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S Jalkanen

Publications and source records attributed to S Jalkanen.

At least 55 records · Page 3Linked to original sources
PubMed1997

Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype-specific, selectin-independent recognition of vascular endothelium in human lymph nodes.

Interactions between lymphocyte surface receptors and their ligands on vascular endothelial cells regulate the exit of lymphocytes from the circulation. Distinct subsets of mononuclear cells bind to high endothelial venules (HEVs) in different lymphoid organs to a different extent, but the molecular mechanisms behind this selectivity have remained poorly characterized. Here we show that vascular adhesion protein-1 (VAP-1) mediates subtype-specific binding of CD8-positive T cells and natural killer cells to human endothelium. VAP-1-dependent, oligosaccharide-dependent peripheral lymph node (PLN) HEV adhesion under shear was independent of L-selectin, P-selectin glycoprotein ligand 1, and alpha4 integrins, the known lymphocyte receptors involved in the initial recognition of endothelial cells. PLN HEV adhesion was also critically dependent on peripheral lymph node vascular addressins (PNAds), but lymphocyte L-selectin was absolutely required for PNAd binding. Most lymphocytes relied on both PNAd and VAP-1 in HEV binding. The overlapping function of L-selectin ligands and VAP-1 in PLN introduces a new control point into the lymphocyte extravasation process. Finally, intravital microscopy revealed that VAP-1 is involved in initial interactions between human lymphocytes and endothelial cells in inflamed rabbit mesenterial venules in vivo. In conclusion, VAP-1 is a novel contact-initiating ligand that discriminates between different subpopulations of mononuclear cells and is an appealing target for selective modulation of adhesion of CD8- and CD16-positive effector cells.

Adult↗
PubMed1997

Ly-6C regulates endothelial adhesion and homing of CD8(+) T cells by activating integrin-dependent adhesion pathways.

Ly-6C belongs to the Ly-6 family of glycosyl phosphatidylinositol-anchored surface glycoproteins and is expressed on a subset of mature CD8(+) T cells. Ly-6C ligation can mediate T cell activation and causes interleukin 2 secretion in cytolytic T cell clones. We characterize herein a new mAb 1G7.G10 against Ly-6C that recognizes an epitope involved in lymphocyte adhesion and in lymphocyte homing. Pretreatment of lymph node lymphocytes and of purified CD8(+) T cells (but not of lymphocytes depleted of CD8(+) T cells) with 1G7.G10 reduced their in vitro binding to lymph node high endothelial venules by 28% and 34%, respectively. This effect was bypassed by cross-linking Ly-6C molecules with 1G7.G10 and a second-step antibody. The in vivo homing of (donor) CD8(+) T lymphocytes to lymph nodes was reduced by Ly-6C blocking with 1G7. G10 (whole antibody) or with its fragments [F(ab) or F(ab)2] by 20% or by 32% and 48%, respectively. Cross-linking of Ly-6C in vitro induced very late antigen-4 and lymphocyte function-associated antigen 1-mediated aggregation of CD8(+) T cells, suggesting that ligand binding to Ly-6C leads to activation of integrins. This activation may facilitate homing of Ly-6C+ CD8(+) T cells in vivo.

Animals↗
PubMed1997

Regulation of CD44v6-containing isoforms during proliferation of normal and malignant epithelial cells.

CD44 is a family of molecules involved in cell-cell and cell-matrix interactions. Various isoforms of CD44 arise by insertion of one or more of the variant exons into the common backbone shared by all forms of CD44. In this work, we studied the expression of CD44 and exon v6-containing CD44 isoforms (CD44v6) in several nonmalignant and malignant conditions and the possibilities for regulating the expression of CD44v6. In primary squamocellular carcinomas of the head and neck, CD44 and CD44v6 were down-regulated in poorly differentiated tumors, whereas these molecules were uniformly expressed in the normal squamocellular epithelium, in proliferating skin diseases, and in nonmalignant tumors. When CD44v6 expression of original tumors and that of squamocellular carcinoma cell lines derived from them were compared, no CD44v6 up-regulation could be observed on in vitro growing cells. Moreover, several regulators were unable to up-regulate CD44v6 expression on cultured cell lines in vitro. When the same cell lines formed tumors after s.c. injection into severe combined immunodeficient mice, some of them up-regulated their CD44v6 expression. These data suggest that cell lines at certain differentiation stages can be induced to express CD44v6. Our results further indicate that CD44v6 positivity cannot be used as a universal indicator of tumor metastasis. Instead, the down-regulation of CD44v6 in squamocellular tumors is a sign of malignant transformation of the epithelium.

Adult↗
PubMed1997

Homing of mucosal leukocytes to joints. Distinct endothelial ligands in synovium mediate leukocyte-subtype specific adhesion.

Inflammation and infection of the gut can be followed by reactive arthritis at a distant joint. Leukocyte recruitment into synovium is essential for this process, but nothing is known about the endothelial adhesion molecules in synovial membrane which direct the homing of activated, gut-derived leukocytes to joints. Here we analyzed the expression of the known endothelial adhesion molecules in inflamed synovium and their function in binding of mucosal leukocytes. Intercellular adhesion molecule-1 (ICAM-1/CD54) and vascular adhesion protein-1 (VAP-1) were most prominently expressed in synovial vessels. All other adhesion molecules were found at lower levels in inflamed synovia, except mucosal addressin which was absent. Binding of macrophages isolated from lamina propria of the gut to synovial endothelium was almost entirely P-selectin-dependent. In contrast, small intestinal lymphocytes and immunoblasts both relied mainly on VAP-1 in recognition of synovial vessels. Thus, endothelial P-selectin and VAP-1 mediate binding of mucosal effector cells to synovium in a leukocyte subtype-selective manner. Antiadhesive therapy against these inducible molecules should ablate the pathogenetic cascade leading to inappropriate homing of leukocytes to joints in arthritis.

Amine Oxidase (Copper-Containing)↗
PubMed1997

Origin and function of circulating CD44 in non-Hodgkin's lymphoma.

Soluble isoforms of various adhesion molecules have recently been found in the circulation, but the physiologic effects of such molecules are still unconfirmed. Our earlier study suggests that the serum level of the 70- to 80-kDa form of CD44 (sCD44) parallels the clinical treatment response in patients with lymphoma. In the present study we investigated the origin and the function of sCD44 in non-Hodgkin's lymphoma. Both peripheral blood and tumor lymphocytes were able to shed soluble CD44 in cell culture. In a SCID mouse model, transplanted Burkitt lymphoma (Namalwa) cells transfected with human CD44 shed soluble CD44. In binding studies sCD44 was able to adhere to hyaluronate and fibronectin, and moreover, sCD44 was able to block the binding of hyaluronate to CD44 on the cell surface and to block the binding of lymphocytes to high endothelial venules, suggesting that sCD44 retains its biological activity although it does not contain the cytoplasmic tail. In conclusion, sCD44 is biologically active and is at least partially shed by lymphoma cells in non-Hodgkin's lymphoma patients.

Animals↗
PubMed1997

Function of lymphocyte homing-associated adhesion molecules on human natural killer and lymphokine-activated killer cells.

We have analyzed the ability of fresh and rIL-2-activated human NK cells to interact with high endothelial venules (HEV) that are known to support physiologic lymphocyte extravasation, and examined the role of different adhesion molecules in this process. In in vitro HEV-binding assays, NK cells bound to both peripheral lymph node (pLN) and mucosal HEV. Activation by rIL-2 slightly decreased adherence to pLN HEV, but increased adherence to mucosal high endothelium. Markedly fewer NK cells than PBL expressed L-selectin, and the expression was diminished further upon treatment with rIL-2. Inhibition studies showed, however, that L-selectin was the most important single molecule to mediate adhesion to pLN HEV. Binding to mucosal HEV was mediated mainly by CD44 and alpha 4 integrin, and the expression level of these molecules was increased by rIL-2, paralleling the results in HEV-binding assays. Higher m.w. forms of CD44, representing differentially glycosylated/variant forms of CD44, were more abundant on large granular lymphocytes than on unseparated PBL. We conclude that, despite weak recirculatory capacity, NK cells or a subpopulation of NK cells with the correct adhesion molecules can interact with and bind to high endothelial cells. Lymphokines can modulate the expression of adhesion molecules that NK cells utilize for HEV binding. Our results suggest that activation of NK cells with IL-2 may facilitate the extravasation of lymphokine-activated killer cells, especially to mucosal sites, whereas homing to peripheral lymphoid tissues may be diminished. This should be taken into consideration when procedures for lymphokine-activated killer cell immunotherapy are planned.

Endothelium, Lymphatic↗
PubMed1997

Differential regulation and function of CD73, a glycosyl-phosphatidylinositol-linked 70-kD adhesion molecule, on lymphocytes and endothelial cells.

CD73, otherwise known as ecto-5'-nucleotidase, is a glycosyl-phosphatidylinositol-linked 70-kD molecule expressed on different cell types, including vascular endothelial cells (EC) and certain subtypes of lymphocytes. There is strong evidence for lymphocyte CD73 having a role in several immunological phenomena such as lymphocyte activation, proliferation, and adhesion to endothelium, but the physiological role of CD73 in other cell types is less clear. To compare the biological characteristics of CD73 in different cell types, we have studied the structure, function, and surface modulation of CD73 on lymphocytes and EC. CD73 molecules on lymphocytes are shed from the cell surface as a consequence of triggering with an anti-CD73 mAb, mimicking ligand binding. In contrast, triggering of endothelial CD73 does not have any effect on its expression. Lymphocyte CD73 is susceptible to phosphatidylinositol phospholipase, whereas only a small portion of CD73 on EC could be removed by this enzyme. Furthermore, CD73 on EC was unable to deliver a tyrosine phosphorylation inducing signal upon mAb triggering, whereas triggering of lymphocyte CD73 can induce tyrosine phosphorylation. Despite the functional differences, CD73 molecules on lymphocytes and EC were practically identical structurally, when studied at the protein, mRNA, and cDNA level. Thus, CD73 is an interesting example of a molecule which lacks structural variants but yet has a wide diversity of biological functions. We suggest that the ligand-induced shedding of lymphocyte CD73 represents an important and novel means of controlling lymphocyte-EC interactions.

5'-Nucleotidase↗
PubMed1997

CD73 mediates lymphocyte binding to vascular endothelium in inflamed human skin.

Inflammatory diseases of the skin are characterized by abundant lymphocytic infiltrates at the site of inflammation, which are critical for the perpetuation of chronic disease. Lymphocytes gain entry to the site of inflammation by the use of adhesion molecules, which recognize their counterparts on vascular endothelial cells. CD73 is a lymphocyte differentiation antigen, which has recently been shown to mediate lymphocyte binding to cultured endothelial cells. Here, we have examined its expression and function in inflammatory situations using inflammatory skin diseases as a model. In several idiopathic and allergic disorders of the skin, a vast majority of the skin-infiltrating lymphocytes were found to express CD73. However, on the circulating lymphocytes of these patients the expression of CD73 does not differ from that of healthy individuals. Of the peripheral blood lymphocytes (PBL) of patients, 13 % are CD73+; of these, 9 % express the cutaneous lymphocyte antigen (CLA), 32 % express CD45RO, and 86 % are L-selectin+. Only 1% of PBL express both CLA and CD73. In contrast, most skin-infiltrating lymphocytes express both molecules, which led us to investigate the role of CD73 in the skin-homing behavior of these cells. In the frozen-section adhesion assay, when PBL were treated with the anti-CD73 monoclonal antibody 4G4, their binding to the vascular endothelium in inflamed skin was inhibited by 70 %. Taken together, our results demonstrate that CD73+ lymphocytes preferentially accumulate into inflamed skin and, most importantly, that CD73 is involved in lymphocyte binding to vessels in inflamed skin. In the future, these findings may offer new means to treat inflammatory disorders of the skin.

5'-Nucleotidase↗
PubMed1997

Organ-selective regulation of vascular adhesion protein-1 expression in man.

Vascular adhesion protein-1 (VAP-1) is an endothelial molecule which mediates lymphocyte binding to endothelium in peripheral lymph nodes and at certain sites of inflammation. The expression of VAP-1 in vivo is strongly up-regulated in inflamed tissues, such as gut and skin. The purpose of this work was to examine the factors responsible for this induction of VAP-1. Since the expression of VAP-1 could not be induced in cultured endothelial cells with a large panel of mediators, we used an organ culture technique for the investigation of the regulation of VAP-1 expression in a more physiological micromilieu. Indeed, we found that the expression of endothelial VAP-1 could be up-regulated in human tonsillar tissue with interleukin (IL)-1, IL-4, tumor necrosis factor (TNF-alpha), interferon (IFN)-gamma and lipopolysaccharide, whereas histamine, thrombin, dibutyryl cAMP, N-formyl-Met-Leu-Phe (fMLP) and phorbol 12-myristate 13-acetate (PMA) had no effect. The induced VAP-1 protein was similar in molecular weight to the non-induced VAP-1, suggesting that VAP-1 synthesized de novo carries appropriate carbohydrate moieties. In contrast to tonsil organ culture, similar inductions performed with human appendix showed no up-regulation of VAP-1 expression, indicating that the regulation of VAP-1 expression exhibits organ-selective characteristics. Furthermore, in these tissues the smooth muscle cells, which constitutively express VAP-1, could not be stimulated to alter their level of expression of this molecule. In conclusion, the expression of VAP-1 can be markedly up-regulated with several mediators in tonsil but not in appendix organ culture, whereas cultured endothelial cells cannot be induced to express VAP-1. These results indicate that the expression of VAP-1 is regulated in a tissue- and cell type-selective manner, and a correct micromilieu is required for the up-regulation to occur.

Amine Oxidase (Copper-Containing)↗
PubMed1997

Binding of malignant lymphoid cells to the white matter of the human central nervous system: role of different CD44 isoforms, beta 1, beta 2 and beta 7 integrins, and L-selectin.

Spreading of reactive and malignant lymphoid cells into the brain parenchyma requires regulated adhesion of the lymphoid cells to the parenchymal cells and/or extracellular matrix of the central nervous system. A multifunctional adhesion molecule CD44 partially mediates binding of lymphocytes to the white matter by interacting with hyaluronate. To analyze which forms of CD44 and what other adhesion molecules mediate this binding. Namalwa cells were transfected to express either standard (CD44st) or variant isoforms of CD44 containing exons v6-v10, v7-v10, and v8-v10. The binding of CD44st and CD44v6-v10 transfectants to human cerebellar white matter was tested and it was about 1.7- and 2-fold greater without and with PMA activation, respectively, compared with vector-transfected control cells. Hyaluronidase digestion of tissue sections decreased binding of CD44 expressing cells to the level of vector-transfected cells. Hermes-1, a monoclonal antibody recognizing the hyaluronate binding site of CD44, inhibited white matter adhesion of CD44v6-v10 and activated CD44st cells and binding of soluble hyaluronate to the CD44 transfectants. Transfectants also expressed beta 1, beta 2 and beta 7 integrins and L-selectin, but antibodies against these molecules did not inhibit adhesion to the white matter. These results suggest: (a) Addition of exons v6-v10 to the membrane proximal region of CD44 does not affect lymphoid cell adhesion to the white matter. (b) The only ligand of CD44 in the central nervous system (CNS) white matter is hyaluronate. (c) Additional adhesion mechanisms other than the ones analyzed above must exist.

Burkitt Lymphoma↗
PubMed1997

Yersinia enterocolitica serotype O:3 alters the expression of serologic HLA-B27 epitopes on human monocytes.

The expression of serologic HLA-B27 epitopes on leukocytes of patients with reactive arthritis or ankylosing spondylitis has been shown to be modified in the course of the disease. The purpose of this work was to study whether phagocytosis of arthritis-triggering microbes in vitro alters the expression of HLA-B27 molecules on human antigen-presenting cells and to characterize the underlying mechanisms. Human monocytes and HLA-B27- or HLA-A2-transfected human U-937 cells were exposed to Yersinia enterocolitica serotype O:3. The expression of different epitopes of HLA-B27 was monitored by using immunofluorescence, and their synthesis was determined by quantitative immunoprecipitation. Our results show that phagocytosis of Y. enterocolitica serotype O:3 changed the expression of serological HLA-B27 epitopes. This was due to the reduced synthesis of HLA-B27 molecules. The expression of especially the epitopes which depend on the presence of peptides in the antigen-binding groove was changed. The expression of the ME1 epitope, which has been shown to be important for T-cell recognition in patients with reactive arthritis, was decreased. Down-regulation of epitopes important for the T-cell recognition may impair the elimination of arthritis-triggering microbes and lead to persistent infection. In addition, Y. enterocolitica serotype O:3 seemed to alter the repertoire of peptides presented by the HLA-B27 molecules on human monocytes. This may have a role in the pathogenesis of reactive arthritis via an autoimmune mechanism.

Brefeldin A↗
PubMed1996

CD73 mediates adhesion of B cells to follicular dendritic cells.

Lymphocyte-vascular adhesion protein-2 was recently identified as CD73. The CD73 molecule, otherwise known as ecto-5'-nucleotidase, is a lymphocyte maturation marker that is involved in intracellular signaling, and lymphocyte proliferation and activation. We now show that CD73, in addition to mediating lymphocyte binding to endothelial cells, also mediates adhesion between B cells and follicular dendritic cells (FDC), as a monoclonal antibody (MoAb) against CD73 inhibited the aggregation of isolated germinal center B cells and FDC in vitro. Cytocentrifuge preparations of isolated germinal center cells and two-color immunofluorescence stainings of different tonsillar B-cell populations show that CD73 is expressed on FDC and on small, recirculating IgD+ B cells, but only on a few B cells inside the germinal center. Thus, we propose that CD73 on FDC has an important role in controlling B cell-FDC interactions and B-cell maturation in germinal centers.

5'-Nucleotidase↗
PubMed1996

Recirculation and homing of lymphocyte subsets: dual homing specificity of beta 7-integrin(high)-lymphocytes in nonobese diabetic mice.

The beta 7-integrin subunit can pair with two alpha-chains, alpha 4 and alpha E, and is expressed mainly on lymphocytes. As an alpha 4-heterodimer it binds to the mucosal addressin MAdCAM-1, thus acting as a mucosal homing receptor. As an alpha E-heterodimer it binds to E-cadherin and is mainly found on intestinal intraepithelial lymphocytes. Consequently, beta 7 is mostly expressed on lymphocytes of the mucosal immune system. To study the compartmentalization of these cells further we compared the distribution of such lymphocytes in two strains of mice (BALB/c and NOD) and found that the distribution of beta 7-positive lymphocytes among various lymphoid tissues in these strains was very different. In NOD mice a conspicuous population of beta 7-integrin(high) lymphocytes expressing either alpha 4, alpha E, or both, was found in nonmucosal lymphoid tissues such as peripheral lymph nodes (PLNs). They mostly expressed the PLN homing receptor L-selectin, and included both naive and memory cells on the basis of their expression of CD44/pgp-1 and CD45RB, as did the few beta 7(high) lymphocytes in BALB/c PLNs. Their homing to Peyer's patches (PPs) and PLNs was equally effective and the cells homing to PPs and PLNs were equal in their level of L-selectin and alpha 4/beta 7 expression. However, functional studies indicated that their homing to PPs mostly depended on alpha 4/beta 7-integrin, whereas they mainly used L-selectin to home to PLNs. beta 7(high) lymphocytes were found also in circulating blood of unmanipulated NOD mice, and their L-selectin expression was higher than in BALB/c mice. These results show that lymphocytes of the mucosal immune system may also express the peripheral node homing receptor L-selectin during their recirculation and that in NOD mice they frequently retain a dual homing specificity, which leads to their accumulation in nonmucosal tissues.

Animals↗
PubMed1996

Human vascular adhesion protein 1 (VAP-1) is a unique sialoglycoprotein that mediates carbohydrate-dependent binding of lymphocytes to endothelial cells.

The regulated interactions of leukocytes with vascular endothelial cells are crucial in controlling leukocyte traffic between blood and tissues. Vascular adhesion protein-1 (VAP-1) is a novel, human endothelial cell molecule that mediates tissue-selective lymphocyte binding. Two species (90 and 170 kD) of VAP-1 exist in lymphoid tissues. Glycosidase digestions revealed that the mature 170-kD form of VAP-1 expressed on the lumenal surfaces of vessels is a heavily sialylated glycoprotein. The sialic acids are indispensable for the function of VAP-1, since the desialylated form of VAP-1 no longer mediates lymphocyte binding. We also show that L-selectin is not required for binding of activated lymphocytes to VAP-1 under conditions of shear stress. The 90-kD form of VAP-1 was only seen in an organ culture model, and may represent a monomeric or proteolytic form of the larger species. These data indicate that L-selectin negative lymphocytes can bind to tonsillar venules via the VAP- 1-mediated pathway. Moreover, our findings extend the role of carbohydrate-mediated binding in lymphocyte-endothelial cell interactions beyond the known selectins. In conclusion, VAP-1 naturally exists as a 170-kD sialoglycoprotein that uses sialic acid residues to interact with its counter-receptors on lymphocytes under nonstatic conditions.

Adult↗
PubMed1996

Lymphocyte binding to vascular endothelium in inflamed skin revisited: a central role for vascular adhesion protein-1 (VAP-1).

The binding of leukocytes to vascular endothelium and their migration into tissues is mediated by adhesion molecules on the endothelial cells and leukocytes. Vascular adhesion protein-1 (VAP-1) is a 170-180/90-kDa endothelial molecule expressed most prominently in high endothelial venules in peripheral lymph node (PLN) type lymphatic tissues. VAP-1 mediates lymphocyte binding to PLN, tonsil and synovium. The expression of VAP-1 is induced in inflammatory diseases such as arthritis and gut inflammation. We examined the expression, structure and function of VAP-1 in normal and inflamed skin and compared it to those of other adhesion molecules implicated in skin homing. In psoriasis lichen ruber planus, pemphigoid and allergic lesions, VAP-1 was markedly upregulated. The expression of VAP-1 was also increased in biopsies of healthy skin of the patients. The VAP-1 molecule induced in skin is decorated with abundant sialic acids. VAP-1 inflamed skin is functional, since inhibition with anti-VAP-1 monoclonal antibodies caused a 60% reduction in lymphocytes adhesion to vascular endothelium. Antibodies against E-selectin, which has been regarded as the major vascular addressin directing cutaneous lymphocyte traffic, and, surprisingly, against peripheral lymph node addressin (PNAd), caused inhibitions of 30% and 60%, respectively, in the frozen section adhesion assay. These findings suggest important roles also for VAP-1 and PNAd in lymphocyte homing into inflamed skin.

Amine Oxidase (Copper-Containing)↗