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Human B Cells (human + b_cell)
Selected AbstractsPooled Human Gammaglobulin Modulates Surface Molecule Expression and Induces Apoptosis in Human B CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2003Mieko Toyoda We have previously shown that the pooled human gammaglobulin (IVIG) inhibited mixed lymphocyte reaction (MLR). In this study, we examined (1) if IVIG contains blocking antibodies reactive with cell surface molecules required for alloantigen recognition and (2) if IVIG modulates these surface molecule expressions using flow cytometry. IVIG does not contain significant amounts of blocking antibodies against CD3, CD4, CD8, CD20, CD14, CD40, MHC class I and class II. It reduces the number of intact B cells and monocytes, reduces or modulates CD19, CD20 and CD40 expression on B cells, and induces morphological changes in B cells. This B-cell modulation results primarily because of apoptosis. IVIG also induces apoptosis in T cells and monocytes, but to a lesser degree. Induction of apoptosis requires the intact IgG molecule. Reduction of intact B cell and monocyte cell numbers, modulation of surface molecule expression on B cells, and deletion of B and T cells by apoptosis could result in inhibition of optimal T-cell activation. This likely represents the primary mechanism responsible for IVIG suppression of the MLR, and may account for many of the observed beneficial effects of IVIG seen in the treatment of human autoimmune and alloimmune disorders. [source] Human B cells express a CD45 isoform that is similar to murine B220 and is downregulated with acquisition of the memory B-cell marker CD27,CYTOMETRY, Issue 1 2003Jack J. H. Bleesing Abstract Background Differences between human and murine B cells exist at all stages of B-cell development, including the stage of memory B-cell formation. B cells in mice are identified with the pan,B-cell,specific CD45 isoform, B220. In initial studies in humans, it appeared that B220 expression did not include all B cells. This study was performed to expand on those preliminary findings. Methods Multiparameter flow cytometric detection of B220 expression on B cells was combined with a variety of B-cell markers. Results In contrast to mice, B220 was not a pan,B-cell marker in humans but was downregulated in the majority of B cells that acquired the human memory B-cell marker, CD27, whereas a minor memory B-cell subset remained B220+, suggesting differences in differentiation. Conclusions The B220 isoform in humans is developmentally regulated in humans, tied to the acquisition of a memory phenotype, and as such can be used as a differentiation-specific CD45 isoform, akin to the use of CD45 isoforms to distinguish between naive and memory T-cell subsets. Patients with immunodeficiency disorders, associated with defective memory B-cell generation and absent or reduced CD27+ B cells, showed a corresponding lack of B220 downregulation consistent with altered differentiation of B-cell subsets. Cytometry Part B (Clin. Cytometry) 51B:1,8, 2003. Published 2002 Wiley-Liss, Inc. [source] Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated mannerIMMUNOLOGY, Issue 2 2008Tanja N. Hartmann Summary Chemokines orchestrate the organization of leucocyte recruitment during inflammation and homeostasis. Despite growing knowledge of chemokine receptors, some orphan chemokine receptors are still not characterized. The gene CCRL2 encodes such a receptor that exists in two splice variants, CRAM-A and CRAM-B. Here, we report that CRAM is expressed by human peripheral blood and bone marrow B cells, and by different B-cell lines dependent on the B-cell maturation stage. Intriguingly, CRAM surface expression on the pre-B-cell lines Nalm6 and G2 is specifically upregulated in response to the inflammatory chemokine CCL5 (RANTES), a chemokine that is well known to play an important role in modulating immune responses. Although Nalm6 cells do not express any of the known CCL5 binding receptors, extracellular signal-regulated kinases 1 and 2 (ERK1/2) are phosphorylated upon CCL5 stimulation, suggesting a direct effect of CCL5 through the CRAM receptor. However, no calcium mobilization or migratory responses upon CCL5 stimulation are induced in B-cell lines or in transfected cells. Also, ERK1/2 phosphorylation cannot be inhibited by pertussis toxin, suggesting that CRAM does not couple to Gi proteins. Our results describe the expression of a novel, non-classical chemokine receptor on B cells that is potentially involved in immunomodulatory functions together with CCL5. [source] To switch or not to switch , the opposing roles of TACI in terminal B cell differentiationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2007Ulrich Salzer MD Abstract The TNF superfamily ligands BAFF and APRIL and their three receptors BAFFR, BCMA, and TACI comprise a network that is critically involved in the development and function of humoral immunity. Failure of this complex system is associated with autoimmune disease, B lymphocyte tumours, and antibody deficiency. While BAFF:BAFFR interactions control peripheral B cell survival and homeostasis, BCMA function seems limited to the survival of long-lived bone marrow plasma cells. The functional activity of the third receptor TACI is, however, ambiguous: while TACI,/, mice predominantly develop autoimmunity and lymphoproliferation, TACI deficiency in humans primarily manifests itself as an antibody deficiency syndrome. An article in this issue of the European Journal of Immunology demonstrates a negative regulation via TACI in human B cells by using TACI specific antibodies. B cell proliferation, class switch recombination, and Ig production induced by various stimuli were inhibited via TACI. Within the BAFF/APRIL network, the expression of the receptors and ligands is spatially, as well as temporally, highly regulated at various stages of B cell development and function. Defining the exact contribution of TACI stimulation by specific triggers in vitro enables us to better understand the complex, context-dependent responses initiated by TACI in vivo. See accompanying article http://dx.doi.org/10.1002/eji.200636623 [source] Divide and conquer: the importance of cell division in regulating B-cell responsesIMMUNOLOGY, Issue 4 2004Stuart G. Tangye Summary Proliferation is an essential characteristic of clonal selection and is required for the expansion of antigen reactive clones leading to the development of antibody of different isotypes and memory cells. New data for mouse and human B cells point to an important role for division in regulating isotype class and in optimizing development of protective immunity by the regulated entry of cells to the plasma cell lineage. [source] A new Groucho TLE4 protein may regulate the repressive activity of Pax5 in human B lymphocytesIMMUNOLOGY, Issue 4 2002Michèle Milili Summary During mouse B-cell development, Pax5 is an essential transcription factor that acts as an activator of B-cell-specific genes and as a repressor of alternative lineage fates. The repressive function is mediated by the recruitment of members of the Groucho co-repressor family. Using an RNA display approach, we have isolated a transcript, called QD, specifically expressed in human pro-B and pre-B cells, which is derived from the human Groucho TLE4 gene. The QD transcript contains the first four TLE4 exons and an intronic sequence 3, of exon 4, demonstrating that QD is a splice variant of TLE4. The putative resulting protein of 94 amino acids corresponds to approximately half of an N-terminal tetramerization domain. We also show specific expression of TLE4 transcripts in human B cells and of TLE4 proteins in B-cell nuclei. Moreover, we demonstrate that recombinant QD protein binds to the TLE4 Q domain and is able to abolish the TLE4/Pax5 interaction. Thus, QD could act as a negative regulator of TLE4 function, in early B-cell differentiation. [source] Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptorsARTHRITIS & RHEUMATISM, Issue 3 2010Sandra Sacre Objective Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen-induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA). Methods Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll-like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast-like synovial cells treated with SSRIs. Results Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin-6, and interferon-,,inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action. Conclusion Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development. [source] Immunomodulatory activity of a methionine aminopeptidase-2 inhibitor on B cell differentiationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2009R. C. Priest Summary Methionine aminopeptidase-2 (MetAP-2) inhibitors have potent anti-angiogenesis activity and are being developed for the treatment of solid tumours. The recently observed specific expression of MetAP-2 in germinal centre B cells suggests that it has a role in regulating B cell function. We have demonstrated a potent MetAP-2-dependent inhibitory effect on the antibody secretion from B cell receptor and CD40 co-stimulated primary human B cells in the presence of interleukin-21. The effect of MetAP-2 inhibition on antibody secretion was due to a block in differentiation of B cells into plasma cells. Immunohistochemical analysis of germinal centres from human, mouse and marmoset spleen showed a similar expression pattern of MetAP-2 in the marmoset and man, whereas mouse spleen showed no detectable expression. In a marmoset, T dependent immunization model, the MetAP-2 inhibitor suppressed an antigen-specific antibody response. Furthermore, histological analysis showed loss of B cells in the spleen and disrupted germinal centre formation. These results provide experimental evidence to support a novel role for MetAP-2 in immunomodulation. These effects of MetAP-2 are mediated by disruption of the germinal centre reaction and a block in the differentiation of B cells into plasma cells. [source] | ||||||||||