Regulation of expression of a human intercellular adhesion molecule (ICAM-1) during lymphohematopoietic differentiation

The intercellular adhesion molecule (ICAM-1) is a cell-surface molecule which binds to leukocyte function antigen-1 (LFA-1) and regulates both leukocyte adhesion to endothelial cells and immune functions requiring cell-cell contact. Membrane expression of ICAM-1 is highly regulated on all hematopoietic lineages. Cell membrane antigen is significantly expressed on a small subset of bone marrow (BM) progenitors but is weak or absent on all cell lineages once they enter the circulation. However, strong expression on tissue macrophages and germinal center B cells suggested that activated cells may show upregulated expression. When B cells, T cells, macrophages, or granulocytes were activated in vitro by suitable mitogens, ICAM-1 expression was induced in all cases. Parallel studies of hematopoietic tumors demonstrated a heterogeneity of expression which correlated with expression on their normal cellular counterparts. In particular, a striking correlation between expression on B-cell tumors and corresponding stages of B-cell differentiation was noted. The widely varying expression of ICAM-1 contrasts with LFA-1 which, while variable, is nevertheless significantly positive at all stages of differentiation. This suggests that the major regulation of homotypic adhesion mediated by the LFA-1/ICAM-1 linkage occurs through control of ICAM-1 expression. In keeping with this notion, ICAM-1 expression was also correlated with the "adhesiveness" of B-lymphoid tumors. Large solitary lymphoma masses showed intense expression of ICAM-1. Conversely, chronic lymphocytic leukemia (CLL) cells and lymphoma cells from tumors exhibiting diffuse, widespread lymph node disease showed weak expression. These observations are discussed in relation to the role of ICAM-1 in regulation of lymphoid recirculation and the biology of lymphoid tumors.     

Homotypic cell aggregations of human myeloma cells with ICAM-1 and LFA-1 molecules

Some myeloma cells freshly isolated from bone marrow aspirates in human myelomas and some myeloma cell lines formed spontaneous cell aggregations in vitro (homotypic cell aggregations). In order to clarify the surface molecules involved in homotypic cell aggregations and physiological roles of these cell aggregations, we investigated the expressions of intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) on 20 samples of freshly isolated myeloma cells and three myeloma cell lines and the effect of anti-ICAM-1 and anti-LFA-1 alpha antibodies on myeloma cell proliferation in vitro. All myeloma cells that we tested expressed ICAM-1 on their surface. Among them, myeloma cells that strongly coexpressed LFA-1 alpha, formed homotypic cell aggregates in vitro. These spontaneous cell aggregations were completely released by adding either anti-ICAM-1 or anti-LFA-1 alpha antibody. During short-term culture, spontaneous proliferation of myeloma cells in vitro and their proliferative responses to recombinant interleukin-6 (rIL-6) were not affected by pretreatment of myeloma cells with anti-ICAM-1 or anti-LFA-1 alpha antibody. Therefore these data suggest that homotypic cell aggregation of myeloma cells is mediated by ICAM-1 and LFA-1 molecules, but myeloma cell proliferation may not be modulated by these adhesion molecules during short-term cultures.     

Adhesion molecule expression on B-cell chronic lymphocytic leukemia cells: malignant cell phenotypes define distinct disease subsets

Expression of surface adhesion molecules of the Ig superfamily (CD54 and CD58), of the integrin family (beta 1, beta 2, and beta 3 chains), of the selectin family (L-selectin), and of the lymphocyte homing receptor (CD44) was analyzed on B-cell chronic lymphocytic leukemia (B- CLL) cells from 74 patients. The aim of the study was the definition of phenotypically distinct disease subsets and the correlation of adhesion molecule phenotypes with clinical parameters. Expression of CD58 on B- CLL cells defined more advanced disease stages. In comparison with beta chain-positive cases, patients whose cells did not express beta 1, beta 2, and beta 3 integrin chains fell into the most favorable prognostic group, with lower lymphocytosis and the absence of splenomegaly, diffuse bone marrow infiltration, and therapy requirement. A novel finding was the expression of beta 3 chains on cells from a minority (12 of 74) of B-CLL cases. beta 3 chains were always coexpressed with beta 1 and beta 2 chains. Two-color immunofluorescence analyses of adhesion molecules such as alpha x beta 2 integrin (LeuM5) and L- selectin (Leu8) showed that these markers were detectable on variable proportions of leukemic cells, thus confirming the intraclonal phenotypic heterogeneity of B-CLL. Differences in the intensity of CD44 expression were also shown among the various B-CLL clones. Finally, no major variations were shown by comparison of adhesion molecule phenotypes of leukemic cells simultaneously obtained from blood and bone marrow, and of CD5+ versus CD5- clones.     

Low expression of lymphocyte function-associated antigen (LFA)-1 and LFA-3 adhesion molecules is a common trait in Burkitt's lymphoma associated with and not associated with Epstein-Barr virus.

Lymphocyte function-associated antigens 1 and 3 (LFA-1, LFA-3) and intercellular adhesion molecule 1 (ICAM-1) are cell surface adhesion molecules necessary for immune processes requiring intercellular contact. It was recently proposed that malignant Burkitt's lymphoma cells (BL) may escape from immunosurveillance through the downregulation of LFA-1 (CD11a/CD18) or LFA-3 (CD58) and ICAM-1 (CD54) molecules. Expression of these three adhesion antigens was investigated in 19 BL lines. LFA-1 or LFA-3 expression was found to be absent or low in 8 of 11 Epstein-Barr virus (EBV) genome positive BL, but strongly expressed on all nonmalignant EBV genome positive lymphoblastoid cell lines (LCL). Negative or weak expression of LFA-1 and LFA-3 was also observed in 7 of 8 EBV genome negative BL. ICAM-1 was found to be expressed on the cell surface of the majority of BL lines. BL lines growing as individual cells did not express LFA-1, whereas clump-forming BL lines expressed this marker involved in B-cell homotypic aggregation. Expression of LFA-1 and LFA-3 was induced on in vitro infection of EBV-negative BL cells with the immortalizing EBV strain B95-8, and weakly with the nonimmortalizing EBV strain P3HR1. EBNA2 and LMP, two EBV encoded proteins expressed in LCL and in BL infected with B95-8 (BL/B95-8), are not expressed in P3HR1 infected BL cells (BL/P3HR1). Stable expression of EBNA2 after gene transfer in a BL/P3HR1 cell line did not restore the level of LFA-1 and LFA-3 found on BL/B95-8 cells. In EBV-positive BL cells expressing LFA-1 and LFA-3, LMP was found coexpressed, supporting the recent finding of the role of LMP in B-cell adhesion receptor activation. Consequently, diminished LFA-1 and LFA-3 expression appears to be a common characteristic of numerous EBV-positive BL as well as EBV-negative BL. These findings are discussed in the framework of BL pathogenesis.     

Adhesion receptors are differentially expressed on developing thymocytes and epithelium in human thymus.

The thymic microenvironment consists of a network of interrelated cells of epithelial, fibroblastic, endothelial, and hemopoietic origin. Within this environment, the development of specific T-lymphocyte subpopulations partially depends on the selective interaction of T-cell precursors with such cells. Human thymic epithelial cell strains, generated with a defective retroviral vector containing simian virus 40 (SV40) large T antigen and the neomycin resistance gene or by transfection with an SV40 plasmid defective in the origin of replication, provide useful tools for understanding the mechanisms contributing to the control of T-cell maturation. Because interepithelial, epithelial-macrophage, and lymphocyte-epithelial cell interactions are important for thymocyte differentiation, the distribution of integrin and nonintegrin adhesion receptors on these cells and on developing thymocytes in vivo and in vitro has been examined in detail. Our results indicate that the transformed human thymic epithelial cell strains express the common very late antigen (VLA)-beta 1 receptor and unique alpha chains VLA-2, VLA-3, and VLA-6. The cells are also positive for LFA-3 and ICAM-1 and weakly express beta 3, beta 4, and VNR alpha. They do not express the Leu-cellular adhesion molecules (CAM). This phenotypic profile on cultured thymic epithelium generally corresponds to the distribution of integrin and other receptor molecules on thymic epithelial cells in tissue sections. The majority of thymocytes also express the integrin VLA-beta 1 and -beta 2 chains as well as VLA-4, VLA-6, and LFA-1 alpha(L). Three-color flow cytometric analyses show differential levels of expression of these adhesion receptors on human thymocyte subsets. Taken together with the immunohistochemical localization of extracellular matrix molecules, these studies suggest that both the distribution of receptor-ligand pairs and the level of expression of adhesion molecules may influence T-cell development within the thymus.     

Role of adhesion molecules in the lymphoid cell distribution in rheumatoid synovial membrane

Summary We studied the staining pattern of a group of adhesion molecules in the lining layer and lymphocytic infiltrates of the rheumatoid synovial membrane, using monoclonal antibodies against lymphocyte function associated antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), VLA-5, endothelial leucocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1). The cells of the the lining layer were strongly ICMA-1 positive and VLA-5 positive, suggesting (1) that ICAM-1 may function to facilitate the adhesion of ICAM-1-bearing type A cells to type B lining cells and (2) that the lining cells may utilize VLA-5 for anchorage to fibronectin at the surface of the synovial membrane. In the lymphocyte-rich and transitional areas, the endothelial cells of the postcapillary venules were both ELAM-1 positive and ICAM-1 positive. ICAM-1 staining was weak in lymphoid aggregates, but strong in the transitional areas, indicating a paucity of ICAM-1-bearing cells in the lymphocyte-rich areas. On the other hand, LFA-1 staining was very strong in the lymphoid aggregates and only moderate in transitional areas. This suggested that the large numbers of T4 cells present in the lymphocyte-rich areas are sufficiently activated to express substantial levels of LFA-1, and also that the LFA-1 molecule is an important receptor for emigration from postcapillary venules. In germinal centre like areas in lymphoid aggregates, most of the cells stained strongly for ICAM-1 and VLA-4, suggesting that the proliferation of B lymphocytes may be facilitated by LFA-1- and VLA4-dependent T and B cell interaction. The VLA molecules stained in the transitional areas may provide appropriate adhesion and anchorage of lymphocytes for the achievement of the variety of immune reactions in which these cells are engaged in these areas.     

Quantitative expression of CD23 and its ligand CD21 in chronic lymphocytic leukemia

BACKGROUND AND OBJECTIVES: Cells from the great majority of patients with chronic lymphocytic leukemia (CLL) express CD23. A recent histologic study has shown that CD23 is expressed more strongly in the proliferating centers of the lymph nodes, where the large prolymphocytoid cells are located. The aim of our study was to quantify the expression of CD23 and CD21 in small and prolymphocytoid cells from patients with CLL and B-cell lymphomas, and correlate this expression with clinical parameters. DESIGN AND METHODS: Using quantitative flow cyto-metry we analyzed the antigen density of CD23 and CD21 in: 1) 101 cases of chronic lymphocytic leukemia, 84 typical, 14 with increased prolymphocytes (CLL/PL) and 3 atypical, 2) 15 cases of CD23 positive B-cell lymphoma with circulating lymphoma cells and 3) 8 normal subjects. The results were correlated with morphology and clinical staging. RESULTS: Cells from CLL and CLL/PL have a significantly higher number of CD23 molecules than normal and lymphoma B-cells (p<0.001 and p<0.001, respectively). Differences were not significant for CD21. CLL and CLL/PL cases had similar values of CD23 and CD21 molecules, but analysis at a single level showed that prolymphocytes in typical CLL and CLL/PL expressed significantly higher CD23 (p=0.001, p=0.006) and CD21 (p=0.001, p=0.001) than small lymphocytes. There was no correlation between CD23 or CD21 antigen density and clinical stages although there was a trend for a brighter CD23 in stage C patients. INTERPRETATION AND CONCLUSIONS: Since interaction between CD23 and CD21 is important for B-cell activation, proliferation and tumor formation, findings that both molecules are upregulated in prolymphocytes suggest that this is the proliferating cell component in CLL and underline the association between progression and increased prolymphocytes in typical CLL and CLL/PL.     

Expression of shared idiotypes in chronic lymphocytic leukemia and small lymphocytic lymphoma

The expression of shared idiotypes (Slds) has been studied on malignant CD5+B cells from patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) using a panel of 37 murine monoclonal antibodies previously demonstrated to be reactive with Slds derived from follicular B-cell lymphomas. Thirteen anti-Slds identified tumor cells from 31 of 105 (30%) CLL patients and 4 of 6 SLL patients. In comparison, the same panel of anti-Slds is reactive with 33% of follicular and diffuse B-cell lymphomas. Ten of these anti-Slds reacted with CLL cases at similar frequencies to that of the B-cell lymphomas. Two anti-Slds, which are known to react with autoantibodies, were significantly more prevalent in CLL than in B-cell lymphomas. These data confirm the presence of Slds in CLL and provide further evidence of an association between CLL and autoimmunity. The identification of a panel of antibodies reactive with a significant number of CLL and SLL patients will facilitate the application of anti-idiotype antibody therapy in these diseases.     

Growth factor-mediated proliferation in B cell non-Hodgkin's lymphomas

The non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of human lymphoid tumors, primarily of B cell lineage, which appear to represent arrested stages in B lymphocyte differentiation. Control of cell proliferation is a fundamentally important but poorly understood area of study in these tumors. We have studied a representative group of B cell NHLs to assess their potential for growth factor-mediated proliferation in vitro. Our results show that purified monoclonal NHL B cells of the small cell (well-differentiated lymphocytic lymphoma, nodular poorly differentiated lymphocytic lymphoma, etc) type, that were positive for the human malignancy-associated nucleolar antigen could be stimulated by human B cell growth factor (BCGF) to proliferate in vitro. Other B cell activators such as insoluble anti-Ig and the mitogen protein A also could stimulate thymidine incorporation in the lymphoma cell populations. In vitro lymphoma cell growth could be maintained in the presence of the growth factor for up to five weeks. The large B cell type NHL, however, appeared to be refractory to in vitro stimulation by BCGF as well as other stimulators of normal B cells. These studies suggest that human B cell lymphoid tumors are not only phenotypically similar to their normal B lymphocyte counterparts, but are also sensitive in some cases, to the same types of immunoregulatory molecules that control normal lymphoid cell growth.     

Cloning and expression of mouse integrin beta p(beta 7): a functional role in Peyer''s patch-specific lymphocyte homing.

Lymphocytes express integrin receptors, termed lymphocyte Peyer's patch high endothelial venule (HEV) adhesion molecules (LPAMs), that mediate their organ-specific adhesion to specialized HEVs found in mucosal lymphoid organs (Peyer's patches). LPAM-1 consists of a murine integrin alpha 4 noncovalently associated with integrin beta p. Here, we describe the cloning and expression of a mouse cDNA encoding beta p, which is an 806-amino acid transmembrane glycoprotein. The genomic Southern blot analysis indicates that beta p is the murine homologue of human beta 7. The function of alpha 4 beta 7 as a Peyer's patch-specific adhesion molecule was tested directly by expression of the murine beta 7 cDNA in an alpha 4+ beta 7-B-cell line or coexpression of the alpha 4 and beta 7 cDNAs in an alpha 4-beta 7-T-cell line. The transfected cells exhibited a new Peyer's patch-specific adhesive phenotype that could be specifically blocked by monoclonal antibodies against alpha 4 and beta 7. Moreover, an anti-beta 7 monoclonal antibody specifically blocked binding of normal lymphocytes to Peyer's patch HEV but did not inhibit their binding to peripheral lymph node HEVs, indicating that beta 7 is a unique component of the Peyer's patch-specific homing receptor.     

Induction of proliferation and blast transformation by interferon in human malignant and non-malignant lymph node B cells

The influence of interferon (IFN) on cellular proliferation, blast transformation, and differentiation was studied in lymph node cells from 17 patients with B-cell lymphomas, one patient with T-cell lymphoma, and eight patients with enlarged, non-malignant lymph nodes. The effects of IFN on lymph node cells were compared with effects on mononuclear blood cells from chronic lymphocytic leukemia (CLL) patients and healthy donors. Natural IFN-alpha (nIFN-alpha) induced a proliferative response in cells from seven of 17 of the B-cell lymphomas, in two of eight of the non-malignant lymph nodes, and in lymphoid blood cells from two of 32 CLL patients. With few exceptions, the proliferating cells were B cells and the data suggest that IFN acts directly on the B cells. Proliferation was not induced with IFN in cells from the T-cell lymphoma or in mononuclear blood cells from 13 healthy donors. nIFN-alpha induced blast transformation in cells from ten of 14 of the B-cell lymphomas and in four of seven of the non- malignant lymph nodes. Also beta- and gamma-IFN were shown to induce proliferation and blast transformation in lymph node cells from some patients. No major effect on the expression of various differentiation markers could be observed following culture in the presence of nIFN- alpha. We conclude that IFNs can induce proliferation and blast transformation in malignant and non-malignant B cells from lymph nodes.     

Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia

CXCL13 is a homeostatic chemokine for lymphocyte homing and positioning within follicles of secondary lymphoid tissues, acting through its cognate receptor, CXCR5. Moreover, the CXCR5-CXCL13 axis plays a unique role in trafficking and homing of B1 cells. Here, we report that chronic lymphocytic leukemia (CLL) B cells express high levels of functional CXCR5. CXCR5 expression levels were similar on CLL B cells and normal CD5+ B cells, and higher compared with normal CD5- B cells, follicular B-helper T cells (T(FH) cells), or neoplastic B cells from other B-cell neoplasias. Stimulation of CLL cells with CXCL13 induces actin polymerization, CXCR5 endocytosis, chemotaxis, and prolonged activation of p44/42 mitogen-activated protein kinases. Anti-CXCR5 antibodies, pertussis toxin, and wortmannin inhibited chemotaxis to CXCL13, demonstrating the importance of Gi proteins and PI3 kinases for CXCR5 signaling. Moreover, CLL patients had significantly higher CXCL13 serum levels than volunteers, and CXCL13 levels correlated with beta2 microglobulin. We detected CXCL13 mRNA expression by nurselike cells, and high levels of CXCL13 protein in supernatants of CLL nurselike cell cultures. By immunohistochemistry, we detected CXCL13+ expression by CD68+ macrophages in situ within CLL lymph nodes. These data suggest that CXCR5 plays a role in CLL cell positioning and cognate interactions between CLL and CXCL13-secreting CD68+ accessory cells in lymphoid tissues.     

Distribution of complement receptor subtypes in non-Hodgkin's lymphomas of B-cell origin

Surface receptors specific for either the C4b (CR1) or C3d (CR2) component of complement were examined on the neoplastic cells from 30 cases of non-Hodgkin's lymphoma of B-cell origin and on cells derived from 9 normal lymphoid tissues. Lymphocyte suspensions from non- neoplastic peripheral blood, tonsils, and lymph node contained three categories of complement receptor lymphocytes (CRL): cells with receptors for both C4b and C3d (CR1+, CR2+); cells with receptors for C4b but not C3d (CR1+, CR2-), and cells with receptors for C3d but not C4b (CR1-, CR2+). The mean of the proportion of total CRL expressing receptors only of C3d (CR1-, CR2+) was 0.35 for non-neoplastic tissues and 0.28 for malignant lymphomas of follicular center cell (FCC) origin. However, the proportion of cells with this phenotype was significantly higher in well differentiated lymphocytic lymphomas (WDL) and chronic lymphocytic leukemia (CLL) (0.65) and in intermediately differentiated lymphocytic lymphomas (IDL) (0.59). Histologic compartmentalization of the CRL subtypes was observed in frozen sections of normal lymphoid tissue. CR1+ cells were present in lymphoid follicles interfollicular areas, and in splenic red pulp. CR2+ cells were confined to lymphoid follicles. These findings strongly suggest that complement receptor phenotypes may be useful markers of B-cell differentiation.     

Circulating microenvironment of CLL: Are nurse-like cells related to tumor-associated macrophages?

B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common hematologic malignancies in Western countries. Accumulation of leukemic lymphocytes in peripheral blood, bone marrow and secondary lymphatic organs of CLL patients is due to decreased apoptosis rather than to increased proliferation. The former is driven by signals from a specific microenvironment, created by stromal cells of mesenchymal origin, follicular dendritic cells, T lymphocytes and others.Nurse-like cells (NLCs) were first described to differentiate from peripheral blood mononuclear cells of CLL patients in vitro, then they have been also found in proliferation centers of their lymphatic tissues. Like tumor-associated macrophages (TAMs) in solid tumors, nurse-like cells promote survival of CLL lymphocytes. NLC gene expression patterns suggest their similarity to TAMs and differ between patients depending on ZAP70 protein expression status. NLC number in vitro corresponds with CD14 expressing cell count and beta-2-microglobulin serum level, and positively correlates with leukemic lymphocyte viability. As NLCs strongly express genes for adhesion molecules and secrete chemokines of antiapoptotic activity, they should be considered as a target for anti-microenvironment therapy of this incurable disease.     

Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia.

The surface antigens expressed by the cells of chronic lymphocytic leukemia (CLL) are well known. Most CLL are monoclonal B-cell lymphoproliferative disorders characterized by the coexpression of B-cell antigens and CD5, an antigen present predominantly on T cells. Very little attention, however, has been paid to the quantitative characteristics of the expression of B-cell antigens in CLL. In this study, we used flow cytometry to analyze the expression of CD20, a well-known B-cell-associated antigen, in lymphocytes from 42 cases of CLL and its tissue counterpart, small lymphocytic lymphoma (SLL), and compared the results with results obtained from the analysis of 21 follicular lymphomas, 20 hyperplastic reactive nodes, and 26 samples of normal peripheral blood. The intensity of CD20 expression in the CLL/SLL cells was significantly lower than that of B cells in the other categories. This antigen expression abnormality does not appear to be a universal phenomenon in CLL/SLL, since CD19, another pan-B antigen, was expressed in CLL/SLL at levels higher than those in follicular lymphomas and comparable to those in reactive lymph nodes. These results indicate that the low CD20 expression can be used as a marker for CLL/SLL. The few cases exhibiting intense CD20 expression may represent a biologically different disease. CLL/SLL cells faintly expressing CD20 also show concomitant low CD5 expression in a manner not observed in normal CD5-expressing B cells.     

Bcl10 in chronic lymphocytic leukaemia and T-cell prolymphocytic leukaemia

Bcl10 is a cancer gene recently identified in B-cell lymphomas of mucosa-associated lymphoid tissues. It has been suggested as a target for mutation in multiple types of tumour including follicular lymphoma, T-cell acute lymphoblastic leukaemia and Sezary syndrome. To evaluate further the role of Bcl10 in human adult haematological cancers, we screened for mutations samples from 24 patients with B-cell chronic lymphocytic leukaemia (CLL) and 18 samples from patients with T-cell prolymphocytic leukaemia (T-PLL). No pathogenic mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not involved in the development of CLL or T-PLL and that its involvement may be restricted to other haematological malignancies.     

Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia.

During fetal development, murine and human B-lineage cells rearrange and express a highly restricted set of immunoglobulin heavy chain variable region genes (VH genes). We noted that a VH gene of the restricted human fetal repertoire, designated 51p1, potentially could encode the VH region of two human IgM rheumatoid factor proteins. These rheumatoid factors share a cross-reactive idiotype (CRI) defined by reactivity with G6, a murine monoclonal antibody that recognizes an antibody heavy chain determinant present on many human IgM autoantibodies, particularly rheumatoid factors. Recently, we found that the G6 CRI also is expressed frequently by neoplastic CD5 (Leu1) B cells from patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. However, neoplastic CD5-negative B cells from patients with lymphomas of follicular center cell origin rarely express this CRI. Here, we report that G6-reactive leukemic cells from two unrelated CLL patients express a VH gene that shares greater than 99% homology with a rearranged VH gene previously isolated from the leukemic cell DNA of another CLL patient and that is identical to VH 51p1. Using the polymerase chain reaction, we find that this VH gene is rearranged, and presumably expressed, in the genomic DNA of all examined cases of G6-reactive CLL or small lymphocytic lymphoma. Thus these data indicate that the autoantibody-associated G6 CRI is a serologic marker for a conserved and developmentally restricted VH1 gene that is expressed at high frequency in CD5 B-cell malignancies and early B-cell ontogeny.     

Expression of adhesion molecules LFA-3 and N-CAM on normal and malignant human plasma cells

Normal and malignant plasma cells were investigated for the expression of seven cellular adhesion molecules by immunofluorescence microscopy. The antigens investigated were CD2 and its ligand, LFA-3 (CD58). LFA-1 alpha (CD11a) and LFA-1 beta (CD18) and their ligand ICAM-1 (CD54), H-CAM (lymphocyte homing receptor; CD44) and N-CAM (CD56). Marrow from 18 patients with myeloma, two with plasma cell leukaemia (PCL), four with monoclonal gammopathy of uncertain significance (MGUS) and 10 normal allogeneic bone marrow donors was studied. All plasma cells from normals and multiple myeloma patients were negative for CD2, CD11a and CD18. All normal and myeloma marrow plasma cells were positive for ICAM-1. 16/18 myeloma cases tested, and all other samples (normal, MGUS and PCL), contained plasma cells positive for H-CAM. Only one normal, but 12/16 myelomas tested were positive for N-CAM (P less than 0.02). One of four MGUS cases was moderately positive and one other weakly positive for N-CAM. Both PCLs were N-CAM negative. 12/18 myelomas were positive for LFA-3, but only two normals (P less than 0.05). All MGUS cases were negative for LFA-3, as was one PCL, the other being weakly positive. Three cases were negative for both adhesion molecules, three cases expressed only N-CAM or LFA-3 and 10 cases expressed both. LFA-3 and N-CAM are expressed significantly in myeloma rather than normal plasma cells. Cases of MGUS may express N-CAM but not, in this small series, LFA-3. Plasma cells in the peripheral blood (PCL) and plasma cell lines express little or no LFA-3 or N-CAM.     

Differential expression of CD54/intercellular adhesion molecule-1 in myeloid leukemias and in lymphoproliferative disorders

Indirect immunofluorescence staining with monoclonal antibody (MoAb) CL203.4 of malignant cells from 269 patients with hematologic malignancies showed a heterogeneous expression of CD54/intercellular adhesion molecule-1 (ICAM-1). This marker was expressed by malignant cells of 57 out of 118 patients with myeloid malignancies and 69 out of 135 with B-lymphoid malignancies. On the other hand, CD54 was not detected on malignant cells of 16 patients with T-lymphoid malignancies. In myeloid malignancies, CD54 is preferentially expressed by "stem cell-derived" malignancies, being detectable on blast cells from almost all patients affected by chronic myelogenous leukemia in blast phase or myelodysplastic syndromes and by only 34% of patients with de novo acute myeloid leukemia (AML). The expression of CD54 did not correlate with any specific myeloid FAB subtype, although three cases of highly undifferentiated AML (FAB MO) displayed maximal levels of the antigen. The expression of CD54 in AML was significantly associated with that of CD34 and HLA-DR antigens. In B-lymphoid malignancies, CD54 expression appears to correlate with the differentiation stage of malignant cells, since B-origin acute lymphoblastic leukemias and conventional B-chronic lymphocytic leukemias (B-CLL; ie, "dim SIg" CLL) expressed lower levels of CD54 than more mature lymphoproliferative disorders ("bright SIg" CLL, prolymphocytic leukemias, and lymphoplasmacytic tumors). "High-grade" B-cell non-Hodgkin's lymphomas (B-NHL) express in general a higher level of CD54 than "low-grade" ones. This finding in conjunction with the expression of CD54 in all 17 patients with "bright SIg" CLL investigated (characterized by marked organomegaly and poor prognosis) suggest that the differential expression of CD54 in lymphoproliferative disorders may also relate to their degree of malignancy.     

Role of adhesion molecules in the development of massive hepatic necrosis in rats

Massive hepatic necrosis develops after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes as a result of microcirculatory disturbance caused by endothelial cell destruction by activated macrophages in the hepatic sinusoids. Immunohistochemical hepatic expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen 1 alpha (LFA-1 alpha) and the effect of monoclonal antibodies against both adhesion molecules on liver necrosis provoked after endotoxin administration was studied in these rats. There were increased stains of ICAM-1 in endothelial cells and LFA-1 alpha in macrophages in the hepatic sinusoids in Propionibacterium acnes-pretreated rats compared with normal rats. Such stains were further increased soon after endotoxin administration, followed by development of hepatic necrosis. Monoclonal antibodies against both adhesion molecules significantly attenuated the extent of liver injury compared with controls, without affecting the infiltration and activation of hepatic macrophages. Polyclonal antibodies against polymorphonuclear leukocytes eradicated circulating neutrophils, but did not change such liver injury, although gum arabic, which suppressed macrophage activation, attenuated the extent of liver injury. Thus, adhesion between endothelial cells and activated macrophages in the hepatic sinusoids via ICAM-1 and LFA-1 alpha is essential for the initiation of massive hepatic necrosis of this type. Contribution of neutrophils seems less likely. (Hepatology 1996 Feb;23(2):320-8)