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  • 51.
    Forsberg, Ulf
    et al.
    Umeå university.
    Jonsson, Per
    Umeå university.
    Stegmayr, Christofer
    Umeå university.
    Jonsson, Fredrik
    Umeå university.
    Nilsson, Bo
    Uppsala university.
    Nilsson Ekdahl, Kristina
    Uppsala university.
    Stegmayr, Bernd
    Umeå university.
    A high blood level in the venous chamber and a wet-stored dialyzer help to reduce exposure for microemboli during hemodialysis2013Ingår i: Hemodialysis International, ISSN 1492-7535, E-ISSN 1542-4758, Vol. 17, nr 4, s. 612-617Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During hemodialysis (HD), microemboli develop in the blood circuit of the apparatus. These microemboli can pass through the venous chamber and enter into the patient's circulation. The aim of this study was to investigate whether it is possible to reduce the risk for exposure of microemboli by altering of the treatment mode. Twenty patients on chronic HD were randomized to a prospective cross-over study of three modes of HD: (a) a dry-stored dialyzer (F8HPS, Fresenius, steam sterilized) with a low blood level in the venous chamber (DL), (b) the same dialyzer as above, but with a high level in the venous chamber (DH), and (c) a wet-stored dialyzer (Rexeed, Asahi Kasei Medical, gamma sterilized) with a high blood level (WH). Microemboli measurements were obtained in a continuous fashion during 180 minutes of HD for all settings. A greater number of microemboli were detected during dialysis with the setting DL vs. WH (odds ratio [OR] 4.07, 95% confidence interval [CI] 4.03-4.11, P<0.0001) and DH vs. WH (OR 1.18, 95% CI 1.17-1.19, P<0.0001) and less for DH vs. DL (OR 0.290, 95% CI 0.288-0.2930.288-0.293, P<0.0001). These data indicate that emboli exposure was least when using WH, greater with DH, and most with DL. This study shows that using a high blood level in the venous chamber and wet-stored dialyzers may reduce the number of microemboli.

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  • 52.
    Fromell, Karin
    et al.
    Uppsala University.
    Duhrkop, Claudia
    Uppsala University.
    Johansson, Ulrika
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Forms of contact-activated C3 associated with AP convertase formation2017Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, s. 141-141Artikel i tidskrift (Övrigt vetenskapligt)
  • 53.
    Fromell, Karin
    et al.
    Uppsala Universit.
    Duhrkop, Claudia
    Uppsala University.
    Kozarcanin, Huda
    Uppsala University.
    Johansson, Ulrika
    Uppsala University.
    Skjoedt, Mikkel-Ole
    Rigshosp, Denmark.
    Garred, Peter
    Rigshosp, Denmark.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin pathway of complement and the contact/kallikrein system are integrated2018Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, s. 151-152Artikel i tidskrift (Övrigt vetenskapligt)
  • 54.
    Fromell, Karin
    et al.
    Uppsala University.
    Johansson, Ulrika
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Duhrkop, Claudia
    Uppsala University.
    Adler, Anna
    Uppsala University.
    Usterud, Emma
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C32018Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, s. 193-193Artikel i tidskrift (Övrigt vetenskapligt)
  • 55.
    Fromell, Karin
    et al.
    Uppsala University.
    Yang, Yi
    University of Gothenburg.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Berglin, Mattias
    Gothenburg University;RISE Res Inst Sweden Chem Mat & Surfaces.
    Elwing, Hans
    University of Gothenburg.
    Absence of conformational change in complement factor 3 and factor XII adsorbed to acrylate polymers is related to a high degree of polymer backbone flexibility2017Ingår i: Biointerphases, ISSN 1934-8630, E-ISSN 1559-4106, Vol. 12, nr 2, artikel-id 02D417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In previous investigations, the authors have examined the adsorption of albumin, immunoglobulin, and fibrinogen to a series of acrylate polymers with different backbone and side-group flexibility. The authors showed that protein adsorption to acrylates with high flexibility, such as poly(lauryl methacrylate) (PLMA), tends to preserve native conformation. In the present study, the authors have continued this work by examining the conformational changes that occur during the binding of complement factor 3 (C3) and coagulation factor XII (FXII). Native C3 adsorbed readily to all solid surfaces tested, including a series of acrylate surfaces of varying backbone flexibility. However, a monoclonal antibody recognizing a "hidden" epitope of C3 (only exposed during C3 activation or denaturation) bound to the C3 on the rigid acrylate surfaces or on polystyrene (also rigid), but not to C3 on the flexible PLMA, indicating that varying degrees of conformational change had occurred with binding to different surfaces. Similarly, FXII was activated only on the rigid poly(butyl methacrylate) surface, as assessed by the formation of FXIIa-antithrombin (AT) complexes; in contrast, it remained in its native form on the flexible PLMA surface. The authors also found that water wettability hysteresis, defined as the difference between the advancing and receding contact angles, was highest for the PLMA surface, indicating that a dynamic change in the interface polymer structure may help protect the adsorbed protein from conformational changes and denaturation. (C) 2017 Author(s).

  • 56. Gong, J
    et al.
    Larsson, R
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Mollnes, T E
    Nilsson, U R
    Nilsson, B
    Chandler loops as a model for cardiopulmonary bypass circuits: Both the biomaterial and the blood- gas interaces induce complement activation in an in vitro model1996Ingår i: Journal of clinical immunology, Vol. 16, s. 223-230Artikel i tidskrift (Refereegranskat)
  • 57. Goto, Masafumo
    et al.
    Tjernberg, Jenny
    Dufrane, Denis
    Elgue, Graciela
    Brandhorst, Daniel
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Brandhorst, Heidi
    Wennberg, Lars
    Kurokawa, Yoshimochi
    Satomi, Susumu
    Gianello, Pierre
    Korsgren, Olle
    Nilsson, Bo
    Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation2008Ingår i: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 15, nr 4, s. 225-234Artikel i tidskrift (Refereegranskat)
  • 58. Gröndahl, G
    et al.
    Johannisson, A
    Jensen-Waern, M
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Opsonization of yeast cells with equine C3 and IgG2001Ingår i: Veterinary immunology and immunopathology, Vol. 6425, s. 1-15Artikel i tidskrift (Refereegranskat)
  • 59.
    Gustafson, Elisabet
    et al.
    Uppsala University Hospital, Sweden.
    Asif, Sana
    Uppsala University, Sweden.
    Kozarcanin, Huda
    Uppsala University, Sweden.
    Elgue, Graciela
    Uppsala University, Sweden.
    Meurling, Staffan
    Uppsala University Hospital, Sweden.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Bo
    Uppsala University, Sweden.
    Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate Versus Heparin2017Ingår i: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, nr 1, s. 71-81Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rapid destruction of hepatocytes after hepatocyte transplantation has hampered the application of this procedure clinically. The instant blood-mediated inflammatory reaction (IBMIR) is a plausible underlying cause for this cell loss. The present study was designed to evaluate the capacity of low molecular weight dextran sulfate (LMW-DS) to control these initial reactions from the innate immune system. Fresh and cryopreserved hepatocytes were tested in an in vitro whole-blood model using ABO-compatible blood. The ability to elicit IBMIR and the capacity of LMW-DS (100 mu g/ml) to attenuate the degree of activation of the cascade systems were monitored. The effect was also compared to conventional anticoagulant therapy using unfractionated heparin (1 IU/ml). Both fresh and freeze thawed hepatocytes elicited IBMIR to the same extent. LMW-DS reduced the platelet loss and maintained the cell counts at the same degree as unfractionated heparin, but controlled the coagulation and complement systems significantly more efficiently than heparin. LMW-DS also attenuated the IBMIR elicited by freeze thawed cells. Therefore, LMW-DS inhibits the cascade systems and maintains the cell counts in blood triggered by both fresh and cryopreserved hepatocytes in direct contact with ABO-matched blood. LMW-DS at a previously used and clinically applicable concentration (100 mu g/ml) inhibits IBMIR in vitro and is therefore a potential IBMIR inhibitor in hepatocyte transplantation.

  • 60.
    Gustafson, Elisabet
    et al.
    Uppsala Univ Hospital, Sweden.
    Hamad, Osama A.
    Uppsala University, Sweden.
    Deckmyn, Hans
    Katholieke Univ Leuven, Belgium.
    Barbu, Andreea
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Bo
    Uppsala University, Sweden.
    Exposure of von Willebrand Factor on Isolated Hepatocytes Promotes Tethering of Platelets to the Cell Surface2019Ingår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, nr 8, s. 1630-1638Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Hepatocyte transplantation (Hctx) is a potentially attractive method for the treatment of acute liver failure and liver-based metabolic disorders. Unfortunately, the procedure is hampered by the instant blood-mediated inflammatory reaction (IBMIR), a thromboinflammatory response elicited by the vascular innate immune system, causing activation of the coagulation and complement systems and clearance of transplanted cells. Observations have also revealed platelets adhered to the surface of the hepatocytes (Hc). To establish Hctx as a clinical treatment, all factors that trigger IBMIR need to be identified and controlled. This work explores the expression of von Willebrand factor (VWF) on isolated Hc resulting in tethering of platelets. Methods. VWF on Hc was studied by flow cytometry, confocal microscopy, immunoblot, and real-time polymerase chain reaction. Interaction between Hc and platelets was studied in a Chandler loop model. Adhesion of platelets to the hepatocyte surface was demonstrated by flow cytometry and confocal microscopy. Results. Isolated Hc constitutively express VWF on their cell surface and mRNA for VWF was found in the cells. Hc and platelets, independently of coagulation formed complexes, were shown by antibody blocking studies to be dependent on hepatocyte-associated VWF and platelet-bound glycoprotein Ib alpha. Conclusions. VWF on isolated Hc causes, in contact with blood, adhesion of platelets, which thereby forms an ideal surface for coagulation. This phenomenon needs to be considered in hepatocyte-based reconstitution therapy and possibly even in other settings of cell transplantation.

  • 61. Gölander, C G
    et al.
    Lassen, B
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Nilsson, U R
    RF-plasma-modified polystyrene surfaces for studying complement activation1993Ingår i: Journal of biomaterials science. Polymer edition, Vol. 4, s. 25-30Artikel i tidskrift (Refereegranskat)
  • 62.
    Hamad, Osama A.
    et al.
    Uppsala University.
    Mitroulis, Ioannis
    Tech Univ Dresden, Germany.
    Fromell, Karin
    Uppsala University.
    Kozarcanin, Huda
    Uppsala University.
    Chavakis, Triantafyllos
    Tech Univ Dresden, Germany.
    Ricklin, Daniel
    Univ Penn, USA.
    Lambris, John D.
    Univ Penn, USA.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD182015Ingår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 114, nr 6, s. 1207-1217Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Complement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16(+)/CD42a(+) PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75-100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.

  • 63. Hamad, Osama A.
    et al.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson, Bo
    Non-proteolytically activated C3 promotes binding of activated platelets and platelet-derived microparticles to leukocytes via CD11b/CD182012Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, nr 11, s. 1191-1191Artikel i tidskrift (Övrigt vetenskapligt)
  • 64. Hamad, Osama A
    et al.
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Nilsson, Per H.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Andersson, Jonas
    Magotti, Paola
    Lambris, John D
    Nilsson, Bo
    Complement activation triggered by chondroitin sulfate reelased by thrombin receptor-activated platelets2008Ingår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, nr 8, s. 1413-1421Artikel i tidskrift (Refereegranskat)
  • 65.
    Hamad, Osama A.
    et al.
    Uppsala University.
    Nilsson, Per H.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Lasaosa, Maria
    University of Pennsylvania, USA.
    Ricklin, Daniel
    University of Pennsylvania, USA.
    Lambris, John D.
    University of Pennsylvania, USA.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV. Uppsala University.
    Contribution of Chondroitin Sulfate A to the Binding of Complement Proteins to Activated Platelets2010Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 9, artikel-id e12889Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Exposure of chondroitin sulfate A (CS-A) on the surface of activated platelets is well established. The aim of the present study was to investigate to what extent CS-A contributes to the binding of the complement recognition molecule C1q and the complement regulators C1 inhibitor (C1INH), C4b-binding protein (C4BP), and factor H to platelets.Principal Findings: Human blood serum was passed over Sepharose conjugated with CS-A, and CS-A-specific binding proteins were identified by Western blotting and mass spectrometric analysis. C1q was shown to be the main protein that specifically bound to CS-A, but C4BP and factor H were also shown to interact. Binding of C1INH was dependent of the presence of C1q and then not bound to CS-A from C1q-depleted serum. The specific interactions observed of these proteins with CS-A were subsequently confirmed by surface plasmon resonance analysis using purified proteins. Importantly, C1q, C4BP, and factor H were also shown to bind to activated platelets and this interaction was inhibited by a CS-A-specific monoclonal antibody, thereby linking the binding of C1q, C4BP, and factor H to exposure of CS-A on activated platelets. CS-A-bound C1q was also shown to amplify the binding of model immune complexes to both microtiter plate-bound CS-A and to activated platelets.

    Conclusions: This study supports the concept that CS-A contributes to the binding of C1q, C4BP, and factor H to platelets, thereby adding CS-A to the previously reported binding sites for these proteins on the platelet surface. CS-A-bound C1q also seems to amplify the binding of immune complexes to activated platelets, suggesting a role for this molecule in immune complex diseases. 

  • 66.
    Hamad, Osama
    et al.
    Uppsala University.
    Bäck, Jennie
    Uppsala University.
    Nilsson, Per H.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Platelets, Complement, and Contact Activation: Partners in inflammation and thrombosis2012Ingår i: Current Topics in Innate Immunity II / [ed] John D. Lambris &George Hajishengallis, Springer, 2012, Vol. 946, nr Current Topics in Innate Immunity II. J. D. Lambris, G. Hajishengallis (eds.), s. 185-205Konferensbidrag (Refereegranskat)
    Abstract [en]

    Platelet activation during thrombotic events is closely associated with complement and contact system activation, which in turn leads to inflammation . Here we review the interactions between activated platelets and the complement and contact activation systems in clotting blood. Chondroitin sulfate A (CS-A), released from alpha granules during platelet activation, is a potent mediator of crosstalk between platelets and the complement system. CS-A activates complement in the fluid phase, generating anaphylatoxins that mediate leukocyte activation. No complement activation seems to occur on the activated platelet surface, but C3 in the form of C3(H2O) is bound to the surfaces of activated platelets . This finding is consistent with the strong expression of membrane-bound complement regulators present at the platelet surface. CS-A exposed on the activated platelets is to a certain amount responsible for recruiting soluble regulators to the surface. Platelet-bound C3(H2O) acts as a ligand for leukocyte CR1 (CD35), potentially enabling platelet–leukocyte interactions. In addition, platelet activation leads to the activation of contact system enzymes, which are specifically inhibited by antithrombin, rather than by C1INH, as is the case when contact activation is induced by material surfaces. Thus, in addition to their traditional role as initiators of secondary hemostasis, platelets also act as mediators and regulators of inflammation in thrombotic events.

  • 67.
    Hamad, Osama
    et al.
    Rudbeck Laboratory, University hospital, Uppsala.
    Nilsson, Per H.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Lambris, John D.
    University of Pennsylvania, USA.
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen. Rudbeck Laboratory, University hospital, Uppsala.
    Nilsson, Bo
    Rudbeck Laboratory, University hospital, Uppsala.
    Binding of complement proteins to activated platelets is independent of complement activation2009Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, nr 14, s. 2853-2853, artikel-id OP95Artikel i tidskrift (Refereegranskat)
  • 68. Hamad, Osama
    et al.
    Nilsson, Per H.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Wouters, Diana
    Lambris, John
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson, Bo
    Complement Component C3 Binds to Activated Normal Platelets without Preceding Proteolytic Activation and Promotes Binding to Complement Receptor 12010Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, nr 5, s. 2686-2692Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It has been reported that complement is activated on the surface of activated platelets, despite the presence of multiple regulators of complement activation. To reinvestigate the mechanisms by which activated platelets bind to complement components, the presence of complement proteins on the surfaces of nonactivated and thrombin receptor-activating peptide-activated platelets was analyzed by flow cytometry and Western blot analyses. C1q, C4, C3, and C9 were found to bind to thrombin receptor-activating peptide-activated platelets in lepirudin-anticoagulated platelet-rich plasma (PRP) and whole blood. However, inhibiting complement activation at the C1q or C3 level did not block the binding of C3 to activated platelets. Diluting PRP and chelating divalent cations also had no effect, further indicating that the deposition of complement components was independent of complement activation. Furthermore, washed, activated platelets bound added C1q and C3 to the same extent as platelets in PRP. The use of mAbs against different forms of C3 demonstrated that the bound C3 consisted of C3(H2O). Furthermore, exogenously added soluble complement receptor 1 was shown to bind to this form of platelet-bound C3. These observations indicate that there is no complement activation on the surface of platelets under physiological conditions. This situation is in direct contrast to a number of pathological conditions in which regulators of complement activation are lacking and thrombocytopenia and thrombotic disease are the ultimate result. However, the generation of C3(H2O) represents nonproteolytic activation of C3 and after factor I cleavage may act as a ligand for receptor binding.

  • 69. Hancock, Viktoria
    et al.
    Huang, Shan
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Anders
    Grundstrom, Gunilla
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Citrate reduces complement and leukocyte activation in vitro in human blood2013Ingår i: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 28, s. 207-208Artikel i tidskrift (Övrigt vetenskapligt)
  • 70.
    Harboe, M.
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Johnson, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nymo, S.
    Nordland Hospital, Norway.
    Ekholt, K.
    Oslo University Hospital Rikshospitalet, Norway.
    Schjalm, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Lindstad, J. K.
    Oslo University Hospital Rikshospitalet, Norway.
    Pharo, A.
    Oslo University Hospital Rikshospitalet, Norway.
    Hellerud, B. C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Mollnes, T. E.
    Oslo University Hospital Rikshospitalet, Norway ; Nordland Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Molecular modelling showed optimal fit between TSR5 in trimeric properdin and C345C in the C3b moiety for stabilization of the alternative convertase, whereas binding to molecular patterns in myeloperoxidase, endothelial cells and Neisseria meningitides was indirectly mediated by initial C3 activation2016Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, nr 10, s. 1205-1205Artikel i tidskrift (Refereegranskat)
  • 71.
    Harboe, Morten
    et al.
    Oslo University Hospital, Norway.
    Johnson, Christina
    Oslo University Hospital, Norway.
    Nymo, Stig
    Nordland Hospital, Norway.
    Ekholt, Karin
    Oslo University Hospital, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Norway.
    Lindstad, Julie K.
    Oslo University Hospital, Norway.
    Pharo, Anne
    Oslo University Hospital, Norway.
    Hellerud, Bernt Christian
    Oslo University Hospital, Norway.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway ; Nordland Hospital, Norway ; University of Oslo, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Nilsson, Per H.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Oslo University Hospital, Norway ; University of Oslo, Norway.
    Properdin binding to complement activating surfaces depends on initial C3b deposition2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 4, s. E534-E539Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two functions have been assigned to properdin; stabilization of the alternative convertase, C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversial. The presence of nonphysiological aggregates in purified properdin preparations and experimental models that do not allow discrimination between the initial binding of properdin and binding secondary to C3b deposition is a critical factor contributing to this controversy. In previous work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not a primary event, but rather is solely dependent on initial C3 deposition. In the present study, we found that properdin in human serum bound dose-dependently to solid-phase myeloperoxidase. This binding was dependent on C3 activation, as demonstrated by the lack of binding in human serum with the C3-inhibitor compstatin Cp40, in C3-depleted human serum, or when purified properdin is applied in buffer. Similarly, binding of properdin to the surface of human umbilical vein endothelial cells or Neisseria meningitidis after incubation with human serum was completely C3-dependent, as detected by flow cytometry. Properdin, which lacks the structural homology shared by other complement pattern recognition molecules and has its major function in stabilizing the C3bBb convertase, was found to bind both exogenous and endogenous molecular patterns in a completely C3-dependent manner. We therefore challenge the view of properdin as a pattern recognition molecule, and argue that the experimental conditions used to test this hypothesis should be carefully considered, with emphasis on controlling initial C3 activation under physiological conditions.

  • 72. Henningsson, A. J
    et al.
    Ernerudh, J
    Sandholm, K
    Carlsson, S-A
    Granlund, H
    Jansson, C
    Nyman, D
    Forsberg, P
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Raised Intrathecal Levels of Complement Components C1q and C3a in Acute Neuroborreliosis2007Ingår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 183, nr 1-2, s. 200-207Artikel i tidskrift (Refereegranskat)
  • 73. Hong, J
    et al.
    Andersson, J
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Elgue, G
    Axén, N
    Larsson, R
    Nilsson, Bo
    Titanium is a highly thrombogenic biomaterial: Possible implications for osteogenesis1999Ingår i: Thrombosis and haemostasis, Vol. 82, s. 58-64Artikel i tidskrift (Refereegranskat)
  • 74. Hong, J
    et al.
    Azens, A
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Granqvist, C G
    Nilsson, B
    Contact between various metal surfaces and whole blood causes material-specific thrombin generation2005Ingår i: Biomaterials, Vol. 26 (12), s. 1397-1403Artikel i tidskrift (Refereegranskat)
  • 75. Hong, J
    et al.
    Larsson, A
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Elgue, G
    Larsson, R
    Nilsson, B
    Contact between a polymer and whole blood: the sequence of events leading to thrombin generation2001Ingår i: The journal of laboratory and clinical medicine, Vol. 138, s. 139-145Artikel i tidskrift (Refereegranskat)
  • 76. Hong, J
    et al.
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Reynolds, H
    Larsson, R
    Nilsson, B
    A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin1999Ingår i: Biomaterials, Vol. 20, s. 603-611Artikel i tidskrift (Refereegranskat)
  • 77.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Engberg, Anna E.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). University and Regional Laboratories Region Skåne.
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nicholls, Ian A.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Mollnes, Tom Eirik
    Oslo University Hospital Rikshopsitalet, Norway;University of Oslo, Norway;Nordland Hospital, Norway; University of Tromsø, Norway;Norwegian University of Science and Technology, Norway.
    Fromell, Karin
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood.2016Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 77, s. 111-119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models.

    METHODS: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release.

    RESULTS: Strong negative correlations were found between 10 cytokines and the ratio of deposited FXII/C1INH, generated FXIIa-C1INH complexes, and kallikrein-C1INH complexes. Formation of FXIIa-C1INH complexes correlated negatively with the amount of C3a and positively with deposited IgG.

    CONCLUSIONS: A reciprocal relationship was found between activation of the contact system and the complement system induced by the polymers studied here. The ratios of FXII/C1INH or C4/C4BP, adsorbed from EDTA-plasma are useful surrogate markers for cytokine release and inflammatory response to materials intended for blood contact.

  • 78.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson, Per H.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Elmlund, Louise
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nicholls, Ian A.
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Regulation of complement in whole blood by heparin molecularly imprinted polymer particles2012Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, nr 11, s. 1199-1199Artikel i tidskrift (Övrigt vetenskapligt)
  • 79.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Anders
    Gambro Lundia AB.
    Wieslander, Anders
    Gambro Lundia AB.
    Grundström, Gunilla
    Gambro Lundia AB.
    Hancock, Viktoria
    Gambro Lundia AB.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood2015Ingår i: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, nr 1, s. 31-37Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.

    METHODS:The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.

    RESULTS:Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.

    CONCLUSIONS:Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.

  • 80.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Jonsson, Nina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Rorsman, Fredrik
    Uppsala University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    An assay to monitor in vitro generation of non-proteolytically activated C3 in human plasmaManuskript (preprint) (Övrigt vetenskapligt)
  • 81.
    Huang, Shan
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    iC3 generation elicited by the presence of ammonia and urea in human plasma2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 145-145Artikel i tidskrift (Övrigt vetenskapligt)
  • 82.
    Huber-Lang, Markus
    et al.
    Univ Hosp Ulm, Germany.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Wiegner, Rebecca
    Univ Hosp Ulm, Germany.
    Fromell, Karin
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions2018Ingår i: Seminars in Immunopathology, ISSN 1863-2297, E-ISSN 1863-2300, Vol. 40, nr 1, s. 87-102Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Activation and regulation of the cascade systems of the blood (the complement system, the coagulation/contact activation/kallikrein system, and the fibrinolytic system) occurs via activation of zymogen molecules to specific active proteolytic enzymes. Despite the fact that the generated proteases are all present together in the blood, under physiological conditions, the activity of the generated proteases is controlled by endogenous protease inhibitors. Consequently, there is remarkable little crosstalk between the different systems in the fluid phase. This concept review article aims at identifying and describing conditions where the strict system-related control is circumvented. These include clinical settings where massive amounts of proteolytic enzymes are released from tissues, e.g., during pancreatitis or post-traumatic tissue damage, resulting in consumption of the natural substrates of the specific proteases and the available protease inhibitor. Another example of cascade system dysregulation is disseminated intravascular coagulation, with canonical activation of all cascade systems of the blood, also leading to specific substrate and protease inhibitor elimination. The present review explains basic concepts in protease biochemistry of importance to understand clinical conditions with extensive protease activation.

  • 83. Janssen, B J C
    et al.
    Huizinga, E G
    Raaijmakers, H C A
    Roos, A
    Daha, M R
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Nilsson, Bo
    Gros, P
    Structures of complement component C3 provide insights into the function and evolution of immunity2005Ingår i: Nature, Vol. 437 (7058), s. 505-511Artikel i tidskrift (Refereegranskat)
  • 84. Johansson, H
    et al.
    Lukinius, A
    Moberg, L
    Lundgren, T
    Berne, C
    Foss, A
    Felldin, M
    Kallen, R
    Salmela, K
    Tibe, A
    Tufveson, G
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Elgue, G
    Korsgren, O
    Nilsson, Bo
    Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation2005Ingår i: Diabetes, Vol. 54 (6), s. 1755-1762Artikel i tidskrift (Refereegranskat)
  • 85. Jokiranta, T S
    et al.
    Westin, J
    Nilsson, B
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hellwage, J
    Gordon, D L
    Nilsson, U R
    Meri, S
    Complement C3b interactions with its ligands measured by Biacore equipment: a new powerful and informative method2001Ingår i: International immunopharmacology, Vol. 1, s. 495-506Artikel i tidskrift (Refereegranskat)
  • 86.
    Jonsson, Nina
    et al.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Asif, Sana
    Uppsala University.
    Teramura, Yuji
    Univ Tokyo, Japan.
    Gustafson, Elisabeth
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Surface modification of primary human hepatocytes with recombinant CD39 protects against thromboinfiammation2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 149-150Artikel i tidskrift (Övrigt vetenskapligt)
  • 87.
    Klapper, Yvonne
    et al.
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Teramura, Yuji
    Uppsala University.
    Leneweit, Gero
    Assoc Promot Canc Therapy, Germany.
    Nienhaus, G. Ulrich
    Karlsruhe Inst Technol KIT, Germany.
    Ricklin, Daniel
    Univ Penn, USA.
    Lambris, John D.
    Univ Penn, USA.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Mediation of a non-proteolytic activation of complement component C3 by phospholipid vesicles2014Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, nr 11, s. 3688-3696Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Liposomes are becoming increasingly important as drug delivery systems, to target a drug to specific cells and tissues and thereby protecting the recipient from toxic effects of the contained drug. Liposome preparations have been described to activate complement. In this study, we have investigated complement activation triggered by neutral dimyristoyl-phosphocholine (DMPC) liposomes in human plasma and whole-blood systems. Incubation in plasma led to the generation of complement activation products (C3a and sC5b-9). Unexpectedly, investigations of surface-bound C3 revealed contact activated, conformationally changed C3 molecules on the liposomes. These changes were characterized by Western blotting with C3 monoclonal antibodies, and by incubating liposomes with purified native C3 and factors I and H. Quartz crystal microbalance analysis confirmed binding of C3 to planar DMPC surfaces. In addition, we demonstrated that DMPC liposomes bound to or were phagocytized by granulocytes in a complement-dependent manner, as evidenced by the use of complement inhibitors. In summary, we have shown that C3 is activated both by convertase-dependent cleavage, preferentially in the fluid phase, by mechanisms which are not well elucidated, and also by contact activation into C3(H2O) on the DMPC surface. In particular, this contact activation has implications for the therapeutic regulation of complement activation during liposome treatment. (C) 2013 Elsevier Ltd. All rights reserved.

  • 88. Klapper, Yvonne
    et al.
    Hamad, Osama
    Teramura, Yuji
    Leneweit, Gero
    Nienhaus, Gerd Ulrich
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nilsson, Bo
    Investigation of complement activation by neutral liposomes2012Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, nr 11, s. 1179-1180Artikel i tidskrift (Övrigt vetenskapligt)
  • 89.
    Klapper, Yvonne
    et al.
    KIT, Germany.
    Maffre, Pauline
    KIT, Germany.
    Shang, Li
    KIT, Germany.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Hettler, Simon
    KIT, Germany.
    Dries, Manuel
    KIT, Germany.
    Gerthsen, Dagmar
    KIT, Germany.
    Nienhaus, G. Ulrich
    KIT, Germany;Univ Illinois, USA.
    Low affinity binding of plasma proteins to lipid-coated quantum dots as observed by in situ fluorescence correlation spectroscopy2015Ingår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 7, nr 22, s. 9980-9984Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein binding to lipid-coated nanoparticles has been pursued quantitatively by using fluorescence correlation spectroscopy. The binding of three important plasma proteins to lipid-enwrapped quantum dots (QDs) shows very low affinity, with an apparent dissociation coefficient in the range of several hundred micromolar. Thus, the tendency to adsorb is orders of magnitude weaker than for QDs coated with dihydrolipoic acid.

  • 90.
    Klinth, Jeanna
    et al.
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Larsson, R
    Andersson, P O
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    A novel application of multi-wavelength TIRF spectroscopy for real time monitoring of antithrombin interactions with immobilized heparin2006Ingår i: Biosensors & bioelectronics, Vol. 21, nr 10, s. 1973-1980Artikel i tidskrift (Refereegranskat)
  • 91.
    Knabl, Ludwig
    et al.
    Medical University of Innsbruck, Austria.
    Berktold, Michael
    Medical University of Innsbruck, Austria.
    Hamad, Osama
    Uppsala university, Sweden.
    Fromell, Karin
    Uppsala university, Sweden.
    Chatterjee, Sneha
    Medical University of Innsbruck, Austria.
    Speth, Cornelia
    Medical University of Innsbruck, Austria.
    Talasz, Herbert
    Medical University of Innsbruck, Austria.
    Lindner, Katharina
    Medical University of Innsbruck, Austria.
    Hermann, Martin
    Medical University of Innsbruck, Austria.
    Nilsson Ekdahl, Kristina
    Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Streif, Werner
    Medical University of Innsbruck, Austria.
    Martini, Judith
    Medical University of Innsbruck, Austria.
    Würzner, Reinhard
    Medical University of Innsbruck, Austria.
    Orth-Höller, Dorothe
    Medical University of Innsbruck, Austria.
    Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets2018Ingår i: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 308, nr 7, s. 969-976Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Escherichia coli-induced hemolytic uremic syndrome (eHUS) is a life-threatening complication of infection with Shiga toxin (Stx), in particular Stx2a-producing Escherichia coli. Enhanced coagulation activation with formation of microthrombiseems to be a key event in development of eHUS. Platelet activation has been postulated as a possible, but controversially debated mechanism.

    The present study investigated the effect of Stx2a on plasmatic coagulation and platelets. Binding studies were initially performed with ELISA and co-immunoprecipitation and supported by quartz crystal microbalance with dissipation monitoring (QCM-D). Antithrombin (AT) activity was measured using the automated BCS XP® system. ROTEM® was used for functional coagulation testing. Platelet binding and activation was studied with FACS and light-transmission aggregometry.

    We found binding of Stx2a to AT, an important inhibitor of blood coagulation, but only a mild albeit significant reduction of AT activity against FXa in the presence of Stx2a. QCM-D analysis also showed binding of Stx2a to heparin and an impaired binding of AT to Stx2a-bound heparin. ROTEM® using Stx2a-treated platelet-poor plasma revealed a significant, but only moderate shortening of clotting time. Neither binding nor activation of platelets by Stx2a could be demonstrated.

    In summary, data of this study suggest that Stx2a binds to AT, but does not induce major effects on plasmatic coagulation. In addition, no interaction with platelets occurred. The well-known non-beneficial administration of heparin in eHUS patients could be explained by the interaction of Stx2a with heparin.

  • 92.
    Kozarcanin, H.
    et al.
    Uppsala University.
    Lood, C.
    Skåne University Hospital;Lund University.
    Munthe-Fog, L.
    University of Copenhagen, Denmark.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Hamad, O. A.
    Uppsala University.
    Bengtsson, A. A.
    Skåne University Hospital;Lund University.
    Skjoedt, M. -O
    University of Copenhagen, Denmark.
    Huber-Lang, M.
    University Hospital of Ulm, Germany.
    Garred, P.
    University of Copenhagen, Denmark.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation2016Ingår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, nr 3, s. 531-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both invitro and invivo. These findings may represent a crossroad between the complement and the coagulation systems. Summary Background The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor invitro. In vivo studies also show that MASP-1 is involved in thrombogenesis. Objectives To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions. Methods Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2. Results Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation. Conclusions MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions invitro and invivo, and may represent a novel activation/amplification mechanism in thromboinflammation.

  • 93.
    Kozarcanin, Huda
    et al.
    Uppsala University.
    Lood, Christian
    Skåne Univ Hosp, Sweden;Lund Univ, Sweden.
    Munthe-Fog, Lea
    Univ Copenhagen, Denmark.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Hamad, Osama
    Uppsala University.
    Skjoedt, Mikkel-Ole
    Univ Copenhagen, Denmark.
    Bengtsson, Anders
    Skåne Univ Hosp, Sweden;Lund Univ, Sweden.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Garred, Peter
    Univ Copenhagen, Denmark.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin complement pathway serine proteases bridges the complement and the coagulation systems in thrombotic diseases2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, nr 1, s. 153-153Artikel i tidskrift (Övrigt vetenskapligt)
  • 94.
    Kumar, Jitender
    et al.
    Uppsala University.
    Lind, P. Monica
    Uppsala University.
    Salihovic, Samira
    Uppsala University.
    van Bavel, Bert
    Örebro University.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Lind, Lars
    Uppsala University.
    Ingelsson, Erik
    Uppsala University.
    Influence of persistent organic pollutants on the complement system in a population-based human sample2014Ingår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 71, s. 94-100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Persistent organic pollutants (POPS) are toxic compounds generated through various industrial activities and have adverse effects on human health. Studies performed in cell cultures and animals have revealed that POPs can alter immune-system functioning. The complement system is part of innate immune system that helps to clear pathogens from the body. We performed a large-scale population-based study to find out associations between summary measures of different POPs and different complement system markers. Methods: In this cross-sectional study, 16 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, octachloro-p-dibenzodioxin, and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) were analyzed for their association with levels of protein complement 3 (C3), 3a (C3a), 4 (C4) and C3a/C3 ratio. A total of 992 individuals (all aged 70 years, 50% females) were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. Regression analysis adjusting for a variety of confounders was performed to study the associations of different POP exposures (total toxic equivalency value or TEQ and sum of 16 PCBs) with protein complements. Results: The TEQ values were found to be positively associated with C3a (beta = 0.07, 95% CI = 0.017-0.131, p = 0.01) and C3a/C3 ratio (beta = 0.07, 95% Cl = 0.015-0.126, p = 0.01) taking possible confounders into account. The association observed was mainly driven by PCB-126. Conclusion: In this study involving 992 elderly individuals from the general population, we showed that POPs, mainly PCB-126, were associated with levels of complement system markers indicating that the association of these toxic compounds with downstream disease could be mediated by activation of immune system. (C) 2014 Elsevier Ltd. All rights reserved.

  • 95. Kuraya, M
    et al.
    Nilsson, B
    Nilsson Ekdahl, Kristina
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Klein, E
    C3d-mediated negative and positive signals on the proliferation of human B cells separated from blood1990Ingår i: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 26, nr 1, s. 51-58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Soluble C3d applied to human blood-derived B lymphocytes inhibited anti-μ, T cell-produced growth factor, and EBV-induced DNA synthesis in serum-free culture. C3d added to the B cell cultures 1 and 2 days after the stimulus, still exerted inhibition, though with gradually diminishing efficiency.

    C3d, fixed on zymosan or attached to the culture wells, induced [3H]thymidine incorporation of the B cells in serum-free medium. The concentration of C3d used to coat the wells was critical, with optimal stimulatory effect of 8.3 μg/ml. These C3d molecules were shown to be denatured.

    Our results are in line with earlier data on B cells derived from mouse spleen and human tonsils showing that depending on the way of presentation and its amounts, the natural ligand of CR2 can exert negative or positive signals. Moreover, we demonstrate that C3d can inhibit even the proliferative stimulus of EBV. 

  • 96.
    Labriere, Christophe
    et al.
    UiT Arctic Univ Norway, Norway;Univ Aberdeen, UK.
    Kondori, Nahid
    University of Gothenburg.
    Caous, Josefin Seth
    RISE Res Inst Sweden.
    Boomgaren, Marc
    UiT Arctic Univ Norway, Norway.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Hansen, Jorn H.
    UiT Arctic Univ Norway, Norway.
    Svenson, Johan
    UiT Arctic Univ Norway, Norway;RISE Res Inst Sweden.
    Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines2018Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 24, nr 7, artikel-id UNSP e3090Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5-diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 mu g/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

  • 97.
    Lambris, John D
    et al.
    University of Pennsylvania, USA.
    Nilsson Ekdahl, KristinaUniversity of Uppsala, Sweden.Ricklin, DanielUniversity of Pennsylvania, USA.Nilsson, BoUniversity of Uppsala, Sweden.
    Immune Responses to Biosurfaces: Mechanisms and Therapeutic Interventions2015Samlingsverk (redaktörskap) (Refereegranskat)
  • 98. Larsson, R
    et al.
    Elgue, G
    Larsson, A
    Nilsson Ekdahl, Kristina
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Nilsson, U R
    Nilsson, B
    Inhibition of complement activation by soluble recombinant CR1 under conditions resembling those in a cardiopulmonary circuit: Reduced up-regulation of CD11b and complete abrogation of binding of PMNs to the biomaterial1997Ingår i: Immunopharmacology, Vol. 38, s. 119-127Artikel i tidskrift (Refereegranskat)
  • 99. Lavö, B
    et al.
    Nilsson, B
    Lööf, L
    Nilsson, U R
    Nilsson Ekdahl, Kristina
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Fc receptor function and circulating immune complexes in gluten sensitive enteropathy - possible significance of serum IgA1991Ingår i: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 32, s. 876-880Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The capacity to clear IgG containing immune complexes from the circulation was studied in patients with coeliac disease (n = 13), dermatitis herpetiformis (n = 8), and coeliac disease with concomitant serum IgA deficiency (n = 4). A small group of patients with active ulcerative colitis (n = 4) was included as a bowel disease control group. Clearance was estimated by measuring the disappearance rate of a bolus dose of intravenously injected IgG coated autologous erythrocytes. The mean T1/2 of clearance was prolonged in both coeliac disease (86 (24) minutes) and dermatitis herpetiformis (111 (35) minutes), compared with healthy subjects (20 (5) minutes) and coeliac patients with concomitant serum IgA deficiency (T1/2 = 17 (6) minutes). Patients with ulcerative colitis had a prolonged clearance, with a T1/2 of 195 (63) minutes. Values of circulating immune complexes were measured by four assays; C1q binding and C3, IgG, and IgA containing immune complexes. C1q binding immune complexes were detected only in IgA deficient gluten sensitive enteropathy. Patients with coeliac disease and dermatitis herpetiformis had higher values of C3, IgG, and IgA containing immune complexes than control subjects and serum IgA deficient patients with coeliac disease. The clearance rate was inversely correlated to the amount of immune complexes for the subgroups of gluten sensitive enteropathy. 

  • 100.
    Lindblom, Rickard P. F.
    et al.
    Karolinska Institutet;Uppsala University.
    Aeinehband, Shainn
    Karolinska Institutet.
    Ström, Mikael
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB).
    Khademi, Mohsen
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Piehl, Fredrik
    Karolinska Institutet.
    Nilsson Ekdahl, Kristina
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för kemi och biomedicin (KOB). Uppsala University.
    Complement receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function2016Ingår i: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 166, s. 89-95Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Besides its vital role in immunity, the complement system also contributes to the shaping of the synaptic circuitry of the brain. We recently described that soluble Complement Receptor 2 (sCR2) is part of the nerve injury response in rodents. We here study CR2 in context of multiple sclerosis (MS) and explore the molecular effects of CR2 on C3 activation.

    Significant increases in sCR2 levels were evident in cerebrospinal fluid (CSF) from both patients with relapsing-remitting MS (n = 33; 6.2 ng/mL) and secondary-progressive MS (n = 9; 7.0 ng/mL) as compared to controls (n = 18; 4.1 ng/mL). Furthermore, CSF sCR2 levels correlated significantly both with CSF C3 and C1q as well as to a disease severity measure. In vitro, sCR2 inhibited the cleavage and down regulation of C3b to iC3b, suggesting that it exerts a modulatory role in complement activation downstream of C3.

    These results propose a novel function for CR2/sCR2 in human neuroinflammatory conditions.

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