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Nilsson Ekdahl, KristinaORCID iD iconorcid.org/0000-0001-7888-1571
Publications (10 of 204) Show all publications
Mohlin, C., Sandholm, K., Kvanta, A., Nilsson Ekdahl, K. & Johansson, K. (2018). A model to study complement involvement in experimental retinal degeneration.. Upsala Journal of Medical Sciences, 123(1), 28-42
Open this publication in new window or tab >>A model to study complement involvement in experimental retinal degeneration.
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2018 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 1, p. 28-42Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system.

METHOD AND MATERIALS: The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19).

RESULTS: Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture.

DISCUSSION: Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keyword
AMD, RPE, complement system, ocular diseases, retina
National Category
Immunology in the medical area
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-71489 (URN)10.1080/03009734.2018.1431744 (DOI)000428060300004 ()29436895 (PubMedID)
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-04-19Bibliographically approved
Huber-Lang, M., Nilsson Ekdahl, K., Wiegner, R., Fromell, K. & Nilsson, B. (2018). Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions. Seminars in Immunopathology, 40(1), 87-102
Open this publication in new window or tab >>Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions
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2018 (English)In: Seminars in Immunopathology, ISSN 1863-2297, E-ISSN 1863-2300, Vol. 40, no 1, p. 87-102Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer, 2018
Keyword
Complement system, Proteases, Protease inhibitors, Trauma
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-70933 (URN)10.1007/s00281-017-0646-9 (DOI)000424058800008 ()28900700 (PubMedID)
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-02-15Bibliographically approved
Nilsson Ekdahl, K., Davoodpour, P., Ekstrand-Hammarström, B., Fromell, K., Hamad, O. A., Hong, J., . . . Nilsson, B. (2018). Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles. Nanomedicine: Nanotechnology, Biology and Medicine, 14(3), 735-744
Open this publication in new window or tab >>Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles
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2018 (English)In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 14, no 3, p. 735-744Article in journal (Refereed) Published
Abstract [en]

Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikreinactivation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.

Place, publisher, year, edition, pages
Elsevier, 2018
Keyword
Contact/kallikrein system, Innate immunity, α-Fe(2)O(3) NPs
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-73041 (URN)10.1016/j.nano.2017.12.008 (DOI)29277639 (PubMedID)
Available from: 2018-04-19 Created: 2018-04-19 Last updated: 2018-04-19Bibliographically approved
van Griensven, M., Ricklin, D., Denk, S., Halbgebauer, R., Braun, C. K., Schultze, A., . . . Huber-Lang, M. (2018). Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock. Shock, February 14
Open this publication in new window or tab >>Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock
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2018 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. February 14Article in journal (Refereed) Epub ahead of print
Abstract [en]

Trauma-induced hemorrhagic shock (HS) plays a decisive role in the development of immune, coagulation, and organ dysfunction often resulting in a poor clinical outcome. Imbalanced complement activation is intricately associated with the molecular danger response and organ damage after HS. Thus, inhibition of the central complement component C3 as turnstile of both inflammation and coagulation is hypothesized as a rational strategy to improve the clinical course after HS.Applying intensive care conditions, anaesthetized, monitored, and protectively ventilated non-human primates (NHP; cynomolgus monkeys) received a pressure-controlled severe HS (60 min at MAP 30 mmHg) with subsequent volume resuscitation. Thirty min after HS, animals were randomly treated with either an analog of the C3 inhibitor compstatin (i.e., Cp40) in saline (n = 4) or with saline alone (n = 4). The observation period lasted 300 min after induction of HS.We observed improved kidney function in compstatin Cp40-treated animals after HS as determined by improved urine output, reduced damage markers and a tendency of less histopathological signs of acute kidney injury. Sham-treated animals revealed classical signs of mucosal edema, especially in the ileum and colon reflected by worsened microscopic intestinal injury scores. In contrast, Cp40-treated HS animals exhibited only minor signs of organ edema and significantly less intestinal damage. Furthermore, early systemic inflammation and coagulation dysfunction were both ameliorated by Cp40.The data suggest that therapeutic inhibition of C3 is capable to significantly improve immune, coagulation and organ function and to preserve organ-barrier integrity early after traumatic HS. C3-targeted complement inhibition may therefore reflect a promising therapeutic strategy in fighting fatal consequences of HS.

National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-73044 (URN)10.1097/SHK.0000000000001127 (DOI)29461464 (PubMedID)
Available from: 2018-04-19 Created: 2018-04-19 Last updated: 2018-05-11
Nilsson, B., Asif, S., Nilsson Ekdahl, K., Manell, E., Biglarnia, A., Jensen-Waern, M. & Teramura, Y. (2017). A protective role of complement regulators linked to a PEG phospholipid construct in reducing ischemic reperfusion injury in transplantation. Paper presented at 16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK. Molecular Immunology, 89, 208-208
Open this publication in new window or tab >>A protective role of complement regulators linked to a PEG phospholipid construct in reducing ischemic reperfusion injury in transplantation
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2017 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 208-208Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-68149 (URN)10.1016/j.molimm.2017.06.214 (DOI)000410014500195 ()
Conference
16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK
Available from: 2017-10-02 Created: 2017-10-02 Last updated: 2018-01-10Bibliographically approved
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, article id 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. (C) 2017 Author(s).

National Category
Biophysics
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-66908 (URN)10.1116/1.4985698 (DOI)000404045100001 ()
Available from: 2017-07-13 Created: 2017-07-13 Last updated: 2017-07-13Bibliographically approved
Nilsson Ekdahl, K., 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, p. 285-296Article, 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Immunology in the medical area
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-64189 (URN)10.1038/nrneph.2017.17 (DOI)000399003200005 ()28239169 (PubMedID)
Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2018-01-13Bibliographically approved
Teramura, Y., Asif, S., Nilsson Ekdahl, K., 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, p. 244-254Article 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
Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-60801 (URN)10.1021/acsami.6b14584 (DOI)000392037400031 ()
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2017-11-29Bibliographically approved
Denk, S., Neher, M. D., Messerer, D. A. C., Wiegner, R., Nilsson, B., Rittirsch, D., . . . Huber-Lang, M. S. (2017). Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects. Journal of Immunology, 198(12), 4846-4854
Open this publication in new window or tab >>Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects
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2017 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 198, no 12, p. 4846-4854Article in journal (Refereed) Published
Abstract [en]

During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.

National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-67105 (URN)10.4049/jimmunol.1700393 (DOI)000405271300030 ()28490576 (PubMedID)
Available from: 2017-07-28 Created: 2017-07-28 Last updated: 2017-07-28Bibliographically approved
Mohlin, C., Petrus-Reurer, S., Lanner, F., Sandholm, K., Kvanta, A., Nilsson, B. & Nilsson Ekdahl, K. (2017). Complement system proteins in human embryonic stem cell-derived retinal pigment epithelial cells co-cultured with or without porcine retina. Paper presented at 16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK. Molecular Immunology, 89, 162-163
Open this publication in new window or tab >>Complement system proteins in human embryonic stem cell-derived retinal pigment epithelial cells co-cultured with or without porcine retina
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2017 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 162-163Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology
Research subject
Biomedical Sciences, Immunology
Identifiers
urn:nbn:se:lnu:diva-68148 (URN)10.1016/j.molimm.2017.06.132 (DOI)000410014500107 ()
Conference
16th European Meeting on Complement in Human Disease (EMCHD), SEP 08-12, 2017, Copenhagen, DENMARK
Available from: 2017-10-02 Created: 2017-10-02 Last updated: 2017-10-02Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-7888-1571

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