signatures associated with c-Myc transcriptional activity and mTORC1 signaling. Both of these pathways are central to the control of cell growth and proliferation in many cell types and are critical in B cells for the GC response (17, 32, 33). Interestingly, Tfh cells recognizing Ag presented by GC B cells also stimulate these pathways in the Ag-presenting GC B cell, leading to positive selection of the GC B cells (18, 19, 37). Thus, one potential mechanism by which TLR9/MyD88 signaling ...
TY - JOUR. T1 - IL-25 dampens the growth of human germinal center-derived B-cell non Hodgkin Lymphoma by curtailing neoangiogenesis. AU - Ferretti, Elisa. AU - Di Carlo, Emma. AU - Ognio, Emanuela. AU - Fraternali-Orcioni, Giulio. AU - Corcione, Anna. AU - Belmonte, Beatrice. AU - Ravetti, Jean Louis. AU - Tripodo, Claudio. AU - Ribatti, Domenico. AU - Pistoia, Vito. PY - 2017. Y1 - 2017. N2 - Interleukin (IL)-25, a member of the IL-17 cytokine superfamily, is produced by immune and non-immune cells and exerts type 2 pro-inflammatory effectsin vitroandin vivo. The IL-25 receptor(R) is composed of the IL-17RA/IL-17RB subunits. Previous work showed that germinal centre (GC)-derived B-cell non Hodgkin lymphomas (B-NHL) expressed IL-17AR, formed by IL-17RA and IL-17RC subunits, and IL-17A/IL-17AR axis promoted B-NHL growth by stimulating neoangiogenesis. Here, we have investigated expression and function of IL-25/IL-25R axis in lymph nodes from human GC-derived B-NHL, i.e. Follicular Lymphoma (FL,10 ...
The ICOS-B7h costimulatory receptor-ligand pair is required for germinal center formation, the production of isotype-switched antibodies, and antibody affinity maturation in response to T cell-dependent antigens. However, the potentially distinct roles of regulated B7h expression on B cells and dendritic cells in T cell-dependent antibody responses have not been defined. We generated transgenic mice with lineage-restricted B7h expression to assess the cell-type specific roles of B7h expression on B cells and dendritic cells in regulating T cell-dependent antibody responses. Our results show that endogenous B7h expression is reduced on B cells after activation in vitro and is also reduced in vivo on antibody-secreting plasma B cells in comparison to both naïve and germinal center B cells from which they are derived. Increasing the level of B7h expression on activated and plasma B cells in B-B7hTg mice led to an increase in the number of antibody-secreting plasma cells generated after immunization and a
Variations in CD45RA antibody staining intensity in immunohistochemistry on tissue sections are present across different anatomical locations. An intense signal was observed in lymphoid tissue in appendix, hematopoietic cells in the bone marrow, germinal center cells in the lymph node, non-germinal center cells in the lymph node, cells in the red pulp in spleen, cells in the white pulp in spleen, germinal center cells in the tonsil and non-germinal center cells in the tonsil. More moderate antibody staining intensity was present in lymphoid tissue in appendix, hematopoietic cells in the bone marrow, germinal center cells in the lymph node, non-germinal center cells in the lymph node, cells in the red pulp in spleen, cells in the white pulp in spleen, germinal center cells in the tonsil and non-germinal center cells in the tonsil. Low, but measureable presence of CD45RA could be seen in. We were unable to detect CD45RA in other tissues. Disease states, inflammation, and other physiological ...
TY - JOUR. T1 - BCL6 represses antiviral resistance in follicular T helper cells. AU - Amet, Tohti. AU - Son, Young Min. AU - Jiang, Li. AU - Cheon, In Su. AU - Huang, Su. AU - Gupta, Samir K.. AU - Dent, Alexander L.. AU - Montaner, Luis J.. AU - Yu, Qigui. AU - Sun, Jie. N1 - Funding Information: This study was supported by the U.S. National Institutes of Health Creative and Novel Ideas in HIV Research (CNIHR) program. Grants R21 AI119612, RO1 AI112844, RO1 HL126647, and RO1 AG047156 were awarded to J.S.; Grant RO1 AI117835 to Q.Y.; and Grants RO1 AI094603, U01 AI110434, and UM1 AI126620 to L.J.M. The authors thank Dr. Shekhar A. Kubal at IUSM (Transplant Surgery) and physicians at IU Riley Hospital for providing human spleen, lymph node, and tonsil specimens.. PY - 2017/8. Y1 - 2017/8. N2 - Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. ...
Follicular T helper (Tfh) cells are essential in the formation of high-affinity antibody producing plasma cells and memory B cells. After antigen encounter naive Tfh cells start to upregulate the chemokine receptor CXCR5. This results in homing of the Tfh cells to lymph node follicles where the Tfh cells specifically ... read more localise in germinal centres (GCs). In the GCs the Tfh cells stimulate B cells to differentiate resulting in the production of antibodies. In systemic lupus erythematosus (SLE) an increased amount of autoantibodies is seen. Recent studies postulate that an increased amount of autoantibodies can be related to Tfh cells. The exact role of Tfh cells in the production of autoantibodies in SLE remains elusive, but some research papers provide information from which potential roles can be drawn. The essence of these research papers is the increased level of the chemokine ligand CXCL13 in SLE. CXCL13 levels correlate with disease severity. Further knowledge concerning the ...
T follicular helper (Tfh) cells were discovered just over a decade ago as germinal centre T cells that help B cells make antibodies. Included in this role is affinity maturation and isotype switching. It is here that their functions become less clear. Tfh cells principally produce IL-21 which inhibits class switching to IgE. Recent studies have questioned whether the germinal centre is the main site of IgE class switching or IgE affinity maturation. In this review, I will examine the evidence that these cells are responsible for regulating IgE class switching and the relationship between Tfh cells and T helper 2 (Th2) effector cells. © 2012 CSI and USTC ...
Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHCII) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHCII surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHCII-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHCII protein turnover. Fluctuations in surface MHCII levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHCII levels, whereas CD83 expression in centrocytes helped to stabilize MHCII at that stage. Defects in MHCII ubiquitination caused GC B cells to
Here we check the part of FoxP3+ regulatory T cells (Tregs) in controlling T follicular helper (Tfh) and germinal-center (GC) B cell responses to influenza. from the Tfh lineage 4, 6-8. Mice in which Bcl6 is eliminated from the T lineage FUT3 fail to develop Tfh cells, do not form GCs and have defects in memory B cells and long-lived plasma cells6-9. The differentiation of Tfh cells Tyclopyrazoflor is governed by a variety of cellular and molecular interactions that together enforce the expression of Bcl6 and repress the expression of competing transcription factors, particularly BLIMP-1 6, 3, 4, 10. For example, signaling by IL-2 through the IL-2R (CD25) on CD4+ T cells inhibits the formation of Tfh by preventing Bcl6 expression via the STAT5 pathway 10-13. As a consequence of prolonged IL-2 signaling, Tfh cells do not develop and the development of GCs and long-lived plasma cells is impaired 11. Thus, the factors that control the physiological availability of IL-2 are likely to regulate Tfh ...
Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that ...
After immunization, activated splenic T cells proliferate in periarteriolar lymphoid sheaths (PALS) and subsequently migrate to the lymphoid follicle where they enter nascent germinal centers. Analysis of TCR V(D)J gene rearrangements indicates extensive emigration, frequently involving more than a single white pulp region. These migrants constitute a unique set of T helper cells that express antigen-specific alpha beta TCR, CD3, and CD4, but little or no Thy-1, a differentiation antigen present on the great majority of peripheral murine T lymphocytes. The origin of CD4+ Thy-1 follicular T cells appears to be the Thy+ population in the PALS, as both sets commonly share identical V(D)J rearrangements. ...
Previously, it was shown that TLR7-MyD88-dependent RNA sensing is absolutely crucial for the formation of Spt-GCs and the development of autoimmunity (2, 9-11). This led us to ask whether cytosolic RNA sensing by RLRs may also be equally crucial for the formation of Spt-GC responses. We also approached this study with the intention of gaining more information about how the analysis of these responses should be approached in autoimmune-prone mouse strains. Whereas endosomal TLR7-MyD88 signaling promotes Spt-GC responses in both healthy and autoimmune-prone mice on a B6 background (10), we found that cytosolic MDA5-MAVS signaling did not have a significant role in the magnitude of GC formation on a similar B6 background. More intriguingly, we found MAVS phenotypes to be dependent on the genetic background as MAVS deficiency on a B6/129 background conversely resulted in nearly absent Spt-GC responses, reminiscent of the Spt-GC responses observed in TLR7KO mice. The lack of Spt-GC response in ...
Butcher, E C.; Rouse, R V.; Coffman, R L.; Nottenburg, C N.; Hardy, I R.; and Weissman, I L., Surface phenotype of peyers patch germinal center cells: implication for the role of germinal centers in b cell differentiation. (1982). Subject Strain Bibliography 1982. 1324 ...
Analysis of splenic latency has shown that three types of APC harbor latent MHV-68: B cells, macrophages, and dendritic cells. Despite this, only latently infected, activated B cells express the ligand that drives the characteristic expansion of Vβ4+CD8+ T cells associated with the infectious mononucleosis stage of MHV-68 infection. Furthermore, although activated B cells with a germinal center phenotype harbor the highest level of reactivatable latent virus and Vβ4+ T cell hybridoma stimulatory capacity, analysis of CD28−/− mice, which fail to form germinal centers, showed that germinal center formation per se was not required for establishment of latency or stimulation of Vβ4+CD8+ T cells.. The identification of dendritic cells and splenic macrophages as reservoirs of latent MHV-68 virus after intranasal infection is an exciting and novel finding. Therefore, it is important to formally demonstrate that the virus is truly latent and not due to slow, chronic lytic infection. ...
Looking for Germinal center? Find out information about Germinal center. in politics, a party following a middle course. The term was first used in France in 1789, when the moderates of the National Assembly sat in the center of... Explanation of Germinal center
Nuclear pore-associated protein; required for biogenesis of the small ribosomal subunit; component of TREX-2 complex (Sac3p-Thp1p-Sus1p-Cdc31p) involved in transcription elongation and mRNA export from the nucleus; involved in post-transcriptional tethering of active genes to the nuclear periphery and to non-nascent mRNP; similar to the human germinal center-associated nuclear protein (GANP) ...
Germinal centers (GCs) are the main site of T cell-dependent antibody responses. Upon antigen challenge, GCs comprise mostly B cells undergoing proliferation, somatic hypermutation and antigen-affinity selection. GC B cells down-modulate the expression of Bcl-2 protein and are highly sensitive to apoptosis to eliminate autoreactive or low-affinity cells. Bcl-2 is still expressed in a few GC cells, whose identity remains unclear. To address this issue, we examined by confocal microscopy the expression of Bcl-2 by different GC lymphocyte subsets in hyperplastic tonsils. We found that the vast majority of Bcl-2+ GC cells are T lymphocytes. Conversely, while in the mantle zone and in the interfollicular areas T cells are almost exclusively Bcl-2 +, in the GC, most T lymphocytes are Bcl-2-. In addition, most of the CD4+ GC T cells are Bcl-2-, while nearly 100% of the CD8+ GC T cells are Bcl-2+. The Bcl-2 downregulation by both B and CD4+ T GC cells supports the concept that these two subsets may ...
Modern vaccines must be designed to generate long-lasting, high-affinity, and broadly neutralizing Ab responses against pathogens. The diversity of B cell clones recruited into germinal center (GC) responses is likely to be important for the Ag-neutralization potential of the Ab-secreting cells and memory cells generated upon immunization. However, the factors that influence the diversity of B cell clones recruited into GCs are unclear. As recirculating naive Ag-specific B cells arrive in Ag-draining secondary lymphoid organs, they may join the ongoing GC response. However, the factors that limit their entry are not well understood, and it is not known how that depends on the stage of the ongoing follicular T cell and GC B cell response. In this article, we show that, in mice, naive B cells have a limited window of time during which they can undergo Ag-driven activation and join ongoing immunization-induced GC responses. However, preloading naive B cells with even a threshold-activating amount ...
Because S1PR2 deficiency reduced the number of Tfh cells in GCs by half (Fig. 2 B), we sought to investigate its impact on GC responses. To eliminate the effects of S1PR2 deficiency in B cells (Green et al., 2011), S1pr2V/V or control CD4+ T cells were transferred to Cd28−/− mice, which have a much reduced number of Tfh cells (Linterman et al., 2009), and analyzed after immunization. As shown in Fig. 5 A, S1pr2V/V and control CD4+ T cells could similarly support GC B cells. Histological analysis showed that the number of CD4+ T cells in GCs was significantly reduced in S1pr2V/V CD4+ T cell-transferred mice compared with control CD4+ T cell-transferred mice, consistent with the data shown in Fig. 2 B (Fig. 5 B and Fig. S4 A). The area of a GC section was not significantly different between two groups (Fig. S4 B). The ratio of CXCR5hi Tfh/GC B cell numbers was not affected by S1PR2 deficiency in T cells, indicating that total Tfh cell formation was unaffected (Fig. S4 C). We also observed ...
Our investigations reveal that cGAS contributes to parasite control, which is essential for the formation of GC-derived humoral immunity. The ability to simultaneously identify and analyze endogenous polyclonal antigen-specific CD4+ T cells and B cells responding to Plasmodium has revealed a profound effect of innate immune control of parasitemia. Control of parasitemia is important for timely development of the GC response, a response critical for both the efficient generation of high-affinity antibodies and durable immune memory (59-62). Furthermore, our ability to track parasitemia throughout the course of infection combined with the potential to rapidly clear blood-stage infection with atovaquone provided us with an elegant system in which the effects of innate control of parasite burden could be disentangled from the effects of early innate signals on the adaptive immune response. Specifically, the collapse of the GC response in cGAS-/- mice as parasitemia persisted could be abolished with ...
Germinal centers (GC)s are sites of intense B-cell proliferation, central for T-cell dependent antibody responses. Although much is known of GC B-cell physiology, the mechanisms of cellular proliferation have remained elusive. Specifically, the role of MYC, a key cell cycle regulator, in GC B-cell proliferation has been questioned. We have identified MYC positive B-cell subpopulations in both immature and mature GCs, and shown through genetic ablation of Myc at these stages that they play indispensable roles in GC formation and maintenance, respectively. The identification of functionally critical MYC-expressing GC B-cell subsets has important implications for B-cell lymphomagenesis, which mostly originates from GC cells and frequently involves MYC deregulation through chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the MYC positive GC subpopulations may represent B-cells with a particularly high risk for malignant ...
Next we performed reanalyses of the mutation patterns of the monoclonal antibodies generated from ACPA+ patient samples based on citrulline reactivity. As seen in Fig. 4 c, the citrulline-specific antibodies displayed fewer overall mutations but higher R/S ratios in their CDRs as compared with the citrulline-negative clones (Fig. 4 d). Traditionally, selection of high-affinity B cells during affinity maturation is primarily dependent on the presentation of antigens to T cells and takes place in germinal centers (Liu et al., 1997). However, it is known that such affinity maturation may also take place at extrafollicular sites (William et al., 2002). To address whether the citrulline-specific antibodies had undergone affinity-driven maturation, we reverted four antibodies with high citrulline reactivity to their predicted germline sequences. Reversion of mutations in these four citrulline-specific monoclonal antibodies led to a loss of reactivity to all the autoantigens (Fig. 2 e). The above ...
Plasmablastic lymphoma (PBL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma. This subtype of lymphoma has a post-germinal center cell-of-origin called the plasmablast, and the immunophenotype is more consistent with that of a plasma cell than a lymphocyte. Because of these unique features, PBL is notoriously difficult to treat. Case reports and small reviews have evaluated the addition of agents directed against plasma cell disorders in combination with traditional lymphoma-directed regimens. We describe the largest case series to date, with the longest follow-up, evaluating bortezomib in combination with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (V-EPOCH) for the treatment of PBL ...
Germinal centre-like structures can form in nonlymphoid tissues following infection, but the requirements for their formation and function are not well characterized; in particular how peripheral tissues are remodeled by infection to facilitate the recruitment of lymphocytes and establish de novo a stromal network. This seminar will focus on how influenza-induced lung germinal centres are formed, and whether these structures follow the same rules as their counterparts in secondary lymphoid tissues ...
Affinity maturation of antibodies during immune responses is achieved by multiple rounds of somatic hypermutation and subsequent preferential selection of those B cells that express B cell receptors with improved binding characteristics for the antigen. The mechanism underlying B cell selection has not yet been defined. By employing an agent-based model, we show that for physiologically reasonable parameter values affinity maturation can be driven by competition for neither binding sites nor antigen--even in the presence of competing secreted antibodies. Within the tested mechanisms, only clonal competition for T cell help or a refractory time for the interaction of centrocytes with follicular dendritic cells is found to enable affinity maturation while generating the experimentally observed germinal centre characteristics and tolerating large variations in the initial antigen density.
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The maturation of antibody affinity during the immune response, discovered as a serological phenomenon in 1964, is critical to the development of high affinity humoral immunity. This process takes place in germinal centers (GCs), which are microanatomical structures composed of antigen-specific B lymphocytes that form in secondary lymphoid organs upon infection or immunization. High affinity B cells are selectively expanded in the GC by iterative rounds of migration between a zone of hypermutation and proliferation (the dark zone, or DZ) and a zone of selection (the light zone, or LZ). The mechanism whereby somatic antibody mutants are selected on the basis of affinity has been elusive. In the first part of this thesis, I demonstrate that affinity-based selection in the GC operates through regulation of proliferation and hypermutation. B cells with affinity-enhancing mutations capture more antigen through their BCRs for presentation as peptide-MHCII to CD4+ T cells. In turn, enhanced T cell help
Cytokines are small, secreted, glycoproteins that specifically affect the interactions and communications between cells. Cytokines are produced transiently and locally, acting in a paracrine or autocrine manner, and they are extremely potent, ligating high affinity cell surface receptors to elicit changes in gene expression and protein synthesis in the responding cell. Cytokines produced during the differentiation of T follicular helper (Tfh) cells and B cells within the germinal center (GC) niche play an important role in ensuring that the humoral immune response is robust, whilst retaining flexibility, during the generation of affinity matured antibodies. Cytokines produced by B cells, antigen presenting cells and stromal cells are important for the differentiation of Tfh cells and Tfh cell produced cytokines act both in an autocrine fashion to firm Tfh cell differentiation and in a paracrine fashion to support the differentiation of memory B cells and plasma cells. In this review, we discuss the role
Our immune system efficiently protects us against the daily onslaught of foreign pathogens. However, the targeting, strength and extent...
Autoimmune disease affects ~5% of individuals globally, and the prevalence is increasing. The cause of diseases such as Systemic Lupus Erthematosus (SLE) and Rheumatoid Arthritis (RA) remains largely unknown and commonly used therapeutic agents present with considerable side effects.Detection of autoantibodies is a common feature of many autoimmune diseases, including SLE and RA. Due to inherent signaling defects B cells produce autoantibodies and directly contribute to the pathogenesis of disease. The Germinal Centre (GC) reaction is therefore a pivotal step in this process, allowing B cells to undergo affinity maturation and differentiation into long-lived plasma cells. While CD4+ Follicular helper T cells (Tfh) migrate into B cell follicles and engage GC B cells to generate antibody responses. This critical collaboration dictates the production of high affinity antibodies, or autoantibodies when the signaling circuitry is altered in B cells or Tfh cells.Understanding the molecular pathways that
3988 Cancer stem cells (CSC) represent the cellular compartment responsible for the initiation, maintenance, and progression of multiple human cancers. CSC retain the capacity to undergo self-renewal as well as produce differentiated cells that form the bulk of the tumor mass. Embryonic signaling pathways, such as Hedgehog (Hh), Wingless (Wnt), and Notch are required for somatic stem cell development. Aberrant re-activation of these pathways has been demonstrated in many human cancers, however their role in regulating CSC phenotypes has not been tested directly. We investigated the role of Hh signaling in the regulation of CSC by examining pathway activation within distinct cellular compartments that constitute the plasma cell malignancy multiple myeloma (MM), in which clonogenic progenitors resemble post-germinal center B cells. In both MM cell lines and clinical bone marrow samples, expression of the Hh signaling pathway components PATCHED (PTCH), SMOOTHENED (SMO), GLI1 as well as ...
Germinal centres (GCs) are involved in the selection of B cells secreting high-affinity antibodies and are also the origin of most human B cell lymphomas. Recent progress has been made in identifying the functionally relevant stages of the GC and the complex trafficking mechanisms of B cells within …
Dr. Craft investigates CD4 T helper cells in conventional and autoimmune responses in mice and in humans, with a primary focus upon the differentiation and function of follicular helper (Tfh) cells that promote B cell maturation in germinal centers (GC). Tfh cell dependent GC responses are critical for development of humoral immunity and B cell memory upon vaccine administration and following infection, and for driving pathogenic autoreactive B cell responses in autoimmune diseases. Dr. Crafts studies on Tfh cells build upon the earlier work of his trainees and him in characterizing novel immune targets in the systemic autoimmune disease lupus, and studies of tolerance, inflammation, and therapy in that disorder. His groups work on Tfh cells focuses upon their development, transcriptional control, and promotion and regulation of GC B cells in normal and autoimmune responses. His lab also has investigated other CD4 T cell populations, including those that promote immune memory and ...
AC50 of HA-specific GC B cells can be used as a proxy for population avidity to PR8 HA. (A) Overview of AC50. GC B cell rHA staining frequency is plotted agains
1.02.2021 - The generation of antibodies in B-cells takes place in a dynamic structure that forms during infections, the germinal center (GC). The formation of GCs lays at the heart of the immune response; this process is highly regulated and not fully understood yet. The Matthias group now provides novel insights into the regulation of GC formation and GC-derived B cell lymphomas, highlighting on
Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. ...
Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. ...
Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. ...
The general goal of this laboratory is to elucidate the pathogenesis of cancers derived from B lymphocytes, known as B cell lymphomas. These tumors originate from the malignant transformation of germinal center B cells, via acquisition of genomic lesions involving oncogenes and tumor suppressor genes. We wish to identify these lesions, determine the mechanism by which they occur and elucidate the contribution of each lesion to tumor development using genetically modified mouse models. These studies are also aimed at identifying targets for therapeutic intervention. Specific lines of investigation include ...
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 ...
If you have a question about this talk, please contact Lorna Jarvis.. Abstract not available. This talk is part of the Immunology and Medicine Seminars series.. ...
Høyoppløselig intravital avbildning med forbedret kontrast til 120 mikrometer dybde i lymfeknuter hos voksne mus oppnås ved romlig...
When we now look at collaborative thinking in this new context, we are not talking about the group work or break out sessions of the past. The characteristics that learners must have in order to work collaboratively in an online environment is largely defined by the nature of the online resources available. The purpose for such activity now takes on the need to solve complex real world problems that will in fact have consequences that will benefit people and their quality of life on a global scale. Consideration must once again be given to the cause and effect construct.The groups that will come together in an online environment with the mandate to research and produce solutions to very real and complex societal problems, will be made up of people who believe that the modern world problems of today can only be solved through a cross disciplinary approach. Unlike the protected silos of knowledge and skillsets of the past, the new collaborative thinking recognizes the need to bring together ...
Composition of the CD95 DISC in freshly isolated and cultured GC B cells. (A) CD95 or (B) FADD was immunoprecipitated (IP) from 107 freshly isolated GC B cells
Learn more about Fibromialgia at Largo Medical Center Términos Relacionados Fibrositis Fibromiositis Síndrome de Dolor Miofascial Miofibrositis Sí...
Reimer, D and Lee, AYS and Bannan, J and Fromm, P and Kara, EE and Comerford, I and McColl, S and Wiede, F and Mielenz, D and Korner, H, Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses, Immunology and Cell Biology, 95, (1) pp. 33-41. ISSN 0818-9641 (2017) [Refereed Article ...
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