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Publications (10 of 27) Show all publications
N.Ekdahl, K., Fromell, K., Mohlin, C., Teramura, Y. & Nilsson, B. (2019). A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity. Science and Technology of Advanced Materials, 20(1), 688-698
Open this publication in new window or tab >>A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity
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2019 (English)In: Science and Technology of Advanced Materials, ISSN 1468-6996, E-ISSN 1878-5514, Vol. 20, no 1, p. 688-698Article, review/survey (Refereed) Published
Abstract [en]

In this review article, we focus on activation of the soluble components of the innate immune system triggered by nonbiological compounds and stress variances in activation due to the difference in size between nanoparticles (NPs) and larger particles or bulk material of the same chemical and physical composition. We then discuss the impact of the so-called protein corona which is formed on the surface of NPs when they come in contact with blood or other body fluids. For example, NPs which bind inert proteins, proteins which are prone to activate the contact system (e.g., factor XII), which may lead to clotting and fibrin formation or the complement system (e.g., IgG or C3), which may result in inflammation and vascular damage. Furthermore, we describe a whole blood model which we have developed to monitor activation and interaction between different components of innate immunity: blood protein cascade systems, platelets, leukocytes, cytokine generation, which are induced by NPs. Finally, we describe our own studies on innate immunity system activation induced by three fundamentally different species of NPs (two types of engineered NPs and diesel NPs) as demonstrator of the utility of an initial determination of the composition of the protein corona formed on NPs exposed to ethylenediaminetetraacetic acid (EDTA) plasma and subsequent analysis in our whole blood model. [GRAPHICS] .

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Coagulation system, complement system, contact, kallikrein system, inflammation, innate immunity, nanoparticles, protein corona, screening, toxicity, whole blood model
National Category
Pharmacology and Toxicology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390411 (URN)10.1080/14686996.2019.1625721 (DOI)000472611100001 ()31275460 (PubMedID)
Funder
Swedish Research Council, 2016-20755-1Swedish Research Council, 2016-04519Swedish Research Council, 2018-04199
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-12-14Bibliographically approved
Nilsson Ekdahl, K., Mohlin, C., Adler, A., Åman, A., Manivel, V. A., Sandholm, K., . . . Nilsson, B. (2019). Is generation of C3(H2O) necessary for activation of the alternative pathway in real life?. Paper presented at 17th European Meeting on Complement in Human Disease (EMCHD), 14-17 September 2019, Madrid, SPAIN. Molecular Immunology, 114, 353-361
Open this publication in new window or tab >>Is generation of C3(H2O) necessary for activation of the alternative pathway in real life?
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2019 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, p. 353-361Article in journal (Refereed) Published
Abstract [en]

In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid-phase and cell-bound regulators resulting in a state of homeostasis. Generation of the “C3b-like” C3(H2O) has been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway despite thorough regulation at different surfaces.

During complement attack in pathological conditions and inflammation, large amounts of C3b are formed by the classical/lectin pathway (CP/LP) convertases. After the discovery of LP's recognition molecules and its tight interaction with the AP, it is increasingly likely that the AP acts in vivo mainly as a powerful amplification mechanism of complement activation that is triggered by previously generated C3b molecules initiated by the binding of specific recognition molecules.

Also in many pathological conditions caused by a dysregulated AP amplification loop such as paroxysmal nocturnal hemoglobulinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), C3b is available due to minute LP and CP activation and/or generated by non-complement proteases. Therefore, C3(H2O) generation in vivo may be less important for AP activation during specific attack or dysregulated homeostasis, but may be an important ligand for C3 receptors in cell-cell interactions and a source of C3 for the intracellular complement reservoir.

Keywords
Complement system, C3(H2O), Conformation, Analysis, Proteases, Alternative pathway
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-396739 (URN)10.1016/j.molimm.2019.07.032 (DOI)000490625600041 ()31446306 (PubMedID)
Conference
17th European Meeting on Complement in Human Disease (EMCHD), 14-17 September 2019, Madrid, SPAIN
Funder
Swedish Research Council, 2016-2075-5.1Swedish Research Council, 2016-04519German Research Foundation (DFG), CRC1149A01
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-12-14Bibliographically approved
Seisenbaeva, G. A., Fromell, K., Vinogradov, V. V., Terekhov, A. N., Pakhomov, A. V., Nilsson, B., . . . Kessler, V. G. (2018). Author Correction: Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins. Scientific Reports, 8, Article ID 4416.
Open this publication in new window or tab >>Author Correction: Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4416Article in journal (Other academic) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-352922 (URN)10.1038/s41598-018-22717-8 (DOI)000426827000001 ()29520072 (PubMedID)
Funder
Swedish Research Council, 2014-3938
Note

WoS title: "Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins (vol 7, 15448, 2017)".

Correction to: Scientific Reports, 2017, vol. 7, Article number: 15448.

DOI: 10.1038/s41598-017-15792-w

Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2018-06-08Bibliographically 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.

Keywords
Complement system, Proteases, Protease inhibitors, Trauma
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-350204 (URN)10.1007/s00281-017-0646-9 (DOI)000424058800008 ()28900700 (PubMedID)
Funder
German Research Foundation (DFG)Swedish Research Council, 2016-01060; 2016-04519EU, FP7, Seventh Framework Programme, 602699
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-12-14Bibliographically 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. alpha-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 alpha-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 alpha-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, 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
Keywords
α-Fe2O3, NPsContact/kallikrein system, Innate immunity
National Category
Immunology in the medical area Nano Technology
Identifiers
urn:nbn:se:uu:diva-343471 (URN)10.1016/j.nano.2017.12.008 (DOI)000429528900010 ()
Funder
Swedish Research Council, 2014-3938 2016-2075-5.1 2016-01060 2016-04519EU, FP7, Seventh Framework Programme, 602699AFA Insurance
Note

Joint and equal contribution to senior authorship by Kristina N. Ekdahl, Padideh Davoodpour and Bo Nilsson

Available from: 2018-02-27 Created: 2018-02-27 Last updated: 2019-12-14Bibliographically approved
Fromell, K., Johansson, U., Dührkop, C., Adler, A., Usterud, E., Hamad, O. A., . . . Nilsson, B. (2018). Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C3. Paper presented at 27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, New Mexico, USA.. Molecular Immunology, 102, 193-193
Open this publication in new window or tab >>Generation of an alternative pathway convertase by contact-activated C3 is dependent on the conformation of C3
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2018 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 193-193Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Complement C3
National Category
Immunology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-365114 (URN)10.1016/j.molimm.2018.06.167 (DOI)000445313600163 ()
Conference
27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, New Mexico, USA.
Available from: 2018-11-15 Created: 2018-11-15 Last updated: 2019-12-14Bibliographically approved
Knabl, L., Berktold, M., Hamad, O. A., Fromell, K., Chatterjee, S., Speth, C., . . . Orth-Holler, D. (2018). Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets. International Journal of Medical Microbiology, 308(7), 969-976
Open this publication in new window or tab >>Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets
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2018 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 308, no 7, p. 969-976Article in journal (Refereed) Published
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 microthrombi seems 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 (R) system. ROTEM (R) 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 (R) 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.

Keywords
Stx2a, Hemolytic uremic syndrome, Plasmatic coagulation, Antithrombin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-369763 (URN)10.1016/j.ijmm.2018.07.008 (DOI)000448628100027 ()30064820 (PubMedID)
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-12-14Bibliographically approved
Fromell, K., Dührkop, C., Kozarcanin, H., Johansson, U., Skjoedt, M.-O., Garred, P., . . . Nilsson, B. (2018). The lectin pathway of complement and the contact/kallikrein system are integrated. Paper presented at 27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, New Mexico, USA.. Molecular Immunology, 102, 151-152
Open this publication in new window or tab >>The lectin pathway of complement and the contact/kallikrein system are integrated
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2018 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 151-152Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2018
Keywords
Lectin pathway, Contact system, Clotting, Fibrin
National Category
Biochemistry and Molecular Biology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-365113 (URN)10.1016/j.molimm.2018.06.071 (DOI)000445313600067 ()
Conference
27th International Complement Workshop (ICW), SEP 16-20, 2018, Santa Fe, New Mexico, USA.
Available from: 2018-11-08 Created: 2018-11-08 Last updated: 2019-12-14Bibliographically 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.

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: 2019-12-14Bibliographically approved
Seisenbaeva, G. A., Fromell, K., Vinogradov, V. V., Terekhov, A. N., Pakhomov, A. V., Nilsson, B., . . . Kessler, V. G. (2017). Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins. Scientific Reports, 7, Article ID 15448.
Open this publication in new window or tab >>Dispersion of TiO2 nanoparticles improves burn wound healing and tissue regeneration through specific interaction with blood serum proteins
Show others...
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15448Article in journal (Refereed) Published
Abstract [en]

Burn wounds are one of the most important causes of mortality and especially morbidity around the world. Burn wound healing and skin tissue regeneration remain thus one of the most important challenges facing the mankind. In the present study we have addressed this challenge, applying a solution-stabilized dispersion TiO2 nanoparticles, hypothesizing that their ability to adsorb proteins will render them a strong capacity in inducing body fluid coagulation and create a protective hybrid material coating. The in vitro study of interaction between human blood and titania resulted at enhanced TiO2 concentrations in formation of rather dense gel composite materials and even at lower content revealed specific adsorption pattern initiating the cascade response, promising to facilitate the regrowth of the skin. The subsequent in vivo study of the healing of burn wounds in rats demonstrated formation of a strongly adherent crust of a nanocomposite, preventing infection and inflammation with quicker reduction of wound area compared to untreated control. The most important result in applying the TiO2 dispersion was the apparently improved regeneration of damaged tissues with appreciable decrease in scar formation and skin color anomalies.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-342390 (URN)10.1038/s41598-017-15792-w (DOI)000415023200009 ()29133853 (PubMedID)
Funder
Swedish Research Council, 2014-3938
Note

Correction in: Scientific Reports, 2018, vol. 8, article Number: 4416.

DOI: 10.1038/s41598-018-22717-8

Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2019-12-14Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8905-8791

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