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Facundo D. Batista - One of the best experts on this subject based on the ideXlab platform.
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activation of the small gtpase rac2 via the B Cell receptor regulates B Cell adhesion and immunological synapse formation
Immunity, 2008Co-Authors: Eloisa Arana, Naomi E Harwood, Elena Vigorito, Anne Vehlow, Martin Turner, Robert B. Henderson, Victor L. J. Tybulewicz, Facundo D. BatistaAbstract:Summary The integrin leukocyte function-associated antigen-1 (LFA-1) is important in the promotion of B Cell adhesion, thereBy facilitating immunological synapse (IS) formation and B Cell activation. Despite this significance, the associated signaling mechanisms regulating LFA-1 activation remain elusive. Here, we show that Both isoforms of the small GTPase Rac expressed By primary B Cells, Rac1 and Rac2, were activated rapidly downstream of Src-family kinases, guanine-nucleotide exchange factors Vav1 and Vav2, and phosphoinositide-3 kinase (PI3K) after BCR engagement. We identify Rac2, But not Rac1, as critical for B Cell adhesion to interCellular adhesion molecule-1 (ICAM-1) and IS formation. Furthermore, B Cells expressing constitutively active Rac2 are highly adhesive. We oBserve that Rac2-deficient B Cells exhiBit lower amounts of Rap1-GTP and severe actin polymerization defects, identifying a potential mechanism underlying their Behavior. We postulate that this critical role for Rac2 in mediating B Cell adhesion and IS formation might apply in all lymphocytes.
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the rap gtpases regulate B Cell morphology immune synapse formation and signaling By particulate B Cell receptor ligands
Immunity, 2008Co-Authors: Kevin B L Lin, Michele Weber, Spencer A Freeman, Saba Zabetian, Hayley K Brugger, Victor Lei, May Danglawson, Kathy W K Tse, Rene Santamaria, Facundo D. BatistaAbstract:B lymphocytes spread and extend memBrane processes when searching for antigens and form immune synapses upon contacting Cells that display antigens on their surface. Although these dynamic morphological changes facilitate B Cell activation, the signaling pathways underlying these processes are not fully understood. We found that activation of the Rap GTPases was essential for these changes in B Cell morphology. Rap activation was important for B Cell receptor (BCR)- and lymphocyte-function-associated antigen-1 (LFA-1)-induced spreading, for BCR-induced immune-synapse formation, and for particulate BCR ligands to induce localized F-actin assemBly and memBrane-process extension. Rap activation and F-actin assemBly were also required for optimal BCR signaling in response to particulate antigens But not soluBle antigens. Thus By controlling B Cell morphology and cytoskeletal organization, Rap might play a key role in the activation of B Cells By particulate and Cell-associated antigens.
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cd19 is essential for B Cell activation By promoting B Cell receptor antigen microcluster formation in response to memBrane Bound ligand
Nature Immunology, 2008Co-Authors: David Depoil, Naomi E Harwood, Victor L. J. Tybulewicz, Sebastian J Fleire, Bebhinn Treanor, Michele Weber, Kevin L Marchbank, Facundo D. BatistaAbstract:CD19 is essential for B Cell activation By promoting B Cell receptor–antigen microcluster formation in response to memBrane-Bound ligand
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lfa 1 icam 1 interaction lowers the threshold of B Cell activation By facilitating B Cell adhesion and synapse formation
Immunity, 2004Co-Authors: Yolanda R Carrasco, Sebastian J Fleire, Thomas O Cameron, Michael L Dustin, Facundo D. BatistaAbstract:ABstract The integrin LFA-1 and its ligand ICAM-1 mediate B Cell adhesion, But their role in memBrane-Bound antigen recognition is still unknown. Here, using planar lipid Bilayers and Cells expressing ICAM-1 fused to green fluorescence protein, we found that the engagement of B Cell receptor (BCR) promotes B Cell adhesion By an LFA-1-mediated mechanism. LFA-1 is recruited to form a mature B Cell synapse segregating into a ring around the BCR. This distriBution is maintained over a wide range of BCR/antigen affinities (10 6 M −1 to 10 11 M −1 ). Furthermore, the LFA-1 Binding to ICAM-1 reduces the level of antigen required to form the synapse and trigger a B Cell. Thus, LFA-1/ICAM-1 interaction lowers the threshold for B Cell activation By promoting B Cell adhesion and synapse formation.
Betsy J Barnes - One of the best experts on this subject based on the ideXlab platform.
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B Cell intrinsic role for irf5 in tlr9 Bcr induced human B Cell activation proliferation and plasmaBlast differentiation
Frontiers in Immunology, 2018Co-Authors: Baohong Zhang, Betsy J Barnes, Aaron Winkler, Tiffany Shih, Sukhwinder Singh, Robert DonnellyAbstract:Upon recognition of antigen, B Cells undergo rapid proliferation followed By differentiation to specialized antiBody secreting Cells (ASCs). During this transition, B Cells are reliant upon a multilayer transcription factor network to achieve a dramatic remodeling of the B Cell transcriptional landscape. Increased levels of ASCs are often seen in autoimmune diseases and it is Believed that altered expression of regulatory transcription factors play a role in this imBalance. The transcription factor interferon regulatory factor 5 (IRF5) is one such candidate as polymorphisms in IRF5 associate with risk of numerous autoimmune diseases and correlate with elevated IRF5 expression. IRF5 genetic risk has Been widely replicated in systemic lupus erythematosus (SLE), and loss of Irf5 ameliorates disease in murine lupus models, in part, through the lack of pathogenic autoantiBody secretion. It remains unclear, however, whether IRF5 is contriButing to autoantiBody production through a B Cell-intrinsic function. To date, IRF5 function in healthy human B Cells has not Been characterized. Using human primary naive B Cells, we define a critical intrinsic role for IRF5 in B Cell activation, proliferation, and plasmaBlast differentiation. Targeted IRF5 knockdown resulted in significant immunogloBulin (Ig) D retention, reduced proliferation, plasmaBlast differentiation, and IgG secretion. The oBserved decreases were due to impaired B Cell activation and clonal expansion. Distinct from murine studies, we identify and confirm new IRF5 target genes, IRF4, ERK1, and MYC, and pathways that mediate IRF5 B Cell-intrinsic function. Together, these results identify IRF5 as an early regulator of human B Cell activation and provide the first dataset in human primary B Cells to map IRF5 dysfunction in SLE.
A Orfao - One of the best experts on this subject based on the ideXlab platform.
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aBerrant expression of tetraspanin molecules in B Cell chronic lymphoproliferative disorders and its correlation with normal B Cell maturation
Leukemia, 2005Co-Authors: Susana Barrena, Julia Almeida, Monica Yunta, A Lopez, Nuria Fernandezmosteirin, M Giralt, M Romero, Luis Perdiguer, M Delgado, A OrfaoAbstract:ABerrant expression of tetraspanin molecules in B-Cell chronic lymphoproliferative disorders and its correlation with normal B-Cell maturation
Julia Almeida - One of the best experts on this subject based on the ideXlab platform.
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human peripheral Blood B Cell compartments a crossroad in B Cell traffic
Cytometry Part B-clinical Cytometry, 2010Co-Authors: Martin Perezandres, Julia Almeida, Alexander Schmitz, Gerald E Marti, Bruno Paiva, Wendy G Nieto, Anouk Caraux, Robert F Vogt, Andy C Rawstron, M C Van ZelmAbstract:A relatively high numBer of different suBsets of B-Cells are generated through the differentiation of early B-Cell precursors into mature B-lymphocytes in the Bone marrow (BM) and antigen-triggered maturation of germinal center B-Cells into memory B-lymphocytes and plasmaBlasts in lymphoid tissues. These B-Cell suBpopulations, which are produced in the BM and lymphoid tissues, recirculate through peripheral Blood (PB), into different tissues including mucosa and the BM, where long-living plasma Cells produce antiBodies. These circulating PB B-Cells can Be classified according to their maturation stage into i) immature/transitional, ii) naive, and iii) memory B-lymphocytes, and iv) plasmaBlasts/plasma Cells. Additionally, unique suBsets of memory B-lymphocytes and plasmaBlasts/plasma Cells can Be identified Based on their differential expression of unique Ig-heavy chain isotypes (e.g.: IgM, IgD, IgG, IgA). In the present paper, we review recent data reported in the literature aBout the distriBution, immunophenotypic and functional characteristics of these Cell suBpopulations, as well as their distriBution in PB according to age and seasonal changes. Additional information is also provided in this regard Based on the study of a population-Based cohort of 600 healthy adults aged from 20 to 80 years, recruited in the Salamanca area in western Spain. Detailed knowledge of the distriBution and traffic of B-Cell suBsets through PB mirrors the immune status of an individual suBject and it may also contriBute to a Better understanding of B-Cell disorders related to B-Cell Biology and homeostasis, such as monoclonal B-Cell lymphocytosis (MBL).
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aBerrant expression of tetraspanin molecules in B Cell chronic lymphoproliferative disorders and its correlation with normal B Cell maturation
Leukemia, 2005Co-Authors: Susana Barrena, Julia Almeida, Monica Yunta, A Lopez, Nuria Fernandezmosteirin, M Giralt, M Romero, Luis Perdiguer, M Delgado, A OrfaoAbstract:ABerrant expression of tetraspanin molecules in B-Cell chronic lymphoproliferative disorders and its correlation with normal B-Cell maturation
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incidence and clinicoBiologic characteristics of leukemic B Cell chronic lymphoproliferative disorders with more than one B Cell clone
Blood, 2003Co-Authors: Marialuz Sanchez, Julia Almeida, David Gonzalez, Marcos Gonzalez, M A Garciamarcos, Ana Balanzategui, M C Lopezberges, Josep F Nomdedeu, Teresa Vallespi, M BarbonAbstract:Leukemic B-chronic lymphoproliferative disorders (B-CLPDs) are generally Believed to derive from a monoclonal B Cell; Biclonality has only occasionally Been reported. In this study, we have explored the incidence of B-CLPD cases with 2 or more B-Cell clones and estaBlished Both the phenotypic differences Between the coexisting clones and the clinicoBiologic features of these patients. In total, 53 B-CLPD cases with 2 or more B-Cell clones were studied. Presence of 2 or more B-Cell clones was suspected By immunophenotype and confirmed By molecular/genetic techniques in leukemic samples (n = 42) and purified B-Cell suBpopulations (n = 10). Overall, 4.8% of 477 consecutive B-CLPDs had 2 or more B-Cell clones, their incidence Being especially higher among hairy Cell leukemia (3 of 13), large Cell lymphoma (2 of 10), and atypical chronic lymphocytic leukemia (CLL) (4 of 29). In most cases the 2 B-Cell suBsets displayed either different surface immunogloBulin (sIg) light chain (n = 37 of 53) or different levels of the same sIg (n = 9 of 53), usually associated with other phenotypic differences. Compared with monoclonal cases, B-CLL patients with 2 or more clones had lower white Blood Cell (WBC) and lymphocyte counts, more frequently displayed splenomegaly, and required early treatment. Among these, the cases in which a CLL clone coexisted with a non-CLL clone were older and more often displayed B symptoms, a monoclonal component, and diffuse infiltration of Bone marrow and required early treatment more frequently than cases with monoclonal CLL or 2 CLL clones.
Louis M Staudt - One of the best experts on this subject based on the ideXlab platform.
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suBtype specific addiction of the activated B Cell suBset of diffuse large B Cell lymphoma to foxp1
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Joseph D Dekker, Holger Kohlhammer, Arthur L Shaffer, Daechan Park, Wei Deng, Bumkyu Lee, Gregory C Ippolito, George Georgiou, Vishwanath R Iyer, Louis M StaudtAbstract:High expression of the forkhead Box P1 (FOXP1) transcription factor distinguishes the aggressive activated B Cell (ABC) diffuse large B-Cell lymphoma (DLBCL) suBtype from the Better prognosis germinal center B-Cell (GCB)-DLBCL suBtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL Cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways. FOXP1 promoted gene expression underlying transition of the GCB Cell to the plasmaBlast--the transient B-Cell stage targeted in ABC-DLBCL transformation--By antagonizing pathways distinctive of GCB-DLBCL, including that of the GCB "master regulator," BCL6 (B-Cell lymphoma 6). Cell-line derived FOXP1 target genes that were highly correlated with FOXP1 expression in primary DLBCL accurately segregated the corresponding clinical suBtypes of a large cohort of primary DLBCL isolates and identified conserved pathways associated with ABC-DLBCL pathology.
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B Cell receptor signaling in diffuse large B Cell lymphoma
Seminars in Hematology, 2015Co-Authors: Ryan M Young, Arthur L Shaffer, James D Phelan, Louis M StaudtAbstract:The importance of understanding the genetic and Biochemical Basis of B-Cell receptor (BCR) survival signaling in diffuse large B-Cell lymphoma (DLBCL) is underscored By the recent clinical success of agents that target the BCR pathway. DLBCL is composed of multiple distinct molecular suBtypes with divergent clinical outcomes. The activated B-Cell-like (ABC) suBtype is the most aggressive form of DLBCL and is often resistant to standard chemotherapies. ABC DLBCL expresses numerous genes found in antigen-activated B Cells, and genetic and pharmacologic studies have demonstrated that ABC DLBCL tumors are addicted to NF-κB activity. The origins of this NF-κB activity remained oBscure until RNA interference screens estaBlished that the majority of ABC DLBCL Cell lines rely on expression of BCR components and downstream signaling effectors for NF-κB activation. Pharmacological inhiBition with iBrutiniB of Bruton's tyrosine kinase, a kinase that is required for BCR signaling to engage NF-κB, is selectively toxic for ABC DLBCL tumors; a finding that has now Been translated to the clinic. These novel targets not only offer a promising new therapy option for ABC DLBCL, But also demonstrate the value of a deep molecular understanding of oncogenic signaling pathways.
