scholarly journals Human lymphocyte motility: normal characteristics and anomalous behavior of chronic lymphocytic leukemia cells

Blood ◽  
1976 ◽  
Vol 48 (5) ◽  
pp. 717-729 ◽  
Author(s):  
SC Jarvis ◽  
R Snyderman ◽  
HJ Cohen
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Human Lymphocyte ◽  
Human Lymphocytes ◽  
Surface Membrane ◽  
Cell Types ◽  
Anomalous Behavior ◽  
Lymphocytic Leukemia ◽  
Boyden Chamber ◽  
Surface Receptor ◽  
Lymphocyte Motility

Abstract The characteristics of human lymphocyte motility and its relationship to the redistribution of surface membrane antigens (capping) are poorly defined. Since chronic lymphocytic leukemia (CLL) cells cap poorly when compared with normal human lymphocytes, this study was undertaken to compare the motility of these two cell types. A modification of the Boyden chamber system was employed to quantify lymphocyte motility by placing lymphocyte suspensions on 8-mum convoluted-pore nitrocellulose filters and measuring the depth of migration of the cells into the filter at 37 degrees C. After 3 hr of incubation, CLL cells migrated significantly less into the filter than normal cells. Incubation in the presence of sodium azide or at 4 degrees C abolished all motility, indicating the active nature of the process. The relative motility of individual CLL patients' cells correlated best with the proportion of abnormal cells present as determined by surface receptor assays. The possibility that decreased cell motility in CLL was a reflection of enrichment by a “bone marrow-derived” (B cell) population was eliminated by the finding that normal B cells purified by gradient separation of rosetted cells migrated faster than normal T cells and considerably faster than CLL cells. Motility of normal and CLL lymphocytes was decreased by cytochalasin B and increased by colchicine, vincristine, and vinblastine. Thus, human lymphocyte motility appears to be dependent on microfilament integrity but not to require the colchicine-sensitive cytoskeleton. The decreased motility of CLL cells is the result of an intrinsic cell abnormality, but this finding cannot fully explain the decreased capping, since in human lymphocytes the latter is not prevented by an inhibitor of motility.

scholarly journals Human lymphocyte motility: normal characteristics and anomalous behavior of chronic lymphocytic leukemia cells

Blood ◽  
1976 ◽  
Vol 48 (5) ◽  
pp. 717-729
Author(s):  
SC Jarvis ◽  
R Snyderman ◽  
HJ Cohen
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Human Lymphocyte ◽  
Human Lymphocytes ◽  
Surface Membrane ◽  
Cell Types ◽  
Anomalous Behavior ◽  
Lymphocytic Leukemia ◽  
Boyden Chamber ◽  
Surface Receptor ◽  
Lymphocyte Motility

The characteristics of human lymphocyte motility and its relationship to the redistribution of surface membrane antigens (capping) are poorly defined. Since chronic lymphocytic leukemia (CLL) cells cap poorly when compared with normal human lymphocytes, this study was undertaken to compare the motility of these two cell types. A modification of the Boyden chamber system was employed to quantify lymphocyte motility by placing lymphocyte suspensions on 8-mum convoluted-pore nitrocellulose filters and measuring the depth of migration of the cells into the filter at 37 degrees C. After 3 hr of incubation, CLL cells migrated significantly less into the filter than normal cells. Incubation in the presence of sodium azide or at 4 degrees C abolished all motility, indicating the active nature of the process. The relative motility of individual CLL patients' cells correlated best with the proportion of abnormal cells present as determined by surface receptor assays. The possibility that decreased cell motility in CLL was a reflection of enrichment by a “bone marrow-derived” (B cell) population was eliminated by the finding that normal B cells purified by gradient separation of rosetted cells migrated faster than normal T cells and considerably faster than CLL cells. Motility of normal and CLL lymphocytes was decreased by cytochalasin B and increased by colchicine, vincristine, and vinblastine. Thus, human lymphocyte motility appears to be dependent on microfilament integrity but not to require the colchicine-sensitive cytoskeleton. The decreased motility of CLL cells is the result of an intrinsic cell abnormality, but this finding cannot fully explain the decreased capping, since in human lymphocytes the latter is not prevented by an inhibitor of motility.

scholarly journals Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1781-1791 ◽  
Author(s):  
Nicholas Chiorazzi ◽  
Manlio Ferrarini
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Lymphocyte ◽  
Expression Profiles ◽  
Surface Membrane ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Marginal Zone B Cells ◽  
Cellular Origin

AbstractSeveral cell types have been suggested as giving rise to chronic lymphocytic leukemia (CLL), and these suggestions have reflected the sophistication of technology available at the time. Although there is no consensus as to the normal cellular counterpart(s) in the disease, an antigen-experienced B lymphocyte appears required based on surface membrane phenotypes and gene expression profiles. However, what is still unclear is whether a single or multiple normal precursors were stimulated to evolve into CLL and at what stage(s) this occurred. A unifying, parsimonious theory is that CLL clones with either mutated or unmutated IGHVs derive from marginal zone B cells. However, evidence for remarkably similar B-cell receptor amino acid sequence and striking differences in polyantigen and autoantigen-binding activity, found in some but not all CLL clones, challenge a single-cell derivation for CLL. In this Perspective, we summarize data regarding normal counterparts of CLL cells and suggest that a multistep process of leukemogenesis is important to consider when assigning a cellular origin for this disease. Finally, although available data do not definitively identify the cell(s) of origin, we offer possibilities for single- and multiple-cell origin models as straw men that can be improved on and hopefully lead to final answers to this puzzle.

Expression of P2X7purinoceptors on human lymphocytes and monocytes: evidence for nonfunctional P2X7receptors

2000 ◽  
Vol 279 (4) ◽  
pp. C1189-C1197 ◽  
Author(s):  
B. J. Gu ◽  
W. Y. Zhang ◽  
L. J. Bendall ◽  
I. P. Chessell ◽  
G. N. Buell ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Adhesion Molecule ◽  
Human Lymphocytes ◽  
Normal Subjects ◽  
Cell Types ◽  
Surface Expression ◽  
Lymphocytic Leukemia ◽  
Functional Responses ◽  
Intracellular Expression ◽  
Selective Channel

Lymphocytes from normal subjects and patients with B-chronic lymphocytic leukemia (B-CLL) show functional responses to extracellular ATP characteristic of the P2X7receptor (previously termed P2Z). These responses include opening of a cation-selective channel/pore that allows entry of the fluorescent dye ethidium and activation of a membrane metalloprotease that sheds the adhesion molecule L-selectin. The surface expression of P2X7receptors was measured in normal leucocytes, platelets, and B-CLL lymphocytes and correlated with their functional responses. Monocytes showed four- to fivefold greater expression of P2X7than B, T, and NK lymphocytes, whereas P2X7expression on neutrophils and platelets was weak. All cell types demonstrated abundant intracellular expression of this receptor. All 12 subjects with B-CLL expressed lymphocyte P2X7at about the same level as B lymphocytes from normal subjects. P2X7function, measured by ATP-induced uptake of ethidium, correlated closely with surface expression of this receptor in normal and B-CLL lymphocytes and monocytes ( n = 47, r = 0.70; P< 0.0001). However, in three patients the ATP-induced uptake of ethidium into the malignant B lymphocytes was low or absent. The lack of P2X7function in these B lymphocytes was confirmed by the failure of ATP to induce Ba2+uptake into their lymphocytes. This lack of function of the P2X7receptor resulted in a failure of ATP-induced shedding of L-selectin, an adhesion molecule that directs the recirculation of lymphocytes from blood into the lymph node.

scholarly journals The B cell IgM Fc receptor: further evidence for the B cell origin of "null" chronic lymphocytic leukemia

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 375-379
Author(s):  
RA Rudders ◽  
PA Poldre
Keyword(s):  
Cell Differentiation ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Surface Membrane ◽  
Fc Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Differentiation ◽  
Facs Analysis ◽  
Membrane Expression ◽  
Surface Immunoglobulin

Fifty-three cases of chronic lymphocytic leukemia (CLL) were studied for the presence of the B cell IgM Fc receptor (Fc microR) using an aggregated IgM reagent. Restricted surface immunoglobulin, using conventional immunofluorescent techniques and FACS analysis, was detected in 43 cases (81%). The cells in the remaining ten cases (19%) expressed negligible surface immunoglobulin (slg-) and did not form E rosettes (E-), but this “null” subset clearly expressed the B cell Fc microR. The coincident membrane expression of the B1 antigen and the la- like antigen, as well as serial studies showing surface membrane light chain acquisition (in one patient), provided additional evidence for the B cell origin of this slg-E- subset. This subgroup of CLL appears to correspond phenotypically to a normal counterpart at a stage of B cell differentiation between the pre-B cell and the slgM+ early B cell. The B cell Fc microR appears to be a consistent and potentially useful marker for sl gE (“null”) CLL.

scholarly journals CD200 and Chronic Lymphocytic Leukemia: Biological and Clinical Relevance

2020 ◽  
Vol 10 ◽  
Author(s):  
Giovanni D’Arena ◽  
Vincenzo De Feo ◽  
Giuseppe Pietrantuono ◽  
Elisa Seneca ◽  
Giovanna Mansueto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Cell ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Mantle Cell ◽  
Type Ia

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin protein superfamily, is broadly expressed on a wide variety of cell types, such as B lymphocytes, a subset of T lymphocytes, dendritic cells, endothelial and neuronal cells. It delivers immunosuppressive signals through its receptor CD200R, which is expressed on monocytes/myeloid cells and T lymphocytes. Moreover, interaction of CD200 with CD200R has also been reported to play a role in the regulation of tumor immunity. Overexpression of CD200 has been reported in chronic lymphocytic leukemia (CLL) and hairy cell leukemia but not in mantle cell lymphoma, thus helping to better discriminate between these different B cell malignancies with different prognosis. In this review, we focus on the role of CD200 expression in the differential diagnosis of mature B-cell neoplasms and on the prognostic significance of CD200 expression in CLL, where conflicting results have been published so far. Of interest, increasing evidences indicate that anti-CD200 treatment might be therapeutically beneficial for treating CD200-expressing malignancies, such as CLL.

scholarly journals Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci

2020 ◽  
Vol 29 (16) ◽  
pp. 2761-2774
Author(s):  
Huihuang Yan ◽  
Shulan Tian ◽  
Geffen Kleinstern ◽  
Zhiquan Wang ◽  
Jeong-Heon Lee ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Cell ◽  
Association Studies ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Gene Promoters ◽  
Functional Variants ◽  
Increased Risk

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.

Different Expression of FcgammaRIIb in Chronic Lymphocytic Leukemia and Human Normal B Lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3134-3134
Author(s):  
Carol Moreno ◽  
Rajendra Damle ◽  
Sonia Jansa ◽  
Gerardo Ferrer ◽  
Pau Abrisqueta ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Lymphocytes ◽  
Surface Membrane ◽  
Memory B Cells ◽  
Lymphocytic Leukemia ◽  
Cd38 Expression ◽  
B Cell Subsets

Abstract The Fcgamma receptors (FcγRs) are a family of molecules that modulate immune responses. FcγRIIb is an inhibitory FcγR that bears immunoreceptor tyrosine-based inhibitory motifs which transduce inhibitory signals on coligation with the surface membrane Ig of the B-cell antigen receptor (BCR). The role of FcγRIIb in controlling B cell activation through inhibition of BCR signaling has been extensively studied in animal models. Nevertheless, data on FcγRIIb are scant in human normal and neoplastic B cells, this being due to the lack of a specific antibody for human FcγRIIb. Consequently, there is little information on this receptor in chronic lymphocytic leukemia (CLL). Considering the activated nature of CLL cells and the central role of the BCR in the biology of the disease, studies of FcγRs are warranted. We used a novel specific mAb directly conjugated with Alexa 488 fluorophore that solely reacts with the human FcγRIIb (MacroGenics, Inc.) to investigate the receptors expression on CLL and normal human B cells. The study population included 84 patients with CLL and 24 age- and sex-matched controls. FcγRIIb expression was assessed as the mean fluorescence intensity (MFI) of surface membrane staining. In CLL cells, FcγRIIb was measured on CD19+CD5+ cells in combination with CD38, CD49d or CD69. Normal B cells were immunostained for CD19, CD5, IgD and CD38 expression and B cell subsets: naïve (IgD+CD38−), activated (IgD+CD38+) and memory B cells (IgD−CD38−) were studied for their relative expression of FcγRIIb. FcγRIIb expression was found significantly higher in naïve B cells compared to activated and memory B cells [median MFI: 17420 (11960–21180) vs. 11.140 (7899–16970) and 11.830 (6984–17100); p&lt;0.001]. Significant differences were also observed between CD5− and CD5+ normal B cells. In contrast, FcγRIIb expression was lower in CLL cells than in CD5+ and CD5− normal B lymphocytes [median MFI: 6901(1034–42600), 10180 (5856–14820) and 12120 (7776–16040); p&lt;0.05)]. Interestingly, FcγRIIb expression was variable within individual CLL clones, this being higher in CD38+ and CD49d+ cells than in CD38− and CD49d− cells (p&lt;0.05). Furthermore, the highest density of FcγRIIb was observed on those cells which coexpressed CD38 and CD49d. In contrast, no significant differences were observed between FcγRIIb and the expression of the activation antigen CD69. Although CD69 and CD38 expression was significantly higher on unmutated IGHV cases, no correlation was found between FcγRIIb levels and IGHV mutational status. Similarly, there was no correlation between FcγRIIb and other poor prognostic variables such as ZAP-70 (≥20%), CD38 (≥ 30%) or high risk cytogenetics. Nevertheless, cases with ≥ 30% CD49d+ cells had higher FcγRIIb expression than those with &lt;30% CD49d+ cells (p=0.006). The findings presented in this study suggest a hierarchy of FcγRIIb expression in normal B-cells, CLL cells and their subpopulations: circulating normal CD5− B cells &gt; circulating normal CD5+ B cells &gt; circulating CD5+ CLL B cells. In addition, although FcγRIIb is present on all normal B cell subsets its expression is higher in naïve B cells. Furthermore, in CLL FcγRIIb density is greater in CD38+ and CD49d+ cells within the clone. Although CD49d and FcγRIIb on CLL clones is linked in a direct manner, there is no relationship with FcγRIIb density and IGHV mutations, ZAP-70, CD38 and unfavorable cytogenetic markers. Finally, the relationship between FcγRIIb expression on CLL cells and functional responses to BCR and other receptor-mediated signals deserve further investigation.

Monocytes/Macrophages Are the Major Targets of the CCL3 Chemokine Produced by CD38+CD49d+ Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2350-2350
Author(s):  
Antonella Zucchetto ◽  
Dania Benedetti ◽  
Claudio Tripodo ◽  
Riccardo Bomben ◽  
Fleur Bossi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Bone Marrow Biopsies ◽  
Tnf Α ◽  
Significant Difference

Abstract Abstract 2350 Poster Board II-327 Introduction: CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Recent gene expression profiling studies comparing CLL cases expressing low versus high levels of CD38 and CD49d, identified CCL3 as a gene upregulated by CD38+CD49d+ CLL. The release of CCL3 by cultured CLL cells was also demonstrated upon CD38 triggering, and CCL3 protein was found in CLL cells from bone marrow biopsies (BMB) of CD38+ cases (Zucchetto et al., Cancer Res, 2009; 69:4001-9). Given the role of CCL3 as potent chemoattractant for different cell types, we aimed at identifying the major targets of CCL3, as produced by CD38+CD49d+ CLL cells. Methods: CLL infiltrates of BMB were characterized by immunohistochemistry (IHC). Expression of the CCL3 receptors CCR1 and CCR5 by PB CLL subpopulations was evaluated by flow cytometry. T lymphocyte and monocyte migrations were performed by in-vitro transwell chemotaxis assays. Results: IHC analysis of BMB from 16 CLL cases revealed a higher number of infiltrating CD68+ cells in the context of CLL-involved areas of BMB from CD38+CD49d+CCL3+, compared to CD38−CD49d−CCL3− cases (p=0.01). CD3+ lymphocytes were interspersed in the CLL aggregates, but with no significant difference between the two subgroups. Evaluation of CCR1 and CCR5 in PB cell subpopulations from 40 CLL cases expressing or not surface CD38 and CD49d, showed the highest mean fluorescence intensity (MFI) levels for both CCR1 (624±60) and CCR5 (64±9) in the monocytic component, irrespective of CD38 and CD49d expression by CLL cells. Conversely, both CLL cells and residual T lymphocytes showed low MFI levels for CCR1 (19±4 and 14±3) and CCR5 (21±2 and 20±2). High CCR1 and CCR5 expression levels were detected in in-vitro differentiated monocytes from purified PB cells of four CD38+CD49d+ CLL. Accordingly, CCR1 expression was documented in macrophage-like cells in BMB from CD38+CD49d+ CLL. Next, we evaluated the capability of purified monocytes and T lymphocytes from 10 CLL cases to migrate in response to CCL3. In keeping with the strong expression of CCR1, monocytes migrated toward CCL3 at a concentration of 3 ng/mL (migration index, MI= 8.8±0.9, p=0.03), whereas T lymphocytes required a higher CCL3 concentration (100 ng/mL) to display slight migration capability (MI= 1.6±0.2, p=ns). The increased infiltration of macrophages in BMB from CCL3-producing CD38+CD49d+ CLL, prompted us to verify the capability of CCL3-stimulated macrophages to induce the expression by endothelial cells (EC) of the CD49d specific ligand VCAM-1. By using two different EC models (HUVEC and ADMEC), we documented a significant up-regulation of VCAM-1 by EC exposed to conditioned media (CM) collected from cultures of macrophages challenged in-vitro with CCL3 (p=0.002). Notably, increased levels of the pro-inflammatory cytokine TNF-α were detected in CCL3-CM (p=0.006), and neutralization of TNF-α by specific antibodies reverted the capability of CCL3-CM to induce VCAM-1 by EC models. In agreement with these in-vitro data, we found a more prominent meshwork of VCAM-1+ stromal/endothelial cells in lymphoid infiltrates from CD38+CD49d+ CLL compared to CD38−CD49d− cases (p=0.002), and engagement of CD49d by VCAM-1 was able to significantly delay the spontaneous apoptosis observed in cultured CLL cells. Conclusions: CD68+ monocytes/macrophages are likely the main targets for the CLL3 chemokine produced by CD38+CD49d+ CLL cells, and are active in determining, through the release of TNF-α and other yet unidentified cytokines, the overexpression of VCAM-1 by endothelial cells. Experiments aimed at investigating further roles of CD68+ monocytes/macrophage in CLL are currently matter of study. Disclosures: No relevant conflicts of interest to declare.

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