Biomedical subjects

S Jalkanen

Publications and source records attributed to S Jalkanen.

At least 73 records · Page 4Linked to original sources

PubMed1996

Expression of MHC class II molecules on human monocytes is regulated independently from each other after phagocytosis of bacteria.

Reactive arthritis is usually self-limiting polyarthritis which develops in HLA-B27 positive individuals after certain gastrointestinal or urogenital infections. The pathogenesis of reactive arthritis is unknown but T cells seem to have a crucial role. Most of the antigen-specific T cells isolated from the synovial fluid have been MHC class II restricted. The role of antigen presentation in the pathogenesis of reactive arthritis has been studied relatively little. In this work the authors studied the effect of arthritis-triggering bacterium (Yersinia enterocolitica O:3) on the expression of MHC class II molecules on human monocytes and found that the expression of different MHC class II molecules was regulated independently from each other in half of the individuals after certain incubation periods. In these cases the expression of HLA-DP was parallel to the expression of HLA-DQ, while HLA-DR expression went to the opposite direction or did not change at all. No difference between HLA-B27 negative and HLA-B27 positive healthy individuals was seen. The authors conclude that independent regulation of the expression of different MHC class II antigens on antigen-presenting cells is a more common phenomenon than usually thought.

Antibodies, Monoclonal↗

PubMed1996

Vascular adhesion protein 1 mediates binding of T cells to human hepatic endothelium.

BACKGROUND & AIMS: Molecules that regulate T-cell adhesion to hepatic endothelium and thereby recirculation of T cells to the liver are poorly understood. Because the adhesion molecule vascular adhesion protein-1 (VAP-1), which mediates lymphocyte binding to lymph node endothelium, is expressed on hepatic endothelium, it could play a role in regulating T-cell recruitment to the liver. The aim of this study was to investigate the distribution of VAP-1 expression in human liver and the ability of VAP-1 to support T-cell binding to hepatic endothelium in vitro. METHODS: Hepatic VAP-1 expression was investigated using immunohistochemistry and specific monoclonal antibodies, and VAP-1-mediated adhesion to hepatic endothelium was investigated with a tissue-binding adhesion assay using human liver sections. RESULTS: VAP-1 was expressed on sinusoidal and vascular endothelium in non-inflamed liver and in inflamed liver from patients with either allograft rejection or primary biliary cirrhosis. T cells from healthy donors bound to hepatic endothelium when added to noninflamed liver sections; this binding was inhibited by a specific anti-VAP-1 antibody but not by antibodies to intercellular adhesion molecule 1, lymphocyte function--associated antigen 1, or very late after activation (antigen) 4. VAP-1--mediated adhesion was unaffected by T-cell activation with phorbol ester. CONCLUSIONS: VAP-1 is constitutively expressed on hepatic endothelium and mediates T-cell adhesion to hepatic endothelium in vitro. VAP-1 could play a critical role in regulating T-cell recirculation to the liver in vivo.

Cell Adhesion↗

PubMed1996

Mucosally activated circulating human B cells in diarrhea express homing receptors directing them back to the gut.

BACKGROUND & AIMS: Recirculation of mucosal lymphocytes has been established in animals but not in humans. Specific antibody-secreting cells in the blood of patients with diarrhea, initially activated in gut mucosa, are potential recirculating cells. The aim of this study was to determine whether these cells circulate back to gut by analyzing their homing receptors. METHODS: Blood mononuclear cells, separated with immunomagnetic cell sorting into receptor-positive and receptor-negative populations, were assayed for pathogen-specific antibody-secreting cells and all immunoglobulin-secreting cells using enzyme-linked immunospot assay. RESULTS: The gut mucosa homing receptor alpha4beta7 was expressed more frequently on pathogen-specific antibody-secreting cells than on immunoglobulin-secreting cells of healthy controls (P<0.001). Conversely, L-selectin, a homing receptor for peripheral lymph nodes, was found on remarkably fewer antibody-secreting cells of the patients compared with immunoglobulin-secreting cells of controls (32.9% and 70.3%, respectively; P<0.001). Three to 6 months after the disease, specific antibody-secreting cells had disappeared and frequency of L-selectin-and alpha4beta7-expressing cells had returned to control levels. CONCLUSIONS: Circulating mucosally activated antibody-secreting cells express a set of homing receptors guiding them back to the gut. This provides evidence for recirculation of mucosal lymphocytes in humans.

Adult↗

PubMed1996

Mucosa-associated (beta 7-integrinhigh) lymphocytes accumulate early in the pancreas of NOD mice and show aberrant recirculation behavior.

The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) becomes expressed on islet vessels of NOD mice early during lymphocyte accumulation in islets. Because MAdCAM-1 preferentially mediates the homing of mucosal lymphocytes, islet-associated MAdCAM-1 could favor the accumulation of mucosal lymphocytes in pancreatic islets. Therefore, we investigated the relative frequency of islet-infiltrating lymphocytes with a mucosal phenotype (alpha 4/beta 7-integrinhigh and L-selectinlow) at early and advanced stages of insulitis. We found that until the age of 12 weeks, lymphocytes with a mucosal phenotype were particularly frequent in the pancreas (percentage of beta 7-integrinhigh-lymphocytes was 48% at 8 weeks and 73% at 12 weeks), whereas in diabetic mice older than 16 weeks, their relative number was smaller (26% of pancreas-infiltrating lymphocytes). To define the origin and homing behavior of beta 7-integrinhigh-lymphocytes before their accumulation in pancreatic islets in NOD mice, we sought for such lymphocytes in different lymphoid organs and studied their recirculation. We found that compared with lymphocytes in several other strains, in NOD mice such lymphocytes were most frequent in nonmucosal lymphoid tissues (peripheral and pancreatic lymph nodes, spleen) from an early age. When injected to blood circulation, mucosal beta 7high-lymphocytes failed to home efficiently back to mucosal lymphoid tissue in NOD mice but homed aberrantly to nonmucosal lymphoid tissues. After adoptive transfer of diabetogenic splenocytes, the first lymphocytes accumulating in the pancreas were predominantly beta 7-integrinhigh. We conclude that mucosa-associated lymphocytes are involved in the early phases of islet-inflammation in NOD mice and that the aberrant homing behavior of lymphocytes expressing high levels of beta 7-integrin may associate with their accumulation in pancreatic islets early during insulitis.

Aging↗

PubMed1995

CD73 is involved in lymphocyte binding to the endothelium: characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73.

We have recently described a monoclonal antibody (mAb) 4G4 recognizing a 70-kD molecule constitutively expressed on human endothelial cells and on subpopulations of lymphocytes. We showed that this molecule, which we named lymphocyte-vascular adhesion protein 2 (L-VAP-2), mediates lymphocyte adhesion to cultured endothelial cells. Protein sequencing of tryptic peptides from immunoaffinity-purified L-VAP-2 revealed sequence identity between L-VAP-2 and CD73 (ecto-5'-nucleotidase, E.C.3.1.3.5), and COS cells transfected with a CD73 cDNA were positively stained with the mAb 4G4, which recognizes L-VAP-2. mAb 4G4 was also able to partially inhibit the ecto-5'-nucleotidase activity of peripheral blood lymphocytes. Moreover, cross-precipitation studies performed with mAb 4G4 and a CD73 workshop mAb 1E9 showed that these two antibodies recognize the same molecule. Since the tissue distribution and biochemical characteristics of the two molecules are also similar, we conclude that L-VAP-2 and CD73 are the same glycoprotein. Adhesion experiments showed significantly increased binding of freshly isolated lymphocytes to COS cells transfected with a CD73 cDNA, as compared to mock-transfected COS cells, and binding of lymphocytes to CD73-expressing COS cells was inhibited by the presence of mAb 4G4 in the adhesion assay. CD73 is a glycosyl phosphatidylinositol-linked molecule previously shown to have a cosignalling role in T lymphocyte proliferation. Our data suggest that it also has a function in mediating lymphocyte adhesion to the endothelium.

5'-Nucleotidase↗

PubMed1995

Tumor endothelium selectively supports binding of IL-2-propagated tumor-infiltrating lymphocytes.

Entrance of activated T cells into the tumor after adoptive transfer is a prerequisite for the efficacy of this form of immunotherapy. Because lymphocyte binding to vascular endothelium is the critical step in which lymphocyte extravasation into the tissue is controlled, we compared adhesion of tumor-infiltrating lymphocytes (TIL) to endothelial cells in tumors, peripheral lymph nodes, mucosa-associated lymphatic tissues, and inflamed synovium. Simultaneously, expression of the known homing-associated Ags both on TIL and tumor vasculature was analyzed. All TIL strongly expressed alpha 4-integrins, LFA-1 and CD44, whereas only a low level of L-selectin expression was detected. Tumor vasculature showed signs of activation in each patient on the basis of elevated levels of intercellular adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1, and/or peripheral lymph node addressin (PNAd). TIL showed significantly enhanced binding to tumor vasculature in comparison with other endothelial specificities. Increased binding was not markedly due to up-regulation of the inflammation-induced endothelial cell adhesion molecules in tumors, because binding to inflamed synovium that expressed the same adhesion molecules was not enhanced. In summary, TIL show preferential binding to tumor vasculature and the binding is partially mediated by currently unknown mechanisms. In vitro analysis of endothelial cell binding properties may help to identify those TIL populations that will have the best potential to home back to tumor tissue after adoptive transfer.

Adult↗

PubMed1995

Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms.

Lymphocytes continuously migrate throughout the body in search of antigens. Virgin lymphocytes recirculate freely between the blood and different lymphatic organs, whereas immunoblasts extravasate preferentially into sites similar to those where they initially responded to antigen. Tissue-specific extravasation of lymphocytes is largely controlled by distinct lymphocyte surface receptors that mediate lymphocyte binding to high endothelial venules (HEV). In the present study, the molecular mechanisms determining the specificity of human mucosal (lamina propria) lymphocyte binding to different endothelial recognition systems were analyzed. Mucosal immunoblasts adhered five times better than small mucosal lymphocytes to mucosal HEV. Importantly, mucosal immunoblasts also bound to synovial HEV almost as efficiently as to mucosal HEV, but they did not adhere to peripheral lymph node HEV. To study the impact of different homing-associated molecules in this dual endothelial binding, we used a gut-derived T cell line and freshly isolated mucosal immunoblasts. Both cell types expressed integrins alpha 4, beta 1, beta 7, and lymphocyte function associated antigen 1 (LFA-1), and were CD44 positive, but practically L-selectin negative. Binding of mucosal immunoblasts to mucosal HEV was almost completely abolished by pretreatment with anti-beta 7 monoclonal antibodies, but it was independent of alpha 4/beta 1 function. In contrast, alpha 4/beta 1 partially mediated immunoblast adherence to synovial HEV, whereas alpha 4/beta 7 had only a minor role in adherence of blasts at this site. CD44 and LFA-1 contributed to HEV-binding both in mucosa and synovium. Taken together, this is the first report that demonstrates a critical role for alpha 4/beta 7 in the binding of gut lymphocytes to mucosal venules in humans. Moreover, a hitherto unknown interaction between mucosal effector cells and synovial endothelial cells was shown to be only partially mediated by the currently known homing receptors. The dual endothelial binding capacity of mucosal blasts may help to explain the pathogenesis of reactive arthritis not uncommonly associated with inflammatory and infectious bowel disease.

Carrier Proteins↗

PubMed1995

Sialyl LewisX carbohydrate is expressed differentially during avian lymphoid cell development.

Sialyl LewisX is a carbohydrate moiety involved in the regulation of white blood cell adhesion to endothelial cells. In this work, we have studied the expression, localization and function of sialyl LewisX carbohydrate on maturing B and T cells and the stroma of avian bursa, thymus and spleen as well as the role of sialyl LewisX in the generation of immune response and formation of germinal centers in the spleen. The expression of sialyl LewisX on bursal B cells decreases during the embryonic period, while on T cells it remains at a stable low level throughout their thymic development. Immediately after hatching, by which time the expression of sialyl LewisX on bursal B cells has already decreased, the stromal microenvironment of the bursa starts to express it. After hatching, sialyl LewisX is localized exclusively in the medullae of the follicles and the number of sialyl LewisX-positive follicles declines gradually during the following weeks. Thymic stroma does not express sialyl LewisX at any stage of development. In spleen, sialyl LewisX is expressed on a number of B and T cells as well as on other cell types in a way that seems not to be restricted to any structurally defined area. The cells or stroma of the germinal centers, however, do not express sialyl LewisX. When given simultaneously with an immunizing agent, anti-sialyl LewisX monoclonal antibody reduced the formation of germinal centers and suppressed antibody response in young birds. These results demonstrate that sialyl LewisX-bearing cell surface molecules are required during the generation of immune responses. They also suggest a role for sialyl LewisX in B cell maturation.

Animals↗

PubMed1995

Different forms of human vascular adhesion protein-1 (VAP-1) in blood vessels in vivo and in cultured endothelial cells: implications for lymphocyte-endothelial cell adhesion models.

Vascular endothelium plays a pivotal role in controlling leukocyte extravasation from the blood into the tissues. Vascular adhesion protein-1 (VAP-1) is a novel endothelial cell molecule which mediates lymphocyte binding to the vascular lining (Salmi, M., and Jalkanen, S., Science 1992. 257:1407). In this study, we analyzed endothelial cell type-specific differences of VAP-1. In vivo, VAP-1 is a 90/170-kDa molecule which is mainly expressed on the lumenal surface and in cytoplasmic granules of peripheral lymph node-type postcapillary venules (high endothelial venules, HEV). In tonsil HEV, VAP-1 is modified with abundant sialic acids. VAP-1 is also detectable in the cytoplasm of human umbilical vein endothelial cells (HUVEC) and in an endothelial cell hybrid EaHy-926, although both cell types lack detectable surface VAP-1. Cultured endothelial cells do not express MECA-79-defined peripheral lymph node addressins either. VAP-1 was not translocated onto the endothelial cell surface after stimulation with multiple cytokines, mitogens or secretagogues which induced expression of other known endothelial adhesion molecules. Biochemical analyses revealed that VAP-1 is a approximately 180-kDa protein in these endothelial cell types. Digestions with neuraminidase, O-glycanase and N-glycanase, as well as treatment of cells with tunicamycin and benzyl-N-acetylgalactosaminide, did not alter the molecular mass of VAP-1 in EaHy-926. Pulse-chase experiments showed that VAP-1 is directly synthesized as a 180-kDa molecule without any detectable precursors. Thus, in cultured endothelial cells, VAP-1 is a 180-kDa protein which is devoid of post-translational modifications, and in particular, lacks the sialic acids crucial for the function of VAP-1 in tonsil vessels. Notably, the endothelial cell types commonly used as a model in studying lymphocyte-endothelial cell interactions lack surface expression of VAP-1 and peripheral node addressins, and hence are inherently of limited use in analyses of the initial adhesion of lymphocytes.

Acetylgalactosamine↗

PubMed1995

CD44v6 expression in non-Hodgkin's lymphoma: an association with low histological grade and poor prognosis.

The family of CD44 glycoproteins has diverse functions in cell-cell and cell-matrix interactions. The standard form of CD44 is of importance in the dissemination of lymphoma, whereas the clinical significance of the variant exon v6-containing forms of CD44 (CD44v6) is not known. The expression of different forms of CD44 was investigated by using antibodies against the constant part of CD44 (CD44c) and CD44v6 in 56 primary and 17 recurrent non-Hodgkin's lymphomas and correlated with several clinicopathological parameters and with prognosis. Fifty-seven per cent of the primary non-Hodgkin's lymphomas expressed CD44v6 and 73 per cent expressed the constant epitope. Expression of both CD44c and CD44v6 was associated with low histological grade of malignancy. CD44c expression was associated with a low cellular proliferation rate as assessed by DNA flow cytometry. Of several factors tested, high expression of the variant from v6 was the only factor that was associated with unfavourable recurrence-free survival (P = 0.04). We conclude that CD44v6 is associated with a low histological grade, but, on the other hand, with an unfavourable outcome, which suggests that the combination of CD44v6 and histological grading may form a particularly strong prognostic parameter in non-Hodgkin's lymphoma.

Adolescent↗

PubMed1995

Usage of beta 1 integrin ligands by B cells is developmentally regulated in avian bursa.

Chicken B cell development takes place in a separate organ, the bursa of Fabricius, which provides the blood-borne stem cells, a microenvironment specialized for B cell maturation. Therefore, chicken can be used as a model to study specifically the molecules and interactions which control the development of the B cell compartment. In this work, we studied expression, localization and function of beta 1 integrins on maturing B cells and bursal stroma. The expression of beta 1 integrins on B cells increases during the embryonic development and beta 1 integrin-positive cells can be found both in the medulla and the cortex throughout the bursal development. The binding assays show that the attachment of B cells to stroma is mediated by beta 1 integrins. Binding to 10-day-old embryonic stroma is fibronectin-independent, whereas fibronectin-mediated binding takes place in an increasing manner during further embryonic maturation. After hatching fibronectin appears to be the main binding site for B cells. However, the epitope of beta 1 integrin which takes part in the adhesion of B cells to stroma and to fibronectin is not crucial for the homing of cells into the bursa in a cell transfer model. Our results indicate that the interaction of beta 1 integrins with their ligands is developmentally regulated in the bursa and suggest that B cell maturation may be partially controlled by this interaction.

Amino Acid Sequence↗

PubMed1994

Serum CD44 in malignant lymphoma: an association with treatment response.

CD44, a cell surface glycoprotein, is involved in lymphocyte trafficking from the blood to lymphatic tissues, and is of importance in dissemination of lymphoma. A variant form of CD44 that has additional amino acids in the common protein backbone (CD44v6) also seems to play a role in the metastatic dissemination of malignancies. We measured serum CD44 and CD44v6 in 34 patients with lymphoma and in healthy controls by dot blot assay. Small amounts of both CD44 (range, 10 to 80 ng/mL) and CD44v6 could be detected in sera of all controls. Serum CD44 was elevated in all patients with lymphoma before treatment (range, 70 to > 2,000 ng/mL, P < .0001), and CD44v6 was also slightly elevated. Serum CD44 levels correlated with response to treatment. Patients with complete response achieved similar CD44 levels as the controls, whereas those with progressive disease had increased serum CD44 levels. We conclude that both the standard and the variant form of CD44 are detectable in sera of healthy individuals, and that serum CD44 may be useful in monitoring treatment response in patients with lymphoma.

Adolescent↗

PubMed1994

Aberrant binding of lamina propria lymphocytes to vascular endothelium in inflammatory bowel diseases.

BACKGROUND/AIMS: Lymphocyte recirculation between the blood and lymphoid tissues as well as lymphocyte migration into inflammatory sites are controlled by lymphocyte interaction with vascular endothelium. The aim of this study was to compare the endothelial binding mechanisms of lamina propria lymphocytes (LPL) isolated from normal and inflamed bowel. METHODS: Binding of LPL from normal and inflamed (inflammatory bowel disease) bowel to endothelium was studied using an in vitro binding assay. Expression of adhesion molecules on LPL and on mucosal endothelial cells was analyzed by flow cytometry and immunohistochemistry. RESULTS: In inflammatory bowel disease, the selectivity of lymphocyte-endothelial interaction was lost, i.e., immunoblasts bound well not only to mucosal vessels but also to peripheral lymph node venules. The set of homing receptors expressed on mucosal immunoblasts did not directly predict the endothelial binding properties of these cells; e.g., L-selectin-negative blasts adhered well to lymph node vessels using peripheral lymph node-specific endothelial adhesion antigen (PNAd). PNAd was aberrantly expressed in vessels in the inflamed mucosa, where it also mediated LPL binding. CONCLUSIONS: These findings are important in understanding the physiology of lymphocyte homing into the gut and suggest an important role for PNAd in the pathogenesis of inflammatory bowel disease.

Antigens, Surface↗

PubMed1994

CD44-hyaluronate interaction mediates in vitro lymphocyte binding to the white matter of the central nervous system.

The cell adhesion molecule CD44 is expressed in the central nervous system, especially on glial cells in the white matter, the extracellular matrix of which also contains one of its ligands, hyaluronate. We investigated the role of CD44 and hyaluronate in the adhesion of human peripheral blood lymphocytes to myelinated areas of cerebellum by an in vitro binding assay. Hermes-1 epitope, which recognizes the hyaluronate binding site of CD44, and Hermes-3 epitope, involved in lymphocyte binding to mucosal high endothelial venules, were both immunohistochemically expressed in the white matter. No immunoreactivity was observed with mAb Var3.1, which sees variant forms of CD44 containing the exon v6 encoding region. The molecular weight analysis showed that CD44 of the white matter was identical to the major 90 kD form of CD44 present on lymphocytes. The binding of both T and B lymphocytes was significantly inhibited by pretreatment of both cells and sections with mAb Hermes-1 but not with Hermes-3. Digestion of the sections and/or lymphocytes with hyaluronidase also reduced lymphocyte binding. These findings implicate that CD44-hyaluronate mediates lymphocyte adhesion to the white matter and this interaction may be involved in the pathogenesis of inflammations and lymphomas of the central nervous system.

Antibodies, Monoclonal↗

PubMed1994

YadA mediates specific binding of enteropathogenic Yersinia enterocolitica to human intestinal submucosa.

The binding of live Yersinia enterocolitica to frozen sections of human intestine was investigated qualitatively by monitoring the binding of bacteria by using Gram or immunoperoxidase staining as well as quantitatively by a new enzyme immunoassay-on-slide method. We have demonstrated that the binding of various Y. enterocolitica serotypes and Escherichia coli clones to frozen sections of human intestine is mediated by the Yersinia adhesin, YadA. The YadA-mediated binding occurs mainly at the submucosal layer of the intestinal wall and only to a limited extent at the mucosal layer; there binding is mostly to the mucin threads. In addition, partially purified YadA binds to frozen sections with a pattern similar to that of intact bacteria. Collagen, laminin, or partially purified YadA only partially inhibited the YadA-mediated binding of bacteria, presumably because YadA is multifunctional. A combination of collagen and laminin inhibited the binding more efficiently. Therefore, YadA may be involved in the interactions with the extracellular matrix molecules after the invasion of the intestinal tissue.

Adhesins, Bacterial↗

PubMed1994

Effect of treatment on the prognostic value of S-phase fraction in non-Hodgkin's lymphoma.

PURPOSE: To investigate the prognostic value of cell proliferation rate in non-Hodgkin's lymphoma, study its association with histologic classification, and investigate whether its predictive value is influenced by the type of treatment given. PATIENTS AND METHODS: The S-phase fraction (SPF) size was determined by DNA flow cytometry from paraffin-embedded tissue obtained at diagnosis from 490 patients with non-Hodgkin's lymphoma, diagnosed in a defined geographic area from 1970 to 1991. Clinical data were collected from hospital records and the files of the Finnish Cancer Registry. RESULTS: SPF size correlated well with histologic grading performed either according to the Working Formulation or Kiel classification (P < .0001 for both). The mean SPFs of low-, intermediate-, and high-grade malignant lymphomas were 4.9% (95% confidence interval [CI], 4.2% to 5.5%), 10.3% (95% CI, 9.3% to 11.4%), and 15.5% (95% CI, 14.0% to 16.9%), respectively. Lymphomas with an SPF lower than the median (7.9%) had a 58% 5-year and 44% 15-year survival rate, whereas those with an SPF larger than the median had a 44% 5-year and 40% 15-year survival rate (P < .0001). SPF size was not significantly associated with prognosis in some subgroups, such as among patients treated primarily with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n = 114) or cyclophosphamide, vincristine, and prednisone (COP) (n = 124) with or without radiotherapy (P > .05), whereas a stronger association was found among patients with stage I or II lymphoma treated with radiotherapy only (n = 100; P = .003) and among patients with stage III or IV lymphoma who did not receive chemotherapy (n = 44; P < .0001). In multivariate analyses that included the factors used to construct the International Prognostic Index, SPF had independent prognostic value both in low-grade and intermediate- or high-grade lymphomas, but not in the subset of patients treated with combination chemotherapy with or without radiotherapy. CONCLUSION: Cell proliferation rate measured as SPF is closely associated with histologic grading in non-Hodgkin's lymphoma, and it has independent prognostic value. The treatment given influences considerably the prognostic value of SPF.

Adolescent↗

PubMed1993

Induction and function of vascular adhesion protein-1 at sites of inflammation.

Emigration of leukocytes from the blood into the tissues is critical in controlling lymphocyte patrolling in different lymphatic organs and in leukocyte accumulation at sites of inflammation. During the first stage of the extravasation process, leukocytes bind to the endothelial lining of vessels. At the molecular level, several adhesion molecules on leukocytes and endothelial cells function as receptor-ligand pairs in mediating this dynamic interaction. Recently, we have identified a novel human endothelial cell molecule, vascular adhesion protein 1 (VAP-1), that mediates lymphocyte binding (Salmi, M., and S. Jalkanen. 1992. Science [Wash. DC] 257:1407). VAP-1 was initially characterized by mAb 1B2 which inhibits lymphocyte adhesion to high endothelial venules (HEV) and to purified VAP-1 protein. Here we report the location and function of VAP-1 in normal and inflamed tissues in humans. VAP-1 is abundant in HEV of lymphatic organs belonging to the peripheral lymph node system, but considerably less is expressed in vessels of mucosa-associated lymphatic tissues. A subset of venules in most normal nonlymphatic tissues like skin, brain, kidney, liver, and heart is also VAP-1 positive. In addition to vessels, VAP-1 is distributed on a few other cell types, most notably in dendritic-like cells of germinal centers. At sites of inflammation, such as in inflammatory bowel diseases and chronic dermatoses, expression of VAP-1 is clearly increased. The induced VAP-1 is functional, since mAb 1B2 inhibits lymphocyte binding to inflamed lamina propria venules by approximately 60%. Thus VAP-1 is an endothelial adhesion molecule that under normal conditions is expressed mainly in HEV of lymphatic tissues. However, expression of functional VAP-1 in vivo is upregulated during an inflammatory reaction at other sites as well. Inducibility of VAP-1 suggests that it may play a significant role, not only in recirculation of lymphocytes, but also in controlling entry of leukocytes into sites of inflammation.

Amine Oxidase (Copper-Containing)↗

PubMed1993

Lymphocyte-vascular adhesion protein-2 is a novel 70-kDa molecule involved in lymphocyte adhesion to vascular endothelium.

Extravasation of leukocytes from the blood is essential for normal lymphocyte recirculation as well as in mounting an adequate inflammatory response in different tissues. Leukocyte migration from the blood is controlled by sophisticated interactions between surface receptors on leukocytes and their corresponding endothelial cell ligands. Here we describe a novel adhesion molecule, lymphocyte-vascular adhesion protein-2 (L-VAP-2), recognized by 4G4 mAb that was produced by immunizing mice with an enriched endothelial cell preparation isolated from inflamed human synovium. mAb 4G4 stains a subpopulation of venules in lymphoid and nonlymphoid tissues as well as a few high endothelial venules in lymphoid tissues. L-VAP-2 is constitutively expressed on human umbilical vein endothelial cells, and its expression cannot be up-regulated by cytokines and mitogens such as TNF-alpha, IL-1, and LPS. The Ag is expressed on approximately 20% of PBL, whereas granulocytes and monocytes are negative. On lymphocytes, L-VAP-2 is preferentially expressed on B cells and CD8+ T cells. The molecular mass of L-VAP-2 is approximately 70 kDa as determined from immunoprecipitated, 125I-labeled endothelial cell lysates. The involvement of L-VAP-2 in lymphocyte binding to endothelium was tested in vitro using human umbilical vein endothelial cells. Both the intact antibody and F(ab')2 fragments of it consistently inhibited lymphocyte binding to human umbilical vein endothelial cells by approximately 25%. On the basis of the molecular mass estimation and the staining of tissue sections, leukocyte populations, and ICAM-1 and ICAM-2 transfectants, L-VAP-2 appears to be a novel Ag involved in the lymphocyte-endothelial cell interaction.

Animals↗