The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Jason G Cyster - One of the best experts on this subject based on the ideXlab platform.
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ubiquitin mediated fluctuations in mhc class ii facilitate efficient germinal center b cell responses
Journal of Experimental Medicine, 2016Co-Authors: Oliver Bannard, Simon J Mcgowan, Jonatan Ersching, Satoshi Ishido, Gabriel D Victora, Jeoungsook Shin, Jason G CysterAbstract: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 accumulate greater amounts of a specific peptide-MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in Centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.
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germinal center Centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection
Immunity, 2013Co-Authors: Oliver Bannard, Christopher D C Allen, Robert M Horton, Takashi Nagasawa, Jason G CysterAbstract:Germinal center (GC) B cells cycle between the dark zone (DZ) and light zone (LZ) during antibody affinity maturation. Whether this movement is necessary for GC function has not been tested. Here we show that CXCR4-deficient GC B cells, which are restricted to the LZ, are gradually outcompeted by WT cells indicating an essential role for DZ access. Remarkably, the transition between DZ centroblast and LZ centrocyte phenotypes occurred independently of positioning. However, CXCR4-deficient cells carried fewer mutations and were overrepresented in the CD73+ memory compartment. These findings are consistent with a model where GC B cells change from DZ to LZ phenotype according to a timed cellular program but suggest that spatial separation of DZ cells facilitates more effective rounds of mutation and selection. Finally, we identify a network of DZ CXCL12-expressing reticular cells that likely support DZ functions.
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germinal center dark and light zone organization is mediated by cxcr4 and cxcr5
Nature Immunology, 2004Co-Authors: Christopher D C Allen, Robin Lesley, Mark K Ansel, Hirokazu Tamamura, Nobutaka Fujii, Jason G CysterAbstract: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.
Oliver Bannard - One of the best experts on this subject based on the ideXlab platform.
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ubiquitin mediated fluctuations in mhc class ii facilitate efficient germinal center b cell responses
Journal of Experimental Medicine, 2016Co-Authors: Oliver Bannard, Simon J Mcgowan, Jonatan Ersching, Satoshi Ishido, Gabriel D Victora, Jeoungsook Shin, Jason G CysterAbstract: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 accumulate greater amounts of a specific peptide-MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in Centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.
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germinal center Centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection
Immunity, 2013Co-Authors: Oliver Bannard, Christopher D C Allen, Robert M Horton, Takashi Nagasawa, Jason G CysterAbstract:Germinal center (GC) B cells cycle between the dark zone (DZ) and light zone (LZ) during antibody affinity maturation. Whether this movement is necessary for GC function has not been tested. Here we show that CXCR4-deficient GC B cells, which are restricted to the LZ, are gradually outcompeted by WT cells indicating an essential role for DZ access. Remarkably, the transition between DZ centroblast and LZ centrocyte phenotypes occurred independently of positioning. However, CXCR4-deficient cells carried fewer mutations and were overrepresented in the CD73+ memory compartment. These findings are consistent with a model where GC B cells change from DZ to LZ phenotype according to a timed cellular program but suggest that spatial separation of DZ cells facilitates more effective rounds of mutation and selection. Finally, we identify a network of DZ CXCL12-expressing reticular cells that likely support DZ functions.
Alan S Perelson - One of the best experts on this subject based on the ideXlab platform.
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somatic mutation leads to efficient affinity maturation when centrocytes recycle back to Centroblasts
Journal of Immunology, 1997Co-Authors: Mihaela Oprea, Alan S PerelsonAbstract:Although most mutations are deleterious, an interplay between somatic mutation and selection within germinal centers (GC) results in rapid generation of high affinity memory B cells. How high affinity B cells with large numbers of mutations are generated and preserved within GC containing at their peak only a few thousand cells has been puzzling. We have developed a model of somatic mutation and B cell expansion within a GC that resolves this puzzle. We show that the frequent recycling of Ag-selected centrocytes back into Centroblasts can lead to efficient affinity maturation. Memory cells are generated in large numbers even when most of the selected centrocytes recycle back into Centroblasts. Our model suggests that a germinal center reaction in which the output of cells is low up to the point of GC dissociation, followed by the release of centrocytes into the periphery, is advantageous for generating high affinity memory.
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somatic mutation leads to efficient affinity maturation when centrocytes recycle back to Centroblasts
Research Papers in Economics, 1996Co-Authors: Mihaela Oprea, Alan S PerelsonAbstract:Though most mutations are deleterious, an interplay between somatic mutation and selection within germinal centers (GC) results in rapid generation of high affinity memory B cells. How high affinity B cells with large numbers of mutations are generated and preserved, within GC containing at their peak only a few thousand cells, has been puzzling. We have developed a model of somatic mutation and B cell expansion within a GC that resolves this puzzle. We show that the frequent recycling of antigen- selected centrocytes back into Centroblasts can lead to efficient affinity maturation. Memory cells are generated in large numbers even when most of the selected centrocytes recycle back into Centroblasts. Our model suggests that a germinal center reaction in which the output of cells is low up to the point of germinal center dissociation, followed by the release of centrocytes into the periphery, is advantageous for generating high affinity memory.
Yasodha Natkunam - One of the best experts on this subject based on the ideXlab platform.
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isolated follicles enriched for Centroblasts and lacking t 14 18 bcl2 in lymphoid tissue diagnostic and clinical implications
PLOS ONE, 2016Co-Authors: Grant E. Nybakken, Rajeev Bala, Dita Gratzinger, James L. Zehnder, Charles D. Bangs, Roger A. Warnke, Carol Jones, Athena M Cherry, Yasodha NatkunamAbstract:We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of Centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.
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Immunohistochemistry of isolated atypical follicles.
2016Co-Authors: Grant E. Nybakken, Rajeev Bala, Dita Gratzinger, Carol D. Jones, James L. Zehnder, Charles D. Bangs, Athena Cherry, Roger A. Warnke, Yasodha NatkunamAbstract:An axillary lymph node dissection in a 58 year-old woman with breast carcinoma (case 3) shows a lymph node with a cluster of follicles (A). BCL2 expression is absent in both the involved and uninvolved follicles (B) and the involved follicle shows diminished CD10 expression relative to the surrounding normal germinal centers (C). CD23 demonstrates an intact follicular dendritic network around the involved follicle (D). Ki-67 is polarized in surrounding reactive follicles, but is not polarized in the involved follicles (E). The involved follicle in case 1 shows lambda light chain-restricted B-cells (F and G). Case 2 shows highly atypical large cells that by situ hybridization (ISH) for immunoglobulin kappa and lambda light chains show kappa-specific RNA in the majority of the atypical cells, confirming light chain restriction in the involved follicle (H and I). A periaortic lymph node from a 53-year old woman (case 4) shows abnormal strong IgM protein expression in the Centroblasts of an involved follicle whereas the uninvolved follicle shows a weak dendritic pattern of IgM reactivity, which is typically seen in normal follicles (J).
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Morphology of isolated atypical follicles.
2016Co-Authors: Grant E. Nybakken, Rajeev Bala, Dita Gratzinger, Carol D. Jones, James L. Zehnder, Charles D. Bangs, Athena Cherry, Roger A. Warnke, Yasodha NatkunamAbstract:An axillary lymph node dissection in a 61 year-old woman with breast carcinoma (case 1) shows one lymph node with scattered follicles containing sheets of Centroblasts (A). The involved follicles exhibit sheets of large atypical cells with highly pleomorphic nuclear outlines and atypical mitoses (B). An axillary lymph node from a 53-year old woman (case 2) shows highly atypical large cells occupying an involved follicle (C). Sections of tonsil in a 6-year old boy (case 5) demonstrate a background of reactive follicular hyperplasia within which isolated follicles (upper left) show sheets of Centroblasts (E and F).
Ian C M Maclennan - One of the best experts on this subject based on the ideXlab platform.
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isolation and characteristics of tonsil Centroblasts with reference to ig class switching
International Immunology, 1995Co-Authors: Jean Feuillard, Dale R Taylor, Montserrat Casamayorpalleja, Gerald D Johnson, Ian C M MaclennanAbstract:Most tonsil B cells have high levels of surface CD44 but this molecule is either expressed at low levels or is absent from germinal centre B cells (GCB). On average 62% of isolated GCB were found to be CD44- and the remainder CD44low. Most CD44- GCB were in cell cycle, indicating that they were Centroblasts, while centrocytes, non-dividing GCB, were mainly CD44low. Immunohistological analysis confirms that centrocytes, which are located in the light zone of germinal centres, express low levels of CD44, while Centroblasts, cells of the dark zone, are CD44-. While most CD77high GCB are Centroblasts and CD77low GCB centrocytes, many Centroblasts and centrocytes express intermediate levels of CD77, making this less reliable than CD44 for discriminating between these cells. Most CD44low and CD44- GCB were shown to have undergone Ig switch recombination in vivo. This indicates that switch recombination is independent of the maturation of Centroblasts to centrocytes and precedes the signals that induce GCB to differentiate to plasma cells or memory B cells. The average rate of entry of the CD44- GCB fraction to apoptosis on culture at 37 degrees C was faster than that of the total GCB preparation. It is suggested that this may reflect strict stromal-dependence of Centroblasts while centrocytes have to survive for long enough to have the chance of receiving antigen-specific selection signals. Inhibition of apoptosis by CD40 mAb with IL-4 or phorbol myristate acetate with ionomycin was similar in the CD44- and CD44low preparations.
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sites of specific b cell activation in primary and secondary responses to t cell dependent and t cell independent antigens
European Journal of Immunology, 1991Co-Authors: Yongjun Liu, Jun Zhang, Peter J L Lane, Eric Y T Chan, Ian C M MaclennanAbstract:Techniques which identify hapten-specific B cells in tissues have been used to determine the sites of B cell activation in rat spleens in response to T cell-dependent (TD) antigens and T cell-independent type-1 (TI-1) antigens. Surface-associated hapten binding by specific memory B cells and. B blasts was distinguished from the strong cytoplasmic hapten binding by specific plasma cells and plasmablasts. Blast cells in S phase were identified in tissue sections by staining cells which had been pulse labeled in vivo with 5-bromo-2′-deoxyuridine. Hapten-specific B blast cells are found in three sites: (a) around interdigitating cells in the T cell-rich zones; (b) in the follicular dendritic cell network and (c) in association with macrophages in the red pulp. Hapten-binding memory B cells, which are not in cell cycle, accumulate in the marginal zones and to a lesser extent the follicular mantles in response to TD and TI-1 antigens. The hapten-specific blast response in T zones is confined to the first few days after antigen is given and is low for primary responses to TD antigens, but massive on secondary challenge, when marginal zone memory B cells migrate to the T zones. Both the primary and secondary T zone responses to TI-1 antigens are impressive and in these responses hapten-specific B blasts are also found in the splenic red pulp. The follicular response to TD antigens starts with a small number of B blasts (fewer than five) entering each follicle. These increase in number exponentially so that by the 4th day after immunization they fill the follicle. The oligoclonality of the response is shown in simultaneous responses to two haptens where 6%–31% of the follicles on day 3 after immunization contain blasts specific for only one of the two haptens. During the 4th day classical zonal pattern of germinal centers develops. The surface immunoglobulin-positive B blasts are lost from the follicle center, while one pole of the follicular dendritic cell network fills with surface immunoglobulin-negative Centroblasts. Centroblasts do not increase in numbers but divide to give rise to centrocytes, which re-express slg and migrate into the follicular dendritic cell network. Cell kinetic studies indicate that the centrocyte population is renewed from Centroblasts every 7 h. Centrocytes either leave the germinal center within this time or die in situ. It is probable that the Centroblasts and centrocytes are derived from the small number of B blasts which initiate the follicular reaction, for the centrocytes show the same oligoclonality observed at the B blast stage. The germinal center reaction declines gradually and 3 weeks after immunization Centroblasts and centrocytes are no longer seen. At this time small clusters of B blasts can be found proliferating in the follicular dendritic cell network. These secondary B blasts characterize the third phase of the follicular reaction, which continues throughout the established phase of TD responses. Some follicular response is seen to TI-1 antigens but this is much less dramatic than that seen during TD responses.
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recombinant 25 kda cd23 and interleukin 1α promote the survival of germinal center b cells evidence for bifurcation in the development of centrocytes rescued from apoptosis
European Journal of Immunology, 1991Co-Authors: Yongjun Liu, Jennifer A Cairns, Michelle J Holder, Sandra D Abbot, Katherin U Jansen, Jeanyves Bonnefoy, John R Gordon, Ian C M MaclennanAbstract:Germinal centers contain a proliferating pool of Centroblasts which give rise to non-dividing centrocytes. Centrocytes are programmed to die by apoptosis unless they receive a positive signal for rescue. Rescue, in vivo, is likely to be dependent, initially, on interaction with antigen held on follicular dendritic cells (FDC). A subset of FDC located in that part of the germinal center furthest from Centroblasts is particularly rich in CD23. Supernatants containing high levels of soluble CD23 were found not only to encourage the survival of germinal center B cells but also to promote their differentiation toward a plasmacytoid morphology; these activities were diminished following removal of CD23 from the supernatants. Recombinant 25-kDa CD23 was initially found to be incapable of providing the signal for germinal center cell development but on the addition of interleukin 1α which, by itself, was inactive, rescue and differentiation of germinal center B cells were now achieved. Apoptosis in germinal center cells could also be prevented by the ligation of surface CD40 with monoclonal antibody: however, rescue via this pathway was not accompanied by plasmacytoid differentiation. These findings provide a functional rationale to the high level expression of CD23 found within a discrete subset of FDC and indicate a bifurcation in the development of germinal center B cells following their rescue from apoptosis.