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S Jalkanen

Publications and source records attributed to S Jalkanen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mouse vascular adhesion protein 1 is a sialoglycoprotein with enzymatic activity and is induced in diabetic insulitis.

The continuous recirculation of lymphocytes requires an adequate expression and function of the molecules mediating the cellular interactions between endothelium and lymphocytes. Human vascular adhesion protein 1 (hVAP-1) is an endothelial cell adhesion molecule that mediates the binding of lymphocytes to venules in peripheral lymph nodes as well as at sites of inflammation. Recently the mouse homologue of hVAP-1 has been cloned. It is a previously unknown molecule with a significant sequence identity to copper-containing amine oxidases. Besides the sequence, very little is known about the expression, structure, and function of mouse VAP-1 (mVAP-1). In this study we demonstrate that mVAP-1 is prominently expressed in endothelial and smooth muscle (but not in other types of muscle cells), as well as in adipocytes. mVAP-1 is a 220-kd homodimeric sialoglycoprotein that displays cell-type-specific differences in glycosylation. The expression of mVAP-1 is induced on inflammation in the vessels of the endocrine pancreas during the development of insulitis, and the up-regulation correlates with the extent of the lymphocytic infiltrate. In general, different mouse strains displayed very similar VAP-1 expression, but the small differences seen in liver and gut suggest that immunostimulation may modulate VAP-1 synthesis in extrapancreatic organs as well. Finally, we show that mVAP-1 has a monoamine oxidase activity against naturally occurring substrates, implying a role in the development of vasculopathies. These data show that mVAP-1 and hVAP-1 are very similar molecules that nevertheless have certain marked differences in expression, biochemical structure, and substrate specificity. Thus mVAP-1 is a novel inflammation-inducible mouse molecule that has a dual adhesive and enzymatic function.

Amine Oxidase (Copper-Containing)↗
PubMed1999

Human vascular adhesion protein-1 in smooth muscle cells.

Human vascular adhesion protein-1 (VAP-1) is a dual-function molecule with adhesive and enzymatic properties. In addition to synthesis in endothelial cells, where it mediates lymphocyte binding, VAP-1 is expressed in smooth muscle cells. Here we studied the expression, biochemical structure, and function of VAP-1 in muscle cells and compared it to those in endothelial cells. VAP-1 is expressed on the plasma membrane of all types of smooth muscle cells, but it is completely absent from cardiac and skeletal muscle cells. In tumors, VAP-1 is retained on all leiomyoma cells, whereas it is lost in half of leiomyosarcoma samples. In smooth muscle VAP-1 predominantly exists as a approximately 165-kd homodimeric glycoprotein, but a trimeric (approximately 250 kd) form of VAP-1 is also found. It contains N-linked oligosaccharide side chains and abundant sialic acid decorations. In comparison, in endothelial cells dimeric VAP-1 is larger, no trimeric forms are found, and VAP-1 does not have N-glycanase-sensitive oligosaccharides. Unlike endothelial VAP-1, VAP-1 localized on smooth muscle cells does not support binding of lymphocytes. Instead, it deaminates exogenous and endogenous primary amines. In conclusion, VAP-1 in smooth muscle cells is structurally and functionally distinct from VAP-1 present on endothelial cells.

Amine Oxidase (Copper-Containing)↗
PubMed1999

Monocytes that have ingested Yersinia enterocolitica serotype O:3 acquire enhanced capacity to bind to nonstimulated vascular endothelial cells via P-selectin.

Reactive arthritis is usually a self-limiting polyarthritis which develops after certain gastrointestinal or urogenital infections. Microbial antigens found in the inflamed joints are thought to play a key role in the development of this disease. It is not known how antigens of the pathogenic organisms migrate from the mucosal tissues into the joints. The data presented here show that mononuclear phagocytes which mediate the dissemination of several intracellular pathogens acquire an enhanced capacity to bind to nonstimulated vascular endothelial cells after phagocytosis of Yersinia enterocolitica O:3, one of the causative organisms of reactive arthritis. The increased binding to previously nonstimulated endothelial cells was mediated by P-selectin, whose translocation to the endothelial cell surface was induced by monocytes with intracellular Yersinia bacteria. These results suggest that mononuclear phagocytes may be responsible for the dissemination of bacterial antigens and the initiation of the joint inflammation in reactive arthritis.

CD18 Antigens↗
PubMed1999

Serum CD44 in non-Hodgkin's lymphoma.

CD44 molecule is a cell surface glycoprotein involved in several cell-cell and cell-matrix interactions. It has been linked to the growth and spread of malignancies. The majority of non-Hodgkin's lymphomas (NHL) express CD44 reflecting the CD44 expression of the normal lymphocytic counterparts. Cell surface CD44 has been suggested to be involved in hematogenous distribution of NHL, and elevated levels of serum CD44 (s-CD44) have been detected in various malignant diseases. Circulating s-CD44 has been found to be functionally active according to several functional studies. In patients with NHL increased s-CD44 levels have been detected at the time of diagnosis and at progression of the disease and s-CD44 levels change in parallel with response to therapy. Moreover, a high s-CD44 level at diagnosis is associated with a high tumor burden, poor response to treatment and unfavorable outcome in NHL.

Biomarkers, Tumor↗
PubMed1998

Isolation, structural characterization, and chromosomal mapping of the mouse vascular adhesion protein-1 gene and promoter.

Vascular adhesion protein-1 (VAP-1) is an endothelial cell adhesion molecule which mediates lymphocyte binding to endothelial cells. The cloning of a mouse VAP-1 (mVAP-1) cDNA revealed that mVAP-1 is a novel 110/220 kDa transmembrane molecule with significant identity to copper-containing amine oxidases. In this work the nucleotide sequence and primary structure of the mVAP-1 gene was determined and the promoter region was structurally characterized. The isolated approximately 14.4-kb mVAP-1 gene consists of 4 exons and 3 introns. Primer extension analysis and 5' rapid amplification of cDNA ends revealed multiple transcription initiation sites in different tissues suggesting that the mVAP-1 transcription is differently regulated in different tissues. Analysis of the sequence immediately upstream of the detected transcription initiation sites showed no canonical TATA or CCAAT elements, but putative regulatory elements were found close to the detected transcription start sites. The cloning of the mVAP-1 gene reveals the first insight into the genomic organization of murine amine oxidases and will, by targeted disruption of the gene, allow us to understand better the importance of VAP-1 in leukocyte trafficking and monoamine oxidase activity for the function of the immune system.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases.

Vascular adhesion protein-1 (VAP-1) is a dimeric 170-kDa endothelial transmembrane molecule that under normal conditions is most strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. It is a glycoprotein that mediates tissue-selective lymphocyte adhesion in a sialic acid-dependent manner. In this study, we report the detection of a soluble form of VAP-1 in circulation. We developed a quantitative sandwich ELISA using novel anti-VAP-1 mAbs and used it to determine the levels of soluble VAP-1 (sVAP-1) in the serum of healthy individuals and in patients with inflammatory diseases. In healthy persons, circulating sVAP-1 concentrations were 49 to 138 ng/ml. Immunoblotting studies revealed that the apparent molecular mass of dimeric sVAP-1 is slightly (approximately 10 kDa) higher than that of transmembrane VAP-1 under nonreducing conditions. In contrast, the electrophoretic mobilities of monomeric sVAP-1 and transmembrane VAP-1 were similar after reduction and boiling. Adhesion assays showed that the circulating sVAP-1 modulates lymphocyte binding to endothelial cells. Inflammation can cause an elevation of serum sVAP-1 levels, because sVAP-1 concentrations in patients with certain liver diseases were two- to fourfold higher than those in normal individuals. In contrast, rheumatoid arthritis and inflammatory bowel diseases were not associated with elevated levels of sVAP-1. These findings indicate that there is a functionally active, soluble form of VAP-1 in circulation and suggest that the serum level of sVAP-1 might be a useful marker of disease activity in inflammatory liver diseases.

Adult↗
PubMed1998

Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule.

Vascular adhesion protein 1 (VAP-1) is a human endothelial sialoglycoprotein whose cell surface expression is induced under inflammatory conditions. It has been shown previously to participate in lymphocyte recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion. We report here that the VAP-1 cDNA encodes a type II transmembrane protein of 84.6 kD with a single transmembrane domain located at the NH2-terminal end of the molecule and six potential N-glycosylation sites in the extracellular domain. In vivo, the protein exists predominantly as a homodimer of 170-180 kD. Ax endothelial cells transfected with a VAP-1 cDNA express VAP-1 on their cell surface and bind lymphocytes, and the binding can be partially inhibited with anti-VAP-1 mAbs. VAP-1 has no similarity to any currently known adhesion molecules, but has significant identity to the copper-containing amine oxidase family and has a monoamine oxidase activity. We propose that VAP-1 is a novel type of adhesion molecule with dual function. With the appropriate glycosylation and in the correct inflammatory setting, its expression on the lumenal endothelial cell surface allows it to mediate lymphocyte adhesion and to function as an adhesion receptor involved in lymphocyte recirculation. Its primary function in other locations where it is expressed, such as smooth muscle, may depend on its inherent monoamine oxidase activity.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Clinical significance of circulating CD44 in non-Hodgkin's lymphoma.

Soluble isoforms of various adhesion molecules have recently been observed in the blood circulation, but the physiological effects of such molecules remain unsettled. Our earlier results indicate that soluble CD44 can be detected in sera of healthy individuals and that significantly higher levels of serum CD44 (s-CD44) can be found in lymphoma patients. The serum level of the standard form of CD44 parallels the clinical treatment response in patients with lymphoma. In the present study, we have investigated the clinical significance of s-CD44 in non-Hodgkin's lymphoma measured at the time of the diagnosis. S-CD44 was measured from the sera of 123 patients with non-Hodgkin's lymphoma by dot blotting high levels of s-CD44 were associated with high serum levels of lactate dehydrogenase and thymidine kinase, high histological grade of malignancy and poor overall survival. However, s-CD44 level did not have independent prognostic value in a multivariate analysis. In conclusion, a high s-CD44 level at the time of diagnosis was associated with poor survival and several other adverse prognostic factors. Our previous and present studies taken together suggest that measurement of s-CD44 is a valuable tool to monitor treatment response in lymphoma patients. However, it may not be an improved prognostic marker.

Adult↗
PubMed1998

Mucosal addressin is required for the development of diabetes in nonobese diabetic mice.

Immune responses are best initiated in the environment of lymphoid tissues wherein circulating lymphocytes enter by interacting with endothelial adhesion molecules. In type 1 diabetes, immune responses against pancreatic islets develop, but the environment in which this occurs remains unidentified. To determine whether lymphocyte homing to lymphoid organs is involved in the pathogenesis of diabetes in nonobese diabetic (NOD) mice, we blocked the function of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is a vascular addressin-mediating lymphocyte homing into mucosal lymphoid tissues, in these mice. While ineffective if started later, a blockade started at 3 wk of age reduced the incidence of diabetes from 50% to 9% (p < 0.01). This finding is associated with Peyer's patch atrophy, a marked decrease of naive (CD44(low) CD45RB(high)) T lymphocytes, and a reduction in the relative numbers of memory (CD44(high)) T lymphocytes in the spleen. The potential of these spleen cells to cause diabetes was diminished. Anti-MAdCAM-1 treatment also inhibited both lymphocyte entry into the pancreas and diabetes development in NOD/SCID recipients after the transfer of lymphocytes derived from the mesenteric lymph nodes of young, but not of diabetic, NOD donors. Therefore, MAdCAM-1 may be required during two distinct steps in an early phase of diabetes development: for the entry of naive lymphocytes into the lymphoid tissues in which diabetes-causing lymphocytes are originally primed, and for the subsequent homing of these lymphocytes into the pancreas. The role of MAdCAM-1 as a mucosal vascular addressin suggests that mucosal lymphoid tissues are involved in the initiation of pathologic immune responses in NOD mice.

Adoptive Transfer↗
PubMed1998

Cloning and characterization of mouse vascular adhesion protein-1 reveals a novel molecule with enzymatic activity.

Human vascular adhesion protein-1 (VAP-1) is a sialylated endothelial cell adhesion molecule mediating the initial L-selectin-independent interactions between lymphocytes and endothelial cells in man. In this work we cloned and characterized mouse VAP-1 (mVAP-1) and produced an anti-mVAP-1 mAb against a recombinant mVAP-1 fusion protein. The isolated cDNA encodes a novel 84.5-kDa mouse molecule. The anti-mVAP-1 mAb stained high endothelial venules in peripheral lymph nodes, and smooth muscle cells and lamina propria vessels in gut. During immunoblotting, this anti-mVAP-1 mAb recognized a 110/220-kDa Ag, suggesting that mVAP-1 is a dimer. Since mVAP-1 has significant sequence identity to members of a family of enzymes called the copper-containing amine oxidases, we showed that mVAP-1 possesses monoamine oxidase activity. Thus, mVAP-1 is the first mouse membrane-bound amine oxidase identified at the molecular level. Based on the 83% identity between the isolated cDNA and human VAP-1 cDNA, the expression pattern, the molecular mass, and the enzyme activity against monoamines, the cloned molecule represents a mouse homologue of human VAP-1. Cloning of mVAP-1 provides a valuable tool for in vivo studies of the significance of VAP-1 for lymphocyte-endothelial cell interactions and of the possible relationship between leukocyte adhesion and amine oxidase activity.

Amine Oxidase (Copper-Containing)↗
PubMed1998

The role of two distinct endothelial molecules, vascular adhesion protein-1 and peripheral lymph node addressin, in the binding of lymphocyte subsets to human lymph nodes.

Lymphocyte binding to high endothelial venules (HEV) in noninflamed peripheral lymph nodes (PLN) relies heavily on two endothelial adhesion molecules called vascular adhesion protein-1 (VAP-1) defined by mAb 1B2 and the peripheral lymph node addressins (PNAd) defined by mAb MECA-79. Data from several different groups indicate that these two molecules share several characteristics in expression, biochemical structure, and function, raising the possibility that VAP-1 may be identical to the 170- and 90-kDa species of PNAd glycoproteins. In this study, we show that many PLN HEV coexpress these two molecules. In parallel SDS-PAGE analyses, the m.w. of the 90- and 170-kDa forms of these molecules are indistinguishable. Nevertheless, we show by different metabolic labelings, by reciprocal cross-precipitations, and by immunofluorescence stainings of newly established VAP-1 transfectants that the 90- and 170-kDa species of PNAd and VAP-1 are distinct molecules. In functional terms, VAP-1 is strikingly selective in mediating PLN HEV adhesion of CD8-positive, but not of CD4-positive T cells. In contrast, PNAd contributes to the adhesion of both CD4-positive and CD8-positive cells to these vessels. Together, these data show that initial adhesion of CD8-positive lymphocytes to PLN HEV requires a PNAd- and a VAP-1-dependent step that are both essential and may occur simultaneously or sequentially.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Labelling lymphocytes with technetium99m-hexamethyl propyleneamine oxime for scintigraphy: an improved labelling procedure.

Leukocyte scintigraphy has been used as a standard diagnostic procedure for the detection of inflammation in vivo. In this study, we developed a method of labelling purified lymphocytes with technetium99m-hexamethyl propyleneamine oxime (Tc99m-HMPAO) without significantly impairing their function. This was confirmed by measurements of in vitro lymphocyte adhesion and migration and of both necrotic and apoptotic cell death. The results of the in vitro control studies indicate that the dysfunction of leukocytes caused by Tc99m-HMPAO labelling can be minimized by using a gentle labelling method and low Tc99m activity. Because lymphocytes have been thought to participate specifically in the pathogenesis of inflammatory bowel disease (IBD), we compared scintigraphies obtained with Tc99m-HMPAO-labelled purified lymphocytes and mixed leukocytes in colitis patients. We found that a lower number of Tc99m-HMPAO-labelled peripheral blood lymphocytes accumulated in the inflamed colon during the first 4 h than labelled mixed leukocytes. The results are likely to reflect the dissimilar kinetics of lymphocyte traffic compared with granulocytes in IBD. We do not recommend the use of Tc99m-HMPAO-labelled purified lymphocytes as a diagnostic tool in chronic colitis. However, the in vitro data indicate that Tc99m-HMPAO-labelled lymphocytes may be suitable for studying short term lymphocyte recirculation and lymphocyte kinetics in other types of inflammation.

Adolescent↗
PubMed1998

Increased synovial endothelium binding and transendothelial migration of mononuclear cells during Salmonella infection.

OBJECTIVE: To investigate the adhesion and extravasation capacity of peripheral blood mononuclear cells (PBMC) and the transport of bacterial antigens within these cells during Salmonella infection. METHODS: Thirteen patients who were part of 2 outbreaks of Salmonella enteritidis infection were included in this study. The capacity of PBMC from these patients to bind to vascular endothelium in inflamed synovium was tested using a Stamper-Woodruff-type frozen-section assay. The same cells were studied for the presence of Salmonella antigens by immunofluorescence staining. The transendothelial migration of mononuclear cells containing Salmonella or its components through unstimulated endothelial cell layer was quantified. RESULTS: The capacity of PBMC to adhere to synovial vessels was significantly increased during Salmonella infection (P=0.0003). Monocytes had a transiently high adhesive state between 2 and 5 weeks after the patients had eaten the contaminated food. The cells containing Salmonella antigens were concentrated in the transmigrated population. CONCLUSION: During acute Salmonella infection the increased binding of PBMC to vascular endothelium in inflamed synovium and enhanced transmigration of PBMC containing Salmonella may be the key factors leading to transport of bacterial antigens through the endothelial barrier and initiation of arthritis in susceptible individuals.

Adult↗
PubMed1998

Endothelial ligands and homing of mucosal leukocytes in extraintestinal manifestations of IBD.

Crohn's disease and ulcerative colitis are quite often complicated with manifestations in extraintestinal organs like joints, eye, and skin. Although the etiopathogenesis of these nonmucosal complications remains unsettled, they all share the characteristic feature of inappropriate leukocyte recruitment in nonlymphatic organs. Under normal conditions, lymphocytes recirculate between the blood and lymphoid organs in search of their cognate antigens, whereas polymorphonuclear leukocytes are excluded from tissues. On inflammation, the leukocyte trafficking changes dramatically. Granulocytes infiltrate into the inflammatory focus very rapidly, and they are followed by lymphocytes, especially activated immunoblasts and memory cells, which now also leave the vasculature at nonlymphoid tissues. Leukocyte extravasation from the blood into the tissue is a multistep process governed by sequential interactions between adhesion molecules expressed on the surface of leukocytes and their ligands on the luminal side of the endothelial cells lining the vessels. In this review, we describe the recirculation routes of mucosal lymphocytes in physiologic conditions, as well as the changes seen in mucosal and extramucosal homing in inflammatory bowel disease (IBD). We present a working model of how adhesive molecular interactions between mucosal immune cells and endothelial cells may explain the pathogenesis of the development of inflammatory cell infiltrate in distant organs in IBD, and how this information may help to plan new antiadhesive therapeutic strategies.

Animals↗
PubMed1998

Structural model of the catalytic domain of an enzyme with cell adhesion activity: human vascular adhesion protein-1 (HVAP-1) D4 domain is an amine oxidase.

Human vascular adhesion protein-1 (HVAP-1) is a multifunctional protein having at least two different cellular roles, functioning both as a lymphocyte-endothelial cell adhesion protein and as an enzyme with monoamine oxidase activity. HVAP-1 is a 180 kDa homodimeric glycoprotein consisting of a membrane-spanning domain and three predicted extracellular copper-containing amine oxidase domains. In HVAP-1 the extracellular domains are composed of a large domain D4, containing the active site and forming the interface of the dimer, while the smaller D2 and D3 domains surround the D4 dimer near the entrance to the active site. The structural model of the catalytic D4 domain of HVAP-1 reveals that all components necessary for enzymatic monoamine oxidase activity are indeed present within the HVAP-1 and pinpoints residues that may be key to substrate entry through a channel to the active site and residues likely to be involved in substrate specificity as well as structural features critical to dimer formation. Proper glycosylation is required for the cell adhesion function of HVAP-1 and the predicted location of the sugar units at the solvent-exposed surface suits this function well.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Cell adhesion and migration. IV. Lymphocyte trafficking in the intestine and liver.

Naive lymphocytes patrol continuously between the blood and different lymphatic tissues to sample the whole body for foreign antigens. During inflammation, leukocyte recruitment into tissue is enhanced to promote the recruitment of a range of effector cells into the affected area. The complex recirculatory pathways that underlie this process are governed by adhesion receptors on blood-borne leukocytes and by their specific ligands expressed on the luminal aspect of endothelial cells lining the vessels. Gut-associated lymphatic tissues are positioned strategically at the major port of entry for foreign antigens. They form a functionally unified entity that utilizes both the afferent and efferent arms of the immune response to respond to the large array of antigens entering via the gut under normal conditions as well as during inflammation. Once antigens have been absorbed from the gut, they may enter the portal vein and the liver where the immune response can be further regulated by the resident immune cells of the liver. Thus the gut and liver form an important barrier to enteral antigens, and leukocyte recruitment to these sites will need to be carefully regulated to ensure effective immune surveillance. In this article, we describe the current concepts of lymphocyte adhesion in these two organs as revealed by animal models. Subsequently, we discuss how well these principles apply to the lymphocyte-endothelial cell interactions in humans and what additional insights can be obtained from human studies.

Cell Adhesion↗
PubMed1997

Elevated serum CD44 level is associated with unfavorable outcome in non-Hodgkin's lymphoma.

CD44 molecule is a cell surface glycoprotein involved in many cell-cell and cell-matrix interactions. Circulating serum CD44 (s-CD44) levels have been found to change in parallel with response to therapy, but little is known about the predictive or prognostic significance of s-CD44. In the present study, we measured s-CD44 levels in sera taken before treatment from 194 patients with non-Hodgkin's lymphoma using a chemiluminescence-enzyme immunoassay method. All except 1 patient were regularly followed-up after therapy at least for 60 months (range, 33 to 143 months). The median pretreatment s-CD44 level was 440 ng/mL (range, 13 to 1,220 ng/mL). Only 32% of the 92 patients with an International Prognostic Index (IPI) score of 0 or 1 had an s-CD44 concentration higher than the median as compared with 67% of the patients with an IPI score >/=2 (P < .0001). Patients with lower than the median s-CD44 achieved more often a complete remission to therapy (P = .0002) and had better survival (P = .007) than those with higher s-CD44 levels. However, in a multivariate analysis, only the IPI score had independent prognostic value (P < .001). The findings were similar if only the patients with diffuse large-cell lymphoma (n = 51) were included in the analysis, but among patients with low-grade lymphoma, the median s-CD44 level was not significantly associated with the IPI or survival. In conclusion, a high s-CD44 level at diagnosis is associated with a high IPI score, poor response to treatment, and unfavorable outcome in non-Hodgkin's lymphoma.

Adolescent↗