scholarly journals The bcl-2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow.

1993 ◽  
Vol 178 (4) ◽  
pp. 1247-1254 ◽  
Author(s):  
S Nisitani ◽  
T Tsubata ◽  
M Murakami ◽  
M Okamoto ◽  
T Honjo
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Transgenic Mice ◽  
Gene Product ◽  
B Lymphocytes ◽  
Immunoglobulin Genes ◽  
Clonal Deletion ◽  
Immature B Cells ◽  
B1 Cells ◽  
Self Antigen

To test whether the product of the bcl-2 proto-oncogene blocks clonal deletion of self-reactive B cells, we have generated transgenic mice carrying the bcl-2 gene and the immunoglobulin genes for the anti-erythrocyte 4C8 antibody. In these transgenic mice, clonal deletion of self-reactive immature B cells in the bone marrow was not inhibited in spite of expression of the bcl-2 gene. In contrast, self-antigen-induced clonal deletion of mature self-reactive Ly-1 B (B1) cells in the peritoneal cavity was inhibited in the transgenic mice. These results indicate that the mechanism for clonal deletion of immature self-reactive B cells in the bone marrow differs from that of mature self-reactive B cells in the periphery.

scholarly journals The Transcription Factor Early Growth Response 1 (Egr-1) Advances Differentiation of Pre-B and Immature B Cells

1998 ◽  
Vol 188 (12) ◽  
pp. 2215-2224 ◽  
Author(s):  
Adelheid Dinkel ◽  
Klaus Warnatz ◽  
Birgit Ledermann ◽  
Antonius Rolink ◽  
Peter F. Zipfel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Growth Response ◽  
Early Growth ◽  
Early Growth Response ◽  
Immature B Cells ◽  
Early Growth Response 1 ◽  
I Cells

In mature B lymphocytes, the zinc finger transcription factor early growth response 1 (Egr-1) is one of the many immediate-early genes induced upon B cell antigen receptor engagement. However, its role during earlier stages of lymphopoiesis has remained unclear. By examining bone marrow B cell subsets, we found Egr-1 transcripts in pro/pre-B and immature B lymphocytes, and Egr-1 protein in pro/pre-B–I cells cultivated on stroma cells in the presence of interleukin (IL)-7. In recombinase-activating gene (RAG)-2–deficient mice overexpressing an Egr-1 transgene in the B lymphocyte lineage, pro/pre-B–I cells could differentiate past a developmental block at the B220low BP-1− stage to the stage of B220low BP-1+ pre-B–I cells, but not further to the B220low BP-1+ CD25+ stage of pre-B–II cells. Therefore, during early B lymphopoiesis progression from the B220low BP-1− IL-2R− pro/pre-B–I stage to the B220low BP-1+ IL-2R+ pre-B–II stage seems to occur in at least two distinct steps, and the first step to the stage of B220low BP-1+ pre-B–I cells can be promoted by the overexpression of Egr-1 alone. Wild-type mice expressing an Egr-1 transgene had increased proportions of mature immunoglobulin (Ig)M+ B220high and decreased proportions of immature IgM+ B220low bone marrow B cells. Since transgenic and control precursor B cells show comparable proliferation patterns, overexpression of Egr-1 seems also to promote entry into the mature B cell stage. Analysis of changes in the expression pattern of potential Egr-1 target genes revealed that Egr-1 enhances the expression of the aminopeptidase BP-1/6C3 in pre-B and immature B cells and upregulates expression of the orphan nuclear receptor nur77 in IgM+ B cells.

scholarly journals ROLES OF T AND B LYMPHOCYTES IN THE TERMINATION OF UNRESPONSIVENESS TO AUTOLOGOUS THYROGLOBULIN IN MICE

1974 ◽  
Vol 139 (3) ◽  
pp. 643-660 ◽  
Author(s):  
James A. Clagett ◽  
William O. Weigle
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
B Lymphocytes ◽  
Bone Marrow Cells ◽  
Antigen Binding ◽  
Binding Studies ◽  
Normal Complement ◽  
Self Antigen

The data presented in this paper support the hypothesis that unresponsiveness to autologous thyroglobulin (Tg) exists in the T cells and responsiveness exists in the B cells. Such a conclusion is based on the results of antigen-binding studies where few, if any, thymocytes recognized syngeneic Tg. Comparable numbers of antigen-binding lymphocytes for syngeneic Tg were found in the spleens of normal intact mice and of nude mice. The latter fact suggested that B cells exist which recognize self-constituents. From antigen-suicide experiments, a clearer picture of the susceptibility of B cells to iodinated self-antigen and of the obligatory role of antibody in the induction of lesions was developed. Only bone marrow cells (B cells) were affected by [125I]syngeneic Tg, in which case the incidence of lesions was diminished. From adoptive transfer experiments, the results demonstrate that unresponsiveness may be terminated by immunization with a mixture of heterologous (cross-reacting) Tg's. In this situation T cells are required since a B-cell reconstituted host failed to make antibody (plaque-forming cells) and to develop lesions. T cells in this form of an unresponsive state may recognize determinants on the heterologous Tg unrelated to autologous Tg and as such stimulate the normal complement of B cells to produce antibody that both reacts with autologous and heterologous Tg.

scholarly journals Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

2019 ◽  
Vol 216 (5) ◽  
pp. 1135-1153 ◽  
Author(s):  
Sarah A. Greaves ◽  
Jacob N. Peterson ◽  
Pamela Strauch ◽  
Raul M. Torres ◽  
Roberta Pelanda
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Peripheral Tolerance ◽  
High Avidity ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Central Tolerance ◽  
Autoreactive B Cells ◽  
Self Antigen

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell–mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell–intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.

scholarly journals B lymphocytes express and lose syndecan at specific stages of differentiation.

1989 ◽  
Vol 1 (1) ◽  
pp. 27-35 ◽  
Author(s):  
R D Sanderson ◽  
P Lalor ◽  
M Bernfield
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Receptor Expression ◽  
Cell Stage ◽  
Precursor B Cells

Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.

scholarly journals Reduced receptor editing in lupus-prone MRL/lpr mice

2007 ◽  
Vol 204 (12) ◽  
pp. 2853-2864 ◽  
Author(s):  
Jennifer L. Lamoureux ◽  
Lisa C. Watson ◽  
Marie Cherrier ◽  
Patrick Skog ◽  
David Nemazee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Messenger Rna ◽  
Immunoglobulin M ◽  
Considerable Proportion ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Immature B Cells

The initial B cell repertoire contains a considerable proportion of autoreactive specificities. The first major B cell tolerance checkpoint is at the stage of the immature B cell, where receptor editing is the primary mode of eliminating self-reactivity. The cells that emigrate from the bone marrow have a second tolerance checkpoint in the transitional compartment in the spleen. Although it is known that the second checkpoint is defective in lupus, it is not clear whether there is any breakdown in central B cell tolerance in the bone marrow. We demonstrate that receptor editing is less efficient in the lupus-prone strain MRL/lpr. In an in vitro system, when receptor-editing signals are given to bone marrow immature B cells by antiidiotype antibody or after in vivo exposure to membrane-bound self-antigen, MRL/lpr 3-83 transgenic immature B cells undergo less endogenous rearrangement and up-regulate recombination activating gene messenger RNA to a lesser extent than B10 transgenic cells. CD19, along with immunoglobulin M, is down-regulated in the bone marrow upon receptor editing, but the extent of down-regulation is fivefold less in MRL/lpr mice. Less efficient receptor editing could allow some autoreactive cells to escape from the bone marrow in lupus-prone mice, thus predisposing to autoimmunity.

scholarly journals Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.

1992 ◽  
Vol 176 (4) ◽  
pp. 991-1005 ◽  
Author(s):  
R Brink ◽  
C C Goodnow ◽  
J Crosbie ◽  
E Adams ◽  
J Eris ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Lymphocyte ◽  
Specific Antigen ◽  
Antigen Receptors ◽  
Antigen B ◽  
Self Antigen ◽  
Clonal Anergy

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

scholarly journals In vitro tolerance induction of neonatal murine B cells.

1976 ◽  
Vol 143 (6) ◽  
pp. 1327-1340 ◽  
Author(s):  
E S Metcalf ◽  
N R Klinman
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Specific Interaction ◽  
Tolerance Induction ◽  
Antigen Receptors ◽  
Spleen Cells ◽  
Protein Conjugates ◽  
Immature B Cells

The susceptibility of neonatal and adult B lymphocytes to tolerance induction was analyzed by a modification of the in vitro splenic focus technique. This technique permits stimulation of individual hapten-specific clonal precursor cells from both neonatal and adult donors. Neonatal or adult BALB/c spleen cells were adoptively transferred into irradiated, syngeneic, adult recipients which had been carrier-primed to hemocyanin (Hy), thus maximizing stimulation to the hapten 2,4-dinitrophenyl coupled by Hy (DNP-Hy). Cultures were initially treated with DNP on several heterologous (non-Hy) carriers and subsequently stimulated with DNP-Hy. Whereas the responsiveness of adult B cells was not diminished by pretreatment with any DNP conjugate, the majority of the neonatal B-cell response was abolished by in vitro culture with all of the DNP-protein conjugates. During the 1st wk of life, the ability to tolerize neonatal splenic B cells progressively decreased. Thus, tolerance in this system is: (a) restricted to B cells early in development; (b) established by both tolerogens and immunogens; (c) achieved at low (10(-9) M determinant) antigen concentrations; and (d) highly specific, discriminating between DNP- and TNP-specific B cells. We conclude that: (a) B lymphocytes, during their development, mature through a stage in which they are extremely susceptible to tolerogenesis; (b) the specific interaction of B-cell antigen receptors with multivalent antigens, while irrelevant to mature B cells, is tolerogenic to neonatal (immature) B cells unless antigen is concomitantly recognized by primed T cells; and (c) differences in the susceptibility of immature and mature B lymphocytes to tolerance induction suggest intrinsic differences between neonatal and adult B cells and may provide a physiologically relevant model for the study of tolerance to self-antigens.

Plasma and Intracellular Concentration of TNF and Its Receptors in Peripheral Blood and Bone Marrow in Different Stages of B-CLL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4781-4781
Author(s):  
Jacek Rolinski ◽  
Agnieszka Bojarska-Junak ◽  
Iwona Hus ◽  
Anna Dmoszynska
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
B Lymphocytes ◽  
Peripheral Blood ◽  
Biological Effects ◽  
Leukemic Cells ◽  
Control Group ◽  
Stage Of Disease ◽  
Positive Correlation

Abstract TNF has been proposed to play a role in the regulation of growth and death of leukemic B-CLL cells. However, the biological effects of TNF on leukemic cells, as well as its role as a prognostic factor need to be further investigated. The aim of the study was to eevaluate the correlation of TNF and its receptors in peripheral blood (PB) and bone marrow (BM) with the stage of B-CLL and some other clinical parameters. PB and BM were taken from 44 newly diagnosed, untreated B-CLL. patients. The control group consisted of 20 healthy subjects. We used flow cytometry technique to assess the capability of T and B lymphocytes to produce TNF and ELISA method to measure plasma levels of TNF and their soluble receptors. We found, that PB and BM plasma TNF concentration in the patients was significantly higher than in the healthy control (2.61 pg/ml. vs 0.62 pg/ml; and 2.91 pg/ml vs 0.75 pg/ml, respectively p<0.001). TNF concentration in PB and BM was significantly higher in Rai stage III–IV than in early stages (p<0.01). There was a correlation between the PB and BM TNF level and lymphocytosis (p<0.005) and the total tumor mass (TTM) (p<0.0001). The PB and BM TNF concentration positively correlated with the percentage of T CD3+ lymphocytes producing intracellular TNF (p<0.01). The percentage of T cells from PB an BM expressing cytoplasmic TNF was significantly higher in patients (PB:39.11±16.97%; BM:40.73±18.19%) than in normal controls (PB:15.74±7.95%; BM:18.80±12.93%) (p< 0.00001; p<0.005, respectively). In PB and BM from B-CLL patients the percentage of CD3+ cells expressing intracellular TNF was significantly higher than the percentage of CD19+/TNF+ cells (p<0.0001). Besides, it was found that the percentage of T cells expressing cytoplasmic TNF positively correlated with the stage of disease (p<0.01). In PB positive correlation were found between the number of T CD3+/TNF+ cells and lymphocytosis (p<0.05) and TTM (p<0.001). The percentage of leukaemic B cells positive for TNF did not correlate with the stage of disease. There was increased expression of TNF-RI and TNF-RII in leukaemic B cells in comparison to normal B-cells was observed (p<0.0001). We found positive correlation between the number of CD5+ B lymphocytes and the levels of soluble TNF-RII (sTNF-RII) (p< 0.05). The sTNF-RII levels in PB and BM significantly correlated with the stage of disease acc. Rai (p<0.0001). Furthermore, the sTNF-RII concentration positively correlated with lymphocytosis and TTM (p<0.0001). These results strongly support the key role TNF in B-CLL pathogenesis. Our results suggest that TNF may function as growth factor for B-CLL cells. CD3+T cells may be the important source of this cytokine in advanced B-CLL. It seems that changes in T cells capability to produce cytoplasmic TNF are associated with disease progression. However, further studies are required to confirm the key role of TNF in B-CLL pathogenesis.

Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2795-2795
Author(s):  
Daniel Trageser ◽  
Lars Klemm ◽  
Sebastian Herzog ◽  
Yong-mi Kim ◽  
Cihangir Duy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Receptor Signaling ◽  
Leukemic Transformation ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

Abstract Pre-B cells within the bone marrow are destined to die unless they are rescued through survival signals from the pre-B cell receptor. Studying the configuration of the immunoglobulin heavy chain locus (IGHV) in sorted human bone marrow pre-B cells by single-cell PCR, we detected a functional IGHV allele consistent with the expression of a functional pre-B cell receptor in the vast majority of normal human pre-B cells. However, only in 10 of 44 cases of BCR-ABL1-transformed pre-B cell-derived acute lymphoblastic leukemia (ALL), we detected a functional IGHV allele. For this reason, we studied the function of the pre-B cell receptor during early B cell development and progressive transformation in a BCR-ABL1-transgenic mouse model: Interestingly, BCR-ABL1-transgenic mice that have not yet undergone leukemic transformation show almost normal pre-B cell receptor selection. In these “pre-leukemic” pre-B cells, however, expression of the BCR-ABL1-transgene is extremely low as compared to full-blown ALL, suggesting that high levels of BCR-ABL1 expression are not compatible with normal expression of the pre-B cell receptor. Consistent with our observations in human ALL, full-blown ALL clones in BCR-ABL1-transgenic mice indeed show defective pre-B cell receptor selection and the pre-B cell receptors expressed on few leukemic cells are not functional. Treatment of leukemic mice with the BCR-ABL1 kinase inhibitor AMN107, however, reinstated normal pre-B cell receptor selection and pre-B cell receptor function within seven days. These data suggest that the transforming signal through BCR-ABL1 and normal survival signals through the pre-B cell receptor are mutually exclusive. In support of this hypothesis, we found that the full-blown leukemia only comprises one to four independent clones of “crippled” pre-B cells - even though all B cell precursors in these mice carry the BCR-ABL1-transgene. To test whether functional pre-B cell receptor signaling vetoes transformation by BCR-ABL1, we transformed murine pre-B cells carrying a deletion of the SLP65 gene, which is required for functional pre-B cell receptor signaling. Unlike SLP65-wildtype pre-B cells, SLP65−/− pre-B cells can be transformed by BCR-ABL1 at a high efficiency. Reconstitution of SLP65 using a retroviral vector, however, induced rapid cell death of BCR-ABL1-transformed pre-B cells. Next, we identified human BCR-ABL1-negative ALL cases with a functional or defective pre-B cell receptor signaling cascade. Transduction of pre-B cell receptor-deficient ALL cells resulted in rapid outgrowth while ALL cells with a functional pre-B cell receptor were not permissive to transduction with BCR-ABL1. We conclude that the pre-B cell receptor represents a potent tumor suppressor and a safeguard against BCR-ABL1-mediated transformation. Only “crippled” pre-B cells with a non-functional pre-B cell receptor are susceptible to BCR-ABL1-mediated transformation.

Flow Cytometry Primary 10 Colours Panel for Chronic Lympho Proliferative Diseases Diagnosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5190-5190
Author(s):  
Jonathan Brauner ◽  
Ingrid Beukinga ◽  
Zoulikha Amraoui ◽  
Zaina Kassengera ◽  
Michel Toungouz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
Cd10 Expression ◽  
Complete Characterisation

Abstract Abstract 5190 Objectives: Definition of the primary antibodies panel for 10 colours flow cytometry able to describe normal and clonal T, B lymphocytes and plamocytes in blood and bone marrow. Once clonalities are detected, the complete characterisation of Chronic Lymphoproliferative Diseases (CLPD) is supported by secondary panels chosen based on the results of CD5/CD10 expression for clonal B lymphocytes, CD27/CD38 for plasmatocytes and CD3/CD27 for clonal T cells. Materials and Methods: Blood and bone marrow of patients (N=50) with CLPD (mainly B-CLL). Samples are enumerated by haematology analyzer DxH 800 then 106 cells are washed three times, stained with the antibodies combination and red blood cells lysed with Versalyse (TM. Beckman Coulter). The samples were analysed on a 10 colours Navios flow cytometer (Beckman Coulter Fullerton, CA). The staining panel consists of 14 antibodies (CD45, CD8, CD4, CD5, CD3, CD19, CD38, λ, κ, CD23, CD5, CD10, CD14, CD27) conjugated with 10 different fluorochromes. The fixed gating strategy allows linking Navios analysis software to the middleware Remisol which drives the choice of the secondary panel. In some cases a third tube is performed for Ki67 or Zap-70 intra-cytoplasmic staining. Results: Monocytes are removed on the basis of their CD14/CD4 expression. B lymphocytes are CD19 positive. Normal naïve/memory B cells, hematogones and plasma cells are defined by their CD27, CD10 and CD38 expression. Eventual monoclonality is sought by analysis of the distribution of Kappa and Lambda light chains. A first classification of B cell lymphoma is achieved with the CD5 and CD10 expression of the clone (CD5+/CD10−: B-CLL MCL and few MZL, CD5−/CD10−: MZL and related, CD5−/CD10+ DLBCL and FL). Analysis of CD27, CD20 and CD23 expression allows discriminating between CD5+/CD10- lymphomas. All the 50 samples were correctly detected as CLPD and the automated Remisol choice of the second panel fit to the final diagnosis of all the cases of this small series. T lymphocytes are defined by their CD3 and CD5 expression. The analysis of CD4/CD8 balance and CD27/CD5 distribution are first line test when T cell clonality is suspected. There is a special gating to detect CD3-CD4+ T cell lymphoma and double negativity of CD4 and CD8 is a surrogate marker for gamma/delta T cells. NK cells are mentioned as not-T not-B lymphocytes, without specific staining. Conclusion/Discussion:This 10 colours 14 antibodies panel allows describing in one tube normal T and B cells, hematogones, memory and naives B cells plasma cells and detects T and B clonalities. This panel follows a similar logic than the Euroflow LST tube but with 10 colours and with Beckman Coulter's technology and antibodies. Moreover, this combination helps discriminating rapidly the CD5+/CD10- lymphomas while the complete characterisation of CD5 negative lymphomas only require less than 6 antibodies second tube. This is a paperless (all the process is driven and controlled by Remisol), fast and inexpensive diagnostic approach (always less than 20 antibodies required). Disclosures: Pradier: Beckman Coulter: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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