Usage of beta1 Integrin Ligands by B Cells is Developmentally Regulated in Avian Bursa

We wish to identify developmental changes in germinal center B cells that may contribute to their rapid growth. SHP-1 is an SH2 domain–containing phosphotyrosine phosphatase that negatively regulates activation of B cells and other cells of hematopoietic lineages. We have found that in all 13 EBV-negative and 11 EBV-positive Burkitt lymphomas with a nonlymphoblastoid phenotype, the mean concentration of SHP-1 was reduced to 5% of that of normal B and T cells. The possibility that this diminished expression of SHP-1 was related to the germinal center phenotype of Burkitt lymphomas was supported by the low to absent immunofluorescent staining for SHP-1 in germinal centers, and by the inverse relationship between the concentration of SHP-1 and the expression of the germinal center marker CD38 on purified tonsillar B cells. In CD38-high B cells, SHP-1 concentration was 20% of that of mantle zone B cells from the same donor. This reduction in SHP-1 is comparable to that of cells from motheaten viable mev/mev mice in which there is dysregulated, spontaneous signaling by cytokine and antigen receptors. Therefore, germinal center B cells may have a developmentally regulated, low threshold for cellular activation.

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Multiple eicosanoid-activated nonselective cation channels regulate B-lymphocyte adhesion to integrin ligands

AJP Cell Physiology ◽

10.1152/ajpcell.00229.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. C873-C882 ◽

Cited By ~ 16

Author(s):

Xiaohong Liu ◽

Peimin Zhu ◽

Bruce D. Freedman

Keyword(s):

Membrane Potential ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Mechanical Strain ◽

Cation Channels ◽

Direct Role ◽

Proinflammatory Mediators ◽

Nonselective Cation Channels ◽

Integrin Ligands

Arachidonic acid (AA) is a substrate for a variety of proinflammatory mediators, which are generated by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P-450 (CYP450) enzymes. COX (e.g., PGs and prostacyclins) and LOX (e.g., leukotrienes) products have well-established proinflammatory roles; however, little is known about the functions of CYP450 products in leukocytes. We previously found that mechanical strain generated by subjecting lymphocytes to hypotonic challenge triggered AA production and that two CYP450 products of AA, 5,6-epoxyeicosatrienoic acid (5,6-EET) and 20-hydroxyeicosatetraenoic acid (20-HETE), as well as a product of LOX, 5-( S)-hydroperoxyeicosatetrenoic acid (5-HPETE), induced Ca2+ entry into primary B cells. The main goal of the present studies, therefore, was to define the biophysically properties of eicosanoid-activated channels responsible for Ca2+ entry and the physiological consequences of activating these channels, including their role in mechanical signaling. We found that 5,6-EET, 20-HETE, and 5-HPETE each activated distinct Ca2+-permeant nonselective cation channels (NSCCs) in primary B cells. These NSCCs each regulate plasma membrane potential and B-cell adhesion to integrin ligands ICAM-1 and VCAM-1. Thus our data demonstrate that proinflammatory mediators produced in response to osmotic and/or physical stress play a direct role in regulating the B-cell membrane potential and their adhesion to specific ECM proteins. These results not only have important implications for understanding normal mechanisms of B-cell activation, differentiation, and trafficking but also point to novel targets for modulating the pathogenesis of B-cell-mediated inflammatory diseases.

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Predominance of fetal type DJH joining in young children with B precursor lymphoblastic leukemia as evidence for an in utero transforming event.

Journal of Experimental Medicine ◽

10.1084/jem.176.6.1577 ◽

1992 ◽

Vol 176 (6) ◽

pp. 1577-1581 ◽

Cited By ~ 59

Author(s):

R Wasserman ◽

N Galili ◽

Y Ito ◽

B A Reichard ◽

S Shane ◽

...

Keyword(s):

B Cells ◽

Young Children ◽

Lymphoblastic Leukemia ◽

In Utero ◽

Developmentally Regulated ◽

Complementarity Determining Region

The presence of N sequences in the complementarity determining region 3 (CDR3) of the rearranged immunoglobulin H chain is developmentally regulated: N regions are generally present in the DJH joinings of adult B cells but are often absent in fetal B cells. Analysis of the CDR3 in 61 B precursor acute lymphoblastic leukemias indicated that 87.5% of the leukemias obtained from children < or = 3 yr old lacked N regions at the DJH junction. In contrast, in children > 3 yr old, only 11.1% of the leukemias lacked N regions at this junction, a frequency similar to what we have observed in B cells from children and adults. These findings suggest that the majority of leukemias presenting within the first 3 yr of age arise from an in utero transforming event.

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Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences.

Journal of Experimental Medicine ◽

10.1084/jem.172.5.1377 ◽

1990 ◽

Vol 172 (5) ◽

pp. 1377-1390 ◽

Cited By ~ 262

Author(s):

A J Feeney

Keyword(s):

T Cells ◽

B Cells ◽

Dna Sequences ◽

B Lymphocyte ◽

Receptor Gene ◽

Newborn Mouse ◽

Developmentally Regulated ◽

Rna Sequences ◽

Variable Regions ◽

Vh Genes

Much of T and B lymphocyte receptor diversity derives from the addition of nontemplated N regions at the junctions of receptor gene elements, although fetal T cells expressing gamma/delta receptors lack N regions. I have sequenced immunoglobulin H chain variable regions of PCR-amplified DNA and cDNA from fetal and newborn mouse liver and spleen cells. These sequences showed an absence of N regions. Only 1/87 DNA sequences and 17/146 RNA sequences contained N regions, in striking contrast to adult Ig sequences. These data show that N region insertion is a developmentally regulated process in B cells as well as in T cells, and demonstrate that receptor diversity in neonatal B cells is limited by the absence of N regions as well as by biased usage of Vh genes.

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Developmentally regulated Fcγ receptor expression in lymphopoiesis FcγR III (CD16) provides an ITAM motif for pro-T and pro-B-cells

Immunology Letters ◽

10.1016/s0165-2478(96)02661-2 ◽

1996 ◽

Vol 54 (2-3) ◽

pp. 123-127 ◽

Cited By ~ 8

Author(s):

Matyas Sandor ◽

Michael Hagen ◽

Belen de Andres ◽

Richard G. Lynch

Keyword(s):

B Cells ◽

Receptor Expression ◽

Fcγ Receptor ◽

Developmentally Regulated

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Developmentally regulated association of a 56-kD member of the surface immunoglobulin M receptor complex.

Journal of Experimental Medicine ◽

10.1084/jem.176.1.129 ◽

1992 ◽

Vol 176 (1) ◽

pp. 129-137 ◽

Cited By ~ 7

Author(s):

A J Yellen-Shaw ◽

J G Monroe

Keyword(s):

B Cells ◽

Antigen Receptor ◽

Immature Stage ◽

Developmental Differences ◽

Immunoglobulin M ◽

Receptor Complex ◽

Developmentally Regulated ◽

Two Dimensional Gel Electrophoresis ◽

Surface Immunoglobulin ◽

Stage Of Development

Immature and mature B cells differ in the signals generated and transduced through their antigen receptor, surface immunoglobulin M (sIgM). Whereas signals generated through sIgM on mature B cells initiate a program leading to the positive activation of these cells, signaling through this receptor at the immature stage of development leads to a state of induced unresponsiveness or tolerance. Our previous studies have described developmental differences in sIgM transmembrane signaling that are independent of ligand-receptor affinity. In an attempt to understand the molecular basis for signaling differences between immature and mature B cells, we have analyzed the sIgM receptor complex in neonatal and adult mouse splenic B cells. While previously described components of this complex do not exhibit marked developmentally regulated differences in their association with sIgM, we have identified a 56-kD protein that associates with sIgM in mature (antigen-responsive), but not immature (tolerance-sensitive) B cells. This protein (p56) associates with sIgM as a homodimer, is constitutively phosphorylated on tyrosine, and is coimmunoprecipitated with IgM but not IgD. The observed inability to iodinate p56 suggests it is an intracellular component of the receptor complex. Based upon its migration in one- and two-dimensional gel electrophoresis we show, however, that p56 is distinct from the blk, lyn, or fyn src family kinases that have been shown to be associated with sIgM in mature B cells. The developmentally regulated participation of p56 in the B cell antigen receptor complex suggests a role in the differential signaling mediated via sIgM on immature and mature B cells.

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Myeloid Development Is Selectively Disrupted in PU.1 Null Mice

Blood ◽

10.1182/blood.v91.10.3702.3702_3702_3710 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3702-3710 ◽

Cited By ~ 5

Author(s):

Karen L. Anderson ◽

Kent A. Smith ◽

Kris Conners ◽

Scott R. McKercher ◽

Richard A. Maki ◽

...

Keyword(s):

B Cells ◽

Gene Disruption ◽

Growth Factor Receptor ◽

Receptor Expression ◽

Developmentally Regulated ◽

Gm Csf ◽

Myeloid Development ◽

Additional Cell ◽

Ets Family ◽

Macrophage Colony

The ets family transcription factor PU.1 is expressed in monocytes/macrophages, neutrophils, mast cells, B cells, and early erythroblasts, but not in T cells. We have recently shown that PU.1 gene disruption results in mice with no detectable monocytes/macrophages and B cells but T-cell development is retained. Although neutrophil development occurred in these mice, it was delayed and markedly reduced. We now proceed to demonstrate that PU.1 null hematopoietic cells fail to proliferate or form colonies in response to macrophage colony-stimulating factor (M-CSF), granulocyte CSF (G-CSF), and granulocyte/macrophage CSF (GM-CSF). In contrast, PU.1 null cells did proliferate and form colonies in response to interleukin-3 (IL-3), although the response was reduced as compared with control littermates. Compared with control cells, PU.1 null cells had minimal expression of G- and GM-CSF receptors and no detectable M-CSF receptors. The size of individual myeloid colonies produced from PU.1 null primitive and committed myeloid progenitors in the presence of IL-3, IL-6, and stem cell factor (SCF) were reduced compared with controls. Under these conditions, PU.1 null progenitors produced neutrophils but not monocytes/macrophages. These observations suggest that PU.1 gene disruption induces additional cell-autonomous effects that are independent of the alterations in myeloid growth factor receptor expression. Our results demonstrate that PU.1 gene disruption affects a number of developmentally regulated hematopoietic processes that can, at least in part, explain the changes in myeloid development and reduction in myeloid and neutrophil expansion observed in PU.1 null mice.

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Myeloid Development Is Selectively Disrupted in PU.1 Null Mice

Blood ◽

10.1182/blood.v91.10.3702 ◽

1998 ◽

Vol 91 (10) ◽

pp. 3702-3710 ◽

Cited By ~ 144

Author(s):

Karen L. Anderson ◽

Kent A. Smith ◽

Kris Conners ◽

Scott R. McKercher ◽

Richard A. Maki ◽

...

Keyword(s):

B Cells ◽

Gene Disruption ◽

Growth Factor Receptor ◽

Receptor Expression ◽

Developmentally Regulated ◽

Gm Csf ◽

Myeloid Development ◽

Additional Cell ◽

Ets Family ◽

Macrophage Colony

Abstract The ets family transcription factor PU.1 is expressed in monocytes/macrophages, neutrophils, mast cells, B cells, and early erythroblasts, but not in T cells. We have recently shown that PU.1 gene disruption results in mice with no detectable monocytes/macrophages and B cells but T-cell development is retained. Although neutrophil development occurred in these mice, it was delayed and markedly reduced. We now proceed to demonstrate that PU.1 null hematopoietic cells fail to proliferate or form colonies in response to macrophage colony-stimulating factor (M-CSF), granulocyte CSF (G-CSF), and granulocyte/macrophage CSF (GM-CSF). In contrast, PU.1 null cells did proliferate and form colonies in response to interleukin-3 (IL-3), although the response was reduced as compared with control littermates. Compared with control cells, PU.1 null cells had minimal expression of G- and GM-CSF receptors and no detectable M-CSF receptors. The size of individual myeloid colonies produced from PU.1 null primitive and committed myeloid progenitors in the presence of IL-3, IL-6, and stem cell factor (SCF) were reduced compared with controls. Under these conditions, PU.1 null progenitors produced neutrophils but not monocytes/macrophages. These observations suggest that PU.1 gene disruption induces additional cell-autonomous effects that are independent of the alterations in myeloid growth factor receptor expression. Our results demonstrate that PU.1 gene disruption affects a number of developmentally regulated hematopoietic processes that can, at least in part, explain the changes in myeloid development and reduction in myeloid and neutrophil expansion observed in PU.1 null mice.

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Chromatin Architecture near a Potential 3′ End of the Igh Locus Involves Modular Regulation of Histone Modifications during B-Cell Development and In Vivo Occupancy at CTCF Sites

Molecular and Cellular Biology ◽

10.1128/mcb.25.4.1511-1525.2005 ◽

2005 ◽

Vol 25 (4) ◽

pp. 1511-1525 ◽

Cited By ~ 87

Author(s):

Francine E. Garrett ◽

Alexander V. Emelyanov ◽

Manuel A. Sepulveda ◽

Patrick Flanagan ◽

Sabrina Volpi ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Histone Modifications ◽

Dnase I ◽

B Cell Development ◽

Open Chromatin ◽

Developmentally Regulated ◽

Dnase I Hypersensitive Sites ◽

Hypersensitive Sites

ABSTRACT The murine Igh locus has a 3′ regulatory region (3′ RR) containing four enhancers (hs3A, hs1,2, hs3B, and hs4) at DNase I-hypersensitive sites. The 3′ RR exerts long-range effects on class switch recombination (CSR) to several isotypes through its control of germ line transcription. By measuring levels of acetylated histones H3 and H4 and of dimethylated H3 (K4) with chromatin immunoprecipitation assays, we found that early in B-cell development, chromatin encompassing the enhancers of the 3′ RR began to attain stepwise modifications typical of an open conformation. The hs4 enhancer was associated with active chromatin initially in pro- and pre-B cells and then together with hs3A, hs1,2, and hs3B in B and plasma cells. Histone modifications were similar in resting splenic B cells and in splenic B cells induced by lipopolysaccharide to undergo CSR. From the pro-B-cell stage onward, the ∼11-kb region immediately downstream of hs4 displayed H3 and H4 modifications indicative of open chromatin. This region contained newly identified DNase I-hypersensitive sites and several CTCF target sites, some of which were occupied in vivo in a developmentally regulated manner. The open chromatin environment of the extended 3′ RR in mature B cells was flanked by regions associated with dimethylated K9 of histone H3. Together, these data suggest that 3′ RR elements are located within a specific chromatin subdomain that contains CTCF binding sites and developmentally regulated modules.

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