What is the nature of the hairy cell and why should we be interested?
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B-Lymphocytes↗
Biomedical subjects
J Burthem
Publications and source records attributed to J Burthem.
Endothelial interactions of hairy cells: the importance of alpha 4 beta 1 in the unusual tissue distribution of the disorder.
The tissue-homing of all lymphocytes involves their interactions with endothelial cells (ECs) and with various tissue accessory cells. However, in hairy cell leukemia (HCL), these processes are particularly prominent and result in diagnostic appearances in the spleen, liver, and bone marrow. The present study explores the mechanisms that underlie these tissue reactions. Using a human umbilical vein EC (HUVEC) model, various possible receptor-ligand interactions between hairy cells (HCs) and ECs were examined and a central importance for alpha 4 beta 1/vascular cell adhesion molecule-1 (VCAM-1) was established. This receptor-ligand pair was shown to be important both for strong adhesion and for HC motility/transmigration. A similar importance for alpha 4 beta 1/VCAM-1 was established for the interaction between HCs and relevant tissue accessory cells. The in vitro relevance of these findings was confirmed by the demonstration of VCAM-1 in HCL spleen and by the fact that, in frozen sections, HCs adhered (via VCAM-1) to the red pulp, but not to other areas of normal spleen. These results indicate that alpha 4 beta 1/VCAM-1 is central to the interaction between HCs and endothelium/accessory cells. Such interactions, together with the intrinsic cell activation characteristic of HCL and the HC's consequent ability to interact with matrix, are responsible for many of the characteristic features of the disease.
Cell Movement↗
Granulocyte-macrophage colony-stimulating factor receptor: stage-specific expression and function on late B cells.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors (GMR) are expressed on myeloid cells throughout their maturational sequence. During myelopoiesis, GM-CSF induces the proliferation of precursors and has multiple effects on more mature cells; such effects include induction of maturation and priming for subsequent stimulation. GMR is expressed on a range of other cell types including acute leukemic blasts of myeloid and lymphoid lineage, but has been little studied on more mature lymphoid cells. Using sensitive triple-layer immunophenotypic techniques, we show here that both the alpha and beta c chains of the GMR are expressed on hairy cells (HCs) and myelomatous plasma cells (PCs), but not on chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) lymphocytes. The receptor was demonstrable on normal PCs in tonsil, but not on either activated or resting tonsillar B cells or on circulating normal B lymphocytes. The expression of the receptor is therefore stage specific, rather than a feature of activation. Perhaps, surprisingly, in view of its effects on myeloid cells, GM-CSF did not stimulate the proliferation or differentiation of HCs and did not protect them from apoptosis. However, the cytokine had a profound effect on the interaction of the HC with its environment. Thus, the cytokine caused a major cytoskeletal reorganization resulting in the inhibition of motility and loss of adhesion to cellular and matrix ligands. These studies indicate the importance of GM-CSF outside myelopoiesis and demonstrate a previously unrecognized stage specific role for the cytokine in B-cell biology. Taken together with our previous report that M-CSF enhances B-cell motility, the present findings indicate that myeloid growth factors act in concert to facilitate the controlled migration of certain B cells into and within tissues.
Apoptosis↗
Integrin function in chronic lymphocytic leukemia.
Integrins are central to many aspects of the tissue localization of normal and malignant lymphocytes. We examined how integrin function, rather than simple expression, might determine disease behavior in chronic lymphocyte leukemia (CLL). Using fluorescence-activated cell sorting (FACS) and immunoprecipitation, we first established the precise integrin heterodimer expression of a representative group of CLL patients (beta1 consistently present, with variable alpha 3, alpha 4, and alpha 5; alpha 4 beta 7 often expressed; alpha L beta 2 high; alpha V beta 3 absent). Regarding function, we initially examined the ability of CLL cells to interact with endothelium, because such interaction is the initial event determining the entry of CLL lymphocytes into tissues. The abnormal lymphocytes were shown to bind at low levels to unstimulated endothelium via beta 2/intercellular adhesion molecule (ICAM). However, when the endothelium was stimulated, markedly enhanced interaction with endothelium was observed in approximately half the cases; in these patients, the neoplastic population expressed alpha 4 beta 1, which conferred the ability to adhere strongly to stimulated endothelium via the alpha 4 beta 1 ligand, vascular cellular adhesion molecule-1 (VCAM-1). In relation to the migration of CLL cells within tissues, the abnormal lymphocytes showed differential binding to various adhesive proteins; they did not attach to basement membrane components, but displayed variable adhesion to fibronectin (FN). Finally, we examined the role of cell activation in these processes, and showed that activated CLL lymphocyte populations showed an increased capacity to adhere to both endothelium and matrix. Moreover, ex vivo CLL cells showed no capacity to migrate through endothelium/stroma, but were able to do so after cytokine stimulation. These studies show how the constitutive integrin expression/function, the intrinsic activation state of the cell, and the capacity of cytokines to modify integrin-mediated function all combine to determine the different patterns of clinical disease observed in CLL.
B-Lymphocytes↗
Integrin receptors and hairy cell leukaemia.
The ability of a cell to recognize and specifically localise within an appropriate tissue environment is essential to the proliferation and survival of that cell. The integrin family of cell-surface adhesion-receptors are essential to such tissue localisation, allowing a migrating cell to specifically recognise, localise within-, and respond to- the cellular or extracellular matrix ligands that characterise a given tissue. We have investigated how the expression and activity of integrin receptors underlies the consistent and unusual tissue distribution of the malignant B lymphocytes of hairy cell leukaemia (HCL). In this report we review our published work in this area. Our findings are then discussed within the context of current knowledge of integrin receptors and their ligands, and in relation to the clinical features of HCL.
Humans↗
Expression of the human mucosal lymphocyte antigen, HML-1, by T cells activated with mitogen or specific antigen in vitro.
Expression of the human mucosal lymphocyte antigen, HML-1 (CD103), recently identified as a novel alpha E beta 7 integrin, was studied on peripheral blood lymphocytes activated with mitogen or specific antigen. HML-1 was up-regulated on PHA activated T-lymphoblasts cultured in 100IU/ml interleukin-2 (IL-2), reaching a peak of > 50% positive cells at day 7, and expression was maintained at this level throughout the 28-day culture period. Following a transient decrease in the percentage of L-selectin cells, expression of this molecule was maintained on most PHA T-lymphoblasts. Cells activated by purified protein derivative of M. tuberculosis (PPD) or in mixed lymphocyte culture also up-regulated and maintained HML-1 expression for 14 days. In contrast, in all cases the percentage of CD25+ cells rose initially but subsequently declined over the same time periods. When freshly isolated cells from tonsil, spleen, mesenteric lymph node and lung were analysed, only lung contained significant numbers (39 +/- 6%) of HML-1+ cells. In both freshly isolated and activated cell populations the great majority of HML-1+ cells co-expressed CD8 although some HML-1+ CD8- cells were also present. Production of TGF-beta 1 peaked early during T-lymphoblast and MLR cultures and was not related to induction of HML-1 expression. Immunoprecipitation studies showed that the HML-1 molecule expressed on 10-day PHA T-lymphoblasts was indistinguishable from that found on intestinal intraepithelial lymphocytes and that no alpha 4 beta 7 integrin was expressed by these cells. Although HML-1 expression is essentially restricted to mucosal leucocytes in vivo, these experiments show that it is readily induced and maintained along with co-expression of L-selectin following CD8+ T-lymphocyte activation in vitro.
Antibodies, Monoclonal↗
Hairy cell interactions with extracellular matrix: expression of specific integrin receptors and their role in the cell's response to specific adhesive proteins.
Integrin/extracellular-matrix interactions are central to the migration, localization, and subsequent function of lymphocytes within tissues. In hairy cell leukemia (HCL) the malignant cells display a highly characteristic tissue distribution in which interactions with extracellular matrix (ECM) are often prominent. Therefore, we used HCL as a model in which to investigate the poorly understood integrin/ECM interactions that underlie the migratory behavior of malignant B lymphocytes. Using a combined approach involving immunocytochemistry, flow cytometry, and immunoprecipitation analysis, hairy cells (HCs) were shown to have a consistent and distinctive phenotype (mainly alpha 4 beta 1, alpha 5 beta 1, alpha v beta 1, and alpha v beta 3). Furthermore, functional studies utilising adhesion assays, time-lapse video-microscopy and image analysis showed that the HCs displayed very specific adhesive behaviour in response to relevant adhesive protein ligands. HCs were able to adhere to different extents on all the adhesive proteins examined, but, on laminin and collagen, binding was weak with little cytoplasmic spreading. In contrast, the cells showed strong adhesion both to fibronectin (FN) and to vitronectin (VN). On FN, the cells spread extensively with nonpolarized cytoplasmic projections, whereas on VN cytoplasmic projections were markedly polarized. This polarized morphology was shown to reflect cell motility. Investigation of the role of individual integrin receptors in the cell movement response suggested that alpha v beta 3 is the major integrin responsible for this motile behavior. These results are discussed in relation to the limited previous data on leukemic and activated B-cell integrins, and we suggest that the HC integrins play a significant role in the characteristic behavior of HCs within tissues.
Actin Cytoskeleton↗
The function of c-fms in hairy-cell leukemia: macrophage colony-stimulating factor stimulates hairy-cell movement.
Hairy cells (HCs) and some activated B cells express high levels of macrophage colony-stimulating factor (M-CSF) (CSF-1) receptor, but the functional effects of the cytokine on B cells have not been previously identified. Using video microscopy, image analysis, and migration assays, M-CSF was shown to induce chemokinetic and chemotactic movement of HCs. This movement response involved transition to a highly mobile, rounded cell form and was accompanied by distinctive changes in F-actin polymerization and distribution. Furthermore, the M-CSF-induced motility was substantially modified by the adhesive protein used as a substratum and involved qualitative changes in the function of the alpha v beta 3 integrin of HCs. It is suggested that the findings are relevant to the pathophysiology of hairy-cell leukemia (HCL) in particular, and to the biology of B-cell migration in general.
Actins↗
The bone marrow fibrosis of hairy-cell leukemia is caused by the synthesis and assembly of a fibronectin matrix by the hairy cells.
Hairy-cell leukemia (HCL) is a proliferation of clonal B-lymphocytes with features of activation. The disease has a number of distinctive characteristics, prominent among which is the fine reticulin fibrosis invariably present in the bone marrow. However, fibroblast infiltration has never been noted in the marrow and the origin of the fibrosis has not been established. The present studies show that the hairy cells (HCs) of HCL produce an insoluble matrix of fibronectin (FN) in vitro. FN synthesis was shown by the appearance of cellular FN on the surface of cells cultured in serum-free medium and by immunoprecipitation of the metabolically labeled protein from HC aggregates. Moreover, the HCs were shown to assemble FN into disulphide-bonded multimers. This assembly was blocked by a 70-kD amino-terminal fragment of the molecule that blocks FN multimer formation by fibroblasts. HCs expressed abundant VLA-5, an FN receptor not present on normal circulating B lymphocytes, but important in matrix formation. Furthermore, HCs were shown to adhere to an FN fragment containing the VLA-5 binding site. It is therefore suggested that the VLA-5 of HCs is implicated in their assembly of FN matrix. The in vivo relevance of the findings was established by the demonstration of FN in association with infiltrating HCs in bone marrow sections from patients with HCL. It is concluded that the HCs synthesise and assemble an FN matrix and that this is at least partly responsible for the bone marrow fibrosis so characteristic of the disease.
Cell Aggregation↗
Specific tissue invasion, localisation and matrix modification in hairy-cell leukemia.
HCs have a distinctive profile of matrix-binding integrin receptors which partly reflects their activated nature. HCs show differing functional responses to individual adhesive proteins, and these are mediated by particular integrin heterodimers. In particular, HCs are motile on Vitronectin (VN), and this motility is mediated by alpha v beta 3. HCs are immobile but actively spread on Fibronectin (FN) and this response is mediated by beta 1 integrins. M-CSF enhances the mobility (chemotaxis and chemokinesis) of HCs, and this response is partly mediated by alpha v beta 3. HCs synthesise and assemble fibronectin and this is, at least partly, the cause of the distinctive bone marrow fibrosis of hairy-cell leukaemia.
Animals↗