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Nilsson Ekdahl, Kristina
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Publications (10 of 107) Show all publications
Fromell, K., Yang, Y., Nilsson Ekdahl, K., Nilsson, B., Berglin, M. & Elwing, H. (2017). Absence of conformational change in complement factor 3 and factor XII adsorbed to acrylate polymers is related to a high degree of polymer backbone flexibility. Biointerphases, 12(2), Article ID 02D417.
Open this publication in new window or tab >>Absence of conformational change in complement factor 3 and factor XII adsorbed to acrylate polymers is related to a high degree of polymer backbone flexibility
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2017 (English)In: Biointerphases, ISSN 1934-8630, E-ISSN 1559-4106, Vol. 12, no 2, 02D417Article in journal (Refereed) Published
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.

National Category
Biophysics Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-329705 (URN)10.1116/1.4985698 (DOI)000404045100001 ()28637352 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602699Swedish Research Council
Available from: 2017-10-05 Created: 2017-10-05 Last updated: 2017-10-05Bibliographically approved
Ekdahl, K. N., Soveri, I., Hilborn, J., Fellström, B. & Nilsson, B. (2017). Cardiovascular disease in haemodialysis: role of the intravascular innate immune system.. Nature Reviews Nephrology, 13(5), 285-296.
Open this publication in new window or tab >>Cardiovascular disease in haemodialysis: role of the intravascular innate immune system.
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2017 (English)In: Nature Reviews Nephrology, ISSN 1759-5061, E-ISSN 1759-507X, Vol. 13, no 5, 285-296 p.Article, review/survey (Refereed) Published
Abstract [en]

Haemodialysis is a life-saving renal replacement modality for end-stage renal disease, but this therapy also represents a major challenge to the intravascular innate immune system, which is comprised of the complement, contact and coagulation systems. Chronic inflammation is strongly associated with cardiovascular disease (CVD) in patients on haemodialysis. Biomaterial-induced contact activation of proteins within the plasma cascade systems occurs during haemodialysis and initially leads to local generation of inflammatory mediators on the biomaterial surface. The inflammation is spread by soluble activation products and mediators that are generated during haemodialysis and transported in the extracorporeal circuit back into the patient together with activated leukocytes and platelets. The combined effect is activation of the endothelium of the cardiovascular system, which loses its anti-thrombotic and anti-inflammatory properties, leading to atherogenesis and arteriosclerosis. This concept suggests that maximum suppression of the intravascular innate immune system is needed to minimize the risk of CVD in patients on haemodialysis. A potential approach to achieve this goal is to treat patients with broad-specificity systemic drugs that target more than one of the intravascular cascade systems. Alternatively, 'stealth' biomaterials that cause minimal cascade system activation could be used in haemodialysis circuits.

National Category
Urology and Nephrology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-319742 (URN)10.1038/nrneph.2017.17 (DOI)000399003200005 ()28239169 (PubMedID)
Funder
Swedish Research Council, 2013-65X-05647-34-4EU, FP7, Seventh Framework Programme, 602699
Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2017-05-11Bibliographically approved
Teramura, Y., Asif, S., Ekdahl, K. N., Gustafson, E. & Nilsson, B. (2017). Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures. ACS Applied Materials and Interfaces, 9(1), 244-254.
Open this publication in new window or tab >>Cell Adhesion Induced Using Surface Modification with Cell-Penetrating Peptide-Conjugated Poly(ethylene glycol)-Lipid: A New Cell Glue for 3D Cell-Based Structures
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2017 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 9, no 1, 244-254 p.Article in journal (Refereed) Published
Abstract [en]

We synthesized a novel material, cell-penetrating peptide conjugated poly(ethylene glycol)-lipid (CPP-PEG-lipid), that can induce the adhesion of floating cells. Firm cell adhesion with spreading could be induced by cell surface modification with the CPP-PEG-lipids. Cell adhesion was induced by CPPs but not by any other cationic short peptides we tested. Here, we demonstrated adherence using the floating cell line CCRF-CEM as well as primary human T cells, B cells, erythrocytes, and hepatocytes. As compared to cells grown in suspension, adherent cells were more rapidly induced to attach to substrates with the cell-surface modification. The critical factor for attachment was localization of CPPs at the cell membrane by PEG-lipids with PEG > 20 kDa. These cationic CPPs on PEG chains were able to interact with substrate surfaces such as polystyrene (PS) surfaces, glass surfaces, and PS microfibers that are negatively charged, inducing firm cell adhesion and cell spreading. Also, as opposed to normal cationic peptides that interact strongly with cell membranes, CPPs were less interactive with the cell surfaces because of their cell-penetrating property, making them more available for adhering cells to the substrate surface. No effects on cell viability or cell proliferation were observed after the induction of cell adhesion. With this technique, cells could be easily immobilized onto PS microfibers, an important step in fabricating 3D cell-based structures. Cells immobilized onto 3D PS microfibers were alive, and human hepatocytes showed normal production of urea and albumin on the microfibers. This method is novel in inducing firm cell adhesion-via a one-step treatment.

Keyword
cell surface modification, poly(ethylene glycol)-conjugated phospholipid (PEG-lipid), cell-penetrating peptide (CPP), cell adhesion, 3D structure
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-316034 (URN)10.1021/acsami.6b14584 (DOI)000392037400031 ()27976850 (PubMedID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2017-11-29Bibliographically approved
Gustafson, E., Asif, S., Kozarcanin, H., Meurling, S., Ekdahl, K. N. & Nilsson, B. (2017). Control of IBMIR induced by fresh and cryopreserved hepatocytes by low molecular weight dextran sulfate. Cell Transplantation, 26(1), 71-81.
Open this publication in new window or tab >>Control of IBMIR induced by fresh and cryopreserved hepatocytes by low molecular weight dextran sulfate
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2017 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 1, 71-81 p.Article in journal (Refereed) Published
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.

Keyword
Innate immunity, IBMIR, Thromboinflammation, Hepatocyte transplantation, Low molecular weight dextran sulfate (LMW-DS)
National Category
Other Medical Sciences
Identifiers
urn:nbn:se:uu:diva-286868 (URN)10.3727/096368916X692609 (DOI)000392785000007 ()
Note

The manusripct of this article is part of the thesis Thromboinflammation: in a Model of Hepatocyte Transplantation http://uu.diva-portal.org/smash/record.jsf?pid=diva2:922111

Available from: 2016-04-22 Created: 2016-04-22 Last updated: 2017-11-30Bibliographically approved
Harboe, M., Johnson, C., Nymo, S., Ekholt, K., Schjalm, C., Lindstad, J. K., . . . Nilsson, P. H. (2017). Properdin binding to complement activating surfaces depends on initial C3b deposition. Proceedings of the National Academy of Sciences of the United States of America, 114(4), E534-E539.
Open this publication in new window or tab >>Properdin binding to complement activating surfaces depends on initial C3b deposition
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 4, E534-E539 p.Article in journal (Refereed) Published
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.

Keyword
complement, properdin, C3, myeloperoxidase, Neisseria meningitidis
National Category
Cell and Molecular Biology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-316023 (URN)10.1073/pnas.1612385114 (DOI)000392597000011 ()28069958 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602699
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-01-13Bibliographically approved
Mohlin, C., Sandholm, K., Nilsson Ekdahl, K. & Nilsson, B. (2017). The link between morphology and complement in ocular disease. Paper presented at 16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK. Molecular Immunology, 89, 84-99.
Open this publication in new window or tab >>The link between morphology and complement in ocular disease
2017 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, 84-99 p.Article in journal (Refereed) Published
Abstract [en]

The complement system is a vital component of the immune-priveliged human eye that is always active at a low-grade level, preventing harmful intraocular injuries caused by accumulation of turnover products and controlling pathogens to preserve eye homeostasis and vision. The complement system is a double-edged sword that is essential for protection but may also become harmful and contribute to eye pathology. Here, we review the evidence for the involvement of complement system dysregulation in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica, highlighting the relationship between morphogical changes and complement system protein expression and regulation in these diseases. The potential benefits of complement inhibition in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica are abundant, as are those of further research to improve our understanding of complement-mediated injury in these diseases.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2017
Keyword
Complement, Eye, Morphology, Age-related macular degeneration, Glaucoma, Uveitis, Neuromyelitis optica
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-335418 (URN)10.1016/j.molimm.2017.05.028 (DOI)000410014500010 ()28622910 (PubMedID)
Conference
16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 602699Medical Research Council of Southeast Sweden (FORSS)
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2017-12-06Bibliographically approved
Ekdahl, K. N., Huang, S., Nilsson, B. & Teramura, Y. (2016). Complement inhibition in biomaterial- and biosurface-induced thromboinflammation. Seminars in Immunology, 28(3), 268-277.
Open this publication in new window or tab >>Complement inhibition in biomaterial- and biosurface-induced thromboinflammation
2016 (English)In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 28, no 3, 268-277 p.Article in journal (Refereed) Published
Abstract [en]

Therapeutic medicine today includes a vast number of procedures involving the use of biomaterials, transplantation of therapeutic cells or cell clusters, as well as of solid organs. These treatment modalities are obviously of great benefit to the patient, but also present a great challenge to the innate immune system, since they involve direct exposure of non-biological materials, cells of non-hematological origin as well as endothelial cells, damaged by ischemia-perfusion in solid organs to proteins and cells in the blood. The result of such an exposure may be an inappropriate activation of the complement and contact/kallikrein systems, which produce mediators capable of triggering the platelets and PMNs and monocytes, which can ultimately result in thrombotic and inflammatory (i.e., a thrombo-inflammatory) response to the treatment modality. In this concept review, we give an overview of the mechanisms of recognition within the innate immunity system, with the aim to identify suitable points for intervention. Finally, we discuss emerging and promising techniques for surface modification of biomaterials and cells with specific inhibitors in order to diminish thromboinflammation and improve clinical outcome.

Keyword
Biomaterials, Coagulation, Complement, Inflammation, Platelets, Therapeutic medicine
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-289071 (URN)10.1016/j.smim.2016.04.006 (DOI)000381845600007 ()27211838 (PubMedID)
Funder
Swedish Research Council, 2013-65X-05647-34-4EU, FP7, Seventh Framework Programme, 602699
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2018-01-10Bibliographically approved
Lindblom, R., Aeinehband, S., Ström, M., Al Nimer, F., Sandholm, K., Khademi, M., . . . Ekdahl Nilsson, K. (2016). Complement Receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function. Clinical Immunology, 166, 89-95.
Open this publication in new window or tab >>Complement Receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function
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2016 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 166, 89-95 p.Article in journal (Refereed) Published
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 0 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 Cab 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.

Keyword
Complement Receptor 2; Complement system; Multiple sclerosis; Neurodegeneration; Neuroinflammation
National Category
Neurology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-285294 (URN)10.1016/j.clim.2016.04.003 (DOI)000378011500010 ()27085202 (PubMedID)
Funder
EU, European Research Council, LSHM-CT-2005-018637Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Ekdahl, K. N., Teramura, Y., Hamad, O. A., Asif, S., Duehrkop, C., Fromell, K., . . . Nilsson, B. (2016). Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunological Reviews, 274(1), 245-269.
Open this publication in new window or tab >>Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation
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2016 (English)In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 274, no 1, 245-269 p.Article, review/survey (Refereed) Published
Abstract [en]

Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.

Keyword
coagulation, complement system, contact activation, kallikrein system, innate immunity, platelets, thromboinflammation
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-313666 (URN)10.1111/imr.12471 (DOI)000387059600017 ()27782319 (PubMedID)
Funder
Swedish Research Council, 2013-65X-05647-34-4EU, FP7, Seventh Framework Programme, 602699The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2017-01-24 Created: 2017-01-23 Last updated: 2018-01-13Bibliographically approved
Duehrkop, C., Leneweit, G., Heyder, C., Fromell, K., Edwards, K., Ekdahl, K. N. & Nilsson, B. (2016). Development and characterization of an innovtive heparin coating to stabilize and protect liposomes against adverse immune reactions. Colloids and Surfaces B: Biointerfaces, 141, 576-583.
Open this publication in new window or tab >>Development and characterization of an innovtive heparin coating to stabilize and protect liposomes against adverse immune reactions
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2016 (English)In: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 141, 576-583 p.Article in journal (Refereed) Published
Abstract [en]

Liposomes have been recognized as excellent drug delivery systems, but when they come in direct contact with different blood components they may trigger an immediate activation of the innate immune system. The aim of the present study was to produce long-circulating, blood-compatible liposomes by developing a construct of liposomes covered by a novel unique heparin complex (CHC; 70 heparin molecules per complex) to avoid recognition by the innate immune system. Unilamellar, cationic liposomes were produced by hand extrusion through a 100-nm polycarbonate membrane. Coating of liposomes with the macromolecular CHC was accomplished by electrostatic interactions. Dynamic light scattering as well as QCM-D measurements were used to verify the electrostatic deposition of the negatively charged CHC to cationic liposomes. The CHC-coated liposomes did not aggregate when in contact with lepirudin anti coagulated plasma. Unlike previous attempts to coat liposomes with heparin, this technique produced freely moveable heparin strands sticking out from the liposome surface, which exposed AT binding sites reflecting the anticoagulant potentials of the liposomes. In experiments using lepirudin-anticoagulated plasma, CHC-coated liposomes, in contrast to non-coated control liposomes, did not activate the complement system, as evidenced by low C3a and sC5b-9 generation and reduced leakage from the liposomes. In conclusion, we show that liposomes can be successfully coated with the biopolymer CHC, resulting in biocompatible and stable liposomes that have significant application potential.

Keyword
Drug delivery system; Cationic liposomes; Surface coating; Novel heparin complex; Complement system
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-279417 (URN)10.1016/j.colsurfb.2016.02.014 (DOI)000374197700068 ()26897551 (PubMedID)
Funder
EU, European Research Council, 324275Swedish Research Council, 2013-65X-05647-34-4EU, European Research Council, 602699Swedish Cancer Society
Available from: 2016-03-01 Created: 2016-03-01 Last updated: 2017-11-30Bibliographically approved
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