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B-cell Development (b-cell + development)
Selected AbstractsHuman 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] Foxo1 regulates marginal zone B-cell developmentEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Jing Chen Abstract A fundamental component of signaling initiated by the BCR and CD19 is the activation of phosphoinositide 3-kinase. Downstream of phosphoinositide 3-kinase, the protein kinase AKT phosphorylates several substrates, including members of the forkhead box subgroup O (Foxo) transcription factor family. Among the Foxo proteins, Foxo1 has unique functions in bone marrow B-cell development and peripheral B-cell function. Here, we report a previously unrecognized role for Foxo1 in controlling the ratio of mature B-cell subsets in the spleen. Conditional deletion of Foxo1 in B cells resulted in an increased percentage of marginal zone B cells and a decrease in follicular (FO) B cells. In addition, Foxo1 deficiency corrected the absence of marginal zone B cells that occurs in CD19-deficient mice. These findings show that Foxo1 regulates the balance of mature B-cell subsets and is required for the marginal zone B-cell deficiency phenotype of mice lacking CD19. [source] Tolerance checkpoints in B-cell development: Johnny B goodEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009Roxane Tussiwand Abstract B-cell development up to the immature B-cell stage takes place in the bone marrow, while final maturation into mature B cells occurs in the spleen. During differentiation, the precursor and immature B cells have to pass several checkpoints, including those in which they are censored for being auto-reactive, and therefore being potentially dangerous. Numerous studies have shown that the immature B-cell stage in the bone marrow and the transitional B-cell stages in the spleen comprise distinct checkpoints at which auto-reactivity is censored. Recently, evidence has been provided that the large pre-BII stage in the bone marrow, at which the pre-BCR is expressed, is yet another B-cell tolerance checkpoint. Here, we review these findings and speculate on directions for possible further experimentation. [source] The 3,IgH regulatory region is active at immature stages of B-cell developmentGENES, CHROMOSOMES AND CANCER, Issue 1 2008Laurence Guglielmi No abstract is available for this article. [source] Response to Guglielmi et al., "The 3,IgH regulatory region is active at immature stages of B-cell development"GENES, CHROMOSOMES AND CANCER, Issue 1 2008Laurel A. Eckhardt No abstract is available for this article. [source] Comparative expressed sequence hybridization studies of high-hyperdiploid childhood acute lymphoblastic leukemiaGENES, CHROMOSOMES AND CANCER, Issue 3 2004Alicja M. Gruszka-Westwood The functional consequences of a high-hyperdiploid karyotype, found in up to one-third of cases of acute lymphoblastic leukemia (ALL), are unknown. Using the technique of comparative expressed sequence hybridization (CESH), we sought to address the question of whether increased chromosome copies in hyperdiploid ALL lead to increased gene expression. Relative expression of hyperdiploid ALL blasts versus peripheral blood mononuclear cells was analyzed in 18 patients. Common regions of overexpression corresponding to the presence of tri-/tetrasomies included: Xp22.1,22.2, 4q28, 6q14,15, 6q24, 10p13, 14q23,24, 17q21, 18q12, and 21q21, identified in 28,89% of cases. However, increased expression without underlying trisomy occurred at 3p21.3, 7q11.2, 8p21, and 8q24.1 in 39,90% of cases. High expression at 7q11.2, the most consistent change detected, was confirmed by quantitative PCR. Poor correlation between the presence of tri-/tetrasomy and overexpression was observed for chromosomes 14 and 17. Two cases were reanalyzed versus (i) B cells, (ii) transformed B cells, and (iii) CD34+19+ cells (the putative counterpart of the leukemic cell). A reduction in the number of relatively overexpressed regions was observed with CD34+19+ cells. In particular, the peak at 7q11.2 disappeared, suggesting up-regulation of genes from this region in the early ontology of normal B-cell development. In conclusion, we have shown that tri-/tetrasomies in hyperdiploid ALL lead to an increase in the expression of associated sequences. The choice of a biologically relevant reference is crucial for data interpretation. © 2004 Wiley-Liss, Inc. [source] The aging of early B-cell precursorsIMMUNOLOGICAL REVIEWS, Issue 1 2005David Allman Summary:, B-cell genesis in the bone marrow declines with advancing age. In this review, we discuss our current understanding of why B-cell production rates decline with age with a special emphasis on why age-related factors might target very early lymphoid precursors. We consider the impact of aging on cytokine responsiveness and how current models for lineage relationships for very early B- and T-cell precursors might influence interpretations of experiments addressing age-associated declines in B- and T-cell differentiation. This discussion centers on the notion that aging affects events associated with the process by which hematopoietic stem cells are guided toward the B-cell pathway. Finally, we present a model in which the age-associated loss of early B-cell precursors is linked to suboptimal function of key transcriptional regulators of very early B-cell development. [source] Exploring lymphocyte differentiation pathwaysIMMUNOLOGICAL REVIEWS, Issue 1 2002Max D. Cooper Summary: Highlights in a 4-decade exploration of lymphocyte differentiation begin with comparative studies in birds and mammals leading to recognition of the separate T- and B-cell differentiation pathways and their cooperative interaction. The global effects of aborting IgM B-cell development with anti-µ antibodies indicated that B cells can undergo immunoglobulin isotype switching. A search for the mammalian bursa equivalent that began with an extended excursion through the gut-associated lymphoepithelial tissues ultimately led to the hematopoietic tissue origin of mammalian B cells. The identification of the precursors of B cells in hematopoietic tissues provided an expanded view of the life history of B cells. A recurring theme in this essay is the interplay between understanding normal lymphocyte differentiation and the defects that underlie immunodeficiency diseases and lymphoid malignancies. [source] Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cellsIMMUNOLOGICAL REVIEWS, Issue 1 2000Fritz Melchers Summary: During B-cell development the surrogate light (SL) chain is selectively expressed in progenitor and precursor B cells during the developmental stages of DH to JH and VH to DH JH rearrangements. Approximately half of all H chains produced by these rearrangements cannot pair with SL chains and cannot form a pre-B-cell receptor (pre-BCR). A spectrum of affinities between VpreB and individual VH domains generates preB cells with pre-BCR of different fitness which, in turn, determines the extent of the pre-B II-cell proliferation and the fidelity of allelic exclusion of the H chain locus. Once pre-BCR is expressed, SL chain expression is turned off. As pre-B II cells proliferate, SL is diluted out, thus limiting pre-BCR formation. As a consequence, pre-B II cells stop proliferating, become small and resting and begin to rearrange the L chain loci. Multiple rearrangements of the k L chain alleles are often detected in wild-type small pre-B II cells. Around 20% of the H chain-expressing small pre-B II cells also express L chains but do not display the Ig on the surface. Hence, it is likely that not all L chains originally generated in resting pre-B II cells can pair with the H chain previously present in that cell. The best fitting ones are selected preferentially to generate sIg+ B cells. Furthermore, the transition of immature B cells from the bone marrow to spleen and their development to mature cells appear as two separate steps controlled by different genes. [source] The role of the preBCR, the interleukin-7 receptor, and homotypic interactions during B-cell developmentIMMUNOLOGICAL REVIEWS, Issue 1 2000Angela Stoddart Summary: Considerable progress has been made in defining intermediate stages in the process leading from stem cells to mature B cells. Cell-bound and secreted molecules direct the progression through these stages and regulate the selection of clones from which the immune repertoire emerges. In fact, a myriad of signals derived from B-cell progenitors themselves and the microenvironment in which they develop direct the differentiation process. These signals are provided by B-cell antigen receptors (BCR) and their surrogates, and by adhesion and cytokine receptors. The co-operation of these receptors to control survival, expansion, and differentiation of early B-cell progenitors is the topic of this review. Specifically, we will summarize recent findings from our laboratory demonstrating that preBCR expression lowers the threshold for interleukin (IL)-7 responsiveness. How signals initiated by these receptors may intersect at this critical point of B-cell selection will be discussed. At the stage following IL-7 responsiveness we have shown that interactions between B-cell progenitors themselves promote their differentiation to immunoglobulin-secreting B cells. We propose that one function of stromal cells, known to be central to B lymphopoiesis, is to promote critical preB,preB homotypic interactions and ensuing signals. [source] Microenvironmental influences on human B-cell developmentIMMUNOLOGICAL REVIEWS, Issue 1 2000F. E. Bertrand Summary: Mammalian B-cell development can be viewed as a developmental performance with several acts. The acts are represented by checkpoints centered around commitment to the B-lineage and functional Ig gene rearrangement , culminating in expression of the pre-B-cell receptor (pre-BCR) and the BCR. Progression of cells through these checkpoints is profoundly influenced by the fetal liver and adult bone marrow (BM) stromal cell microenvironments. Our laboratory has developed a model of human B-cell development that utilizes freshly isolated/non-transformed human BM stromal cells as an in vitro microenvironment. Human CD34+ hematopoietic stem cells plated in this human BM stromal cell microenvironment commit to the B lineage and progress through the pre-BCR and BCR checkpoints. This human BM stromal cell microenvironment also provides survival signals that prevent apoptosis in human B-lineage cells. Human B-lineage cells exhibit differential expression of Notch receptors and human BM stromal cells express the Notch ligand Jagged-1. These results suggest a potential role for Notch in regulating B-lineage commitment and/or progression through the pre-BCR and BCR checkpoints. [source] The chicken B-cell receptor complex and its role in avian B-cell developmentIMMUNOLOGICAL REVIEWS, Issue 1 2000Camil E. Sayegh Summary: The bursa of Fabricius is critical to normal B-lymphocyte development in birds. During embryonic life, B-cell precursors migrate to the bursal rudiment and those which have undergone productive V(D)J recombination colonize lymphoid follicles and undergo immunoglobulin V gene diversification by gene conversion. The chicken surface IgM complex appears structurally and functionally equivalent to its mammalian counterpart, with homologs to CD79a and CD79b. Expression of a truncated Ig chain is sufficient to drive the early stages of B-cell development in the embryo bursa. Bursal cells expressing the truncated receptor complex proliferate in bursal follicles, and those which contain V gene rearrangements undergo V gene diversification by gene conversion. The bursa is a gut-associated organ and antigen is focused to bursal lymphoid follicles after hatch. While expression of the truncated chain is sufficient to support B-cell development in the embryo, B cells expressing this receptor are rapidly eliminated after hatch. We suggest the possibility that B-cell development in the bursa after hatch is driven by encounter with antigen leading to redistribution of B cells within the lymphoid follicle, B-cell proliferation and V gene repertoire development by gene conversion. [source] B-cell antigen-receptor signalling in lymphocyte developmentIMMUNOLOGY, Issue 4 2003Leo D. Wang Summary Signalling through the B-cell antigen receptor (BCR) is required throughout B-cell development and peripheral maturation. Targeted disruption of BCR components or downstream effectors indicates that specific signalling mechanisms are preferentially required for central B-cell development, peripheral maturation and repertoire selection. Additionally, the avidity and the context in which antigen is encountered determine both cell fate and differentiation in the periphery. Although the signalling and receptor components required at each stage have been largely elucidated, the molecular mechanisms through which specific signalling are evoked at each stage are still obscure. In particular, it is not known how the pre-BCR initiates the signals required for normal development or how immature B cells regulate the signalling pathways that determine cell fate. In this review, we will summarize the recent studies that have defined the molecules required for B-cell development and maturation as well as the theories on how signals may be regulated at each stage. [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] Disrupted B-lymphocyte development and survival in interleukin-2-deficient miceIMMUNOLOGY, Issue 2 2001Michael Schultz Summary Interleukin-2-deficient (IL-2,/,) mice develop a spontaneous, progressive, CD4+ T-cell-mediated colitis with an age-related decrease in the number of B lymphocytes. The aim of this study was to determine the mechanisms of B-cell loss in IL-2,/, mice. Serum immunoglobulin G1 (IgG1) levels in 8-week-old IL-2,/, mice were above normal but then decreased dramatically with advancing age. Between 8 and 11 weeks of age, the number of B-cell progenitors (B220+ IgM,) in the bone marrow of IL-2,/, mice was less than half of those in IL-2+/+ littermates. By 22 weeks of age, very few progenitor cells remained in the bone marrow of most mice, and spleens were almost devoid of B cells. Likewise, B1 cells were not present in the peritoneal cavity of aged IL-2,/, mice. Flow cytometry analysis of B-cell differentiation in the bone marrow suggested a progressive loss of B cells from the most mature to the least mature stages, which was not dependent on IL-2 receptor-, (IL-2R,) expression. B cells transferred from normal animals had similar survival rates in IL-2,/, and wild-type mice. We conclude that conventional B cells in older IL-2,/, mice are lost by attrition owing to a derangement in B-cell development. Because B1 cells are less dependent on the bone marrow, a separate mechanism for their loss is suggested. [source] Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 43JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003S Amadio Study aim: the Ebf gene family has been implicated in several developmental processes, ranging from B-cell development to neuronal differentiation. As the murine Ebf2 gene is expressed in numerous sites of nervous system, Ebf2-null mice develop hypogonadotropic hypogonadism, due to defective migration of gonadotropin releasing hormone-synthesizing neurons, and a peripheral neuropathy as well. Therefore, we aimed to study whether electrophysiological tests would be able to detect abnormalities of peripheral nerve function. Methods: 2 groups of mice were studied, which consisted of 8 Ebf2-/- mice and 9 age-matched controls. The sciatic nerve was stimulated at the ankle and at the ischiatic notch; the compound motor action potential (cMAP) was recorded from the paw muscles with a pair of needle electrodes to measure the motor conduction velocity (MCV). Results: MCV mean values were lower in Ebf2-/-(21.8 m/sec; SD 2.9) than in controls (35.2 m/sec; SD 2.6) and the difference was significant (p < 0.001). The mean cMAP amplitude was also decreased in Ebf2-/-(6.2 mV; SD 2.7) as compared to controls (9.3 mV; SD 2.6, p < 0.05). Conclusions: electrophysiological tests demonstrated a sharp decrease of sciatic MCV in Ebf2-/- mouse, as consequence of defective axon sorting, segmental dysmyelination and axonal damage revealed by pathological study. [source] | ||||||||||