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  • 51.
    Mohlin, Camilla
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    The link between morphology and complement in ocular disease2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 84-99Article, review/survey (Refereed)
    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.

  • 52.
    Moll, Guido
    et al.
    Karolinska Institutet;Karolinska University Hospital Huddinge.
    Alm, Jessica J.
    Karolinska University Hospital Huddinge.
    Davies, Lindsay C.
    Cardiff University, UK.
    von Bahr, Lena
    Karolinska University Hospital Huddinge.
    Heldring, Nina
    Karolinska University Hospital Huddinge.
    Stenbeck-Funke, Lillemor
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Hinsch, Robin
    Karolinska University Hospital Huddinge.
    Ignatowicz, Lech
    Locke, Matthew
    Cardiff University, UK.
    Lönnies, Helena
    Karolinska Institutet;Karolinska University Hospital Huddinge.
    Lambris, John D.
    University of Pennsylvania School of Medicine, USA.
    Teramura, Yuji
    Uppsala University;The University of Tokyo, Japan.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Le Blanc, Katarina
    Karolinska Institutet;Karolinska University Hospital Huddinge.
    Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?2014In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 32, no 9, p. 2430-2442Article in journal (Refereed)
    Abstract [en]

    We have recently reported that therapeutic mesenchymal stromal cells (MSCs) have low engraftment and trigger the instant blood mediated inflammatory reaction (IBMIR) after systemic delivery to patients, resulting in compromised cell function. In order to optimize the product, we compared the immunomodulatory, blood regulatory, and therapeutic properties of freeze-thawed and freshly harvested cells. We found that freeze-thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties. Freeze-thawed MSCs demonstrated reduced responsiveness to proinflammatory stimuli, an impaired production of anti-inflammatory mediators, increased triggering of the IBMIR, and a strong activation of the complement cascade compared to fresh cells. This resulted in twice the efficiency in lysis of thawed MSCs after 1 hour of serum exposure. We found a 50% and 80% reduction in viable cells with freshly detached as opposed to thawed in vitro cells, indicating a small benefit for fresh cells. In evaluation of clinical response, we report a trend that fresh cells, and cells of low passage, demonstrate improved clinical outcome. Patients treated with freshly harvested cells in low passage had a 100% response rate, twice the response rate of 50% observed in a comparable group of patients treated with freeze-thawed cells at higher passage. We conclude that cryobanked MSCs have reduced immunomodulatory and blood regulatory properties directly after thawing, resulting in faster complement-mediated elimination after blood exposure. These changes seem to be paired by differences in therapeutic efficacy in treatment of immune ailments after hematopoietic stem cell transplantation. Stem Cells 2014;32:2430–2442

  • 53.
    Mollnes, T.
    et al.
    University of Oslo, Norway.
    Baratt-Due, A.
    University of Oslo, Norway.
    Pischke, S.
    Oslo University Hospital, Norway.
    Sandanger, I.
    Oslo University Hospital, Norway.
    Nilsson, Per H.
    University of Oslo, Norway.
    Lambris, J.
    University of Philadelphia, USA.
    Nunn, M.
    Centre for Ecology and Hydrology, Oxford, UK.
    Denk, S.
    University of Ulm, Germany.
    Espevik, T.
    Norwegian University of Science and Technology, Norway.
    Huber-Lang, M.
    University of Ulm, Germany.
    Double-blockade of CD14 and complement component C5 abolish the inflammatory storm and improve survival in mouse polymicrobial sepsis2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3, p. 294-294Article in journal (Refereed)
  • 54.
    Mollnes, Tom E
    et al.
    University of Oslo, Rikshospitalet, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Rikshospitalet, Norway.
    Letter to the Editor.2013In: Journal of clinical biochemistry and nutrition, ISSN 0912-0009, E-ISSN 1880-5086, Vol. 52, no 3, p. 253-254Article in journal (Refereed)
  • 55.
    Nilsson, Bo
    et al.
    Uppsala University.
    Asif, Sana
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Manell, Elin
    Swedish University of Agricultural Sciences.
    Biglarnia, Alireza
    Skåne University Hospital.
    Jensen-Waern, Marianne
    Swedish University of Agricultural Sciences.
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    A protective role of complement regulators linked to a PEG phospholipid construct in reducing ischemic reperfusion injury in transplantation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 208-208Article in journal (Other academic)
  • 56.
    Nilsson, Bo
    et al.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Complement Diagnostics: Concepts, Indications, and Practical Guidelines2012In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, article id 962702Article, review/survey (Refereed)
    Abstract [en]

    Aberrations in the complement system have been shown to be direct or indirect pathophysiological mechanisms in a number of diseases and pathological conditions such as autoimmune disease, infections, cancer, allogeneic and xenogeneic transplantation, and inflammation. Complement analyses have been performed on these conditions in both prospective and retrospective studies and significant differences have been found between groups of patients, but in many diseases, it has not been possible to make predictions for individual patients because of the lack of sensitivity and specificity of many of the assays used. The basic indications for serological diagnostic complement analysis today may be divided into three major categories: (a) acquired and inherited complement deficiencies; (b) disorders with complement activation; (c) inherited and acquired C1INH deficiencies. Here, we summarize indications, techniques, and interpretations for basic complement analyses and present an algorithm, which we follow in our routine laboratory.

  • 57. Nilsson, Bo
    et al.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Components of the alternative pathway1998In: The complement system / [ed] Klaus Rother, Gerd O Till, Gertrud Maria Hänsch, Springer, 1998, 2, p. 23-49Chapter in book (Refereed)
    Abstract [en]

    Its key role in life preserving functions such as host defense against infections or inflammatory reactions has put the serum complement system at the forefront of biomedical research in both the laboratory and the clinic. This book describes the basic regulation of the complement systems, presenting its biological functions, the target cell receptors for such functions and their interactions with ligands to induce specific cellular responses. The biological functions are also discussed in the context of more complex conditions, for example in host defense, chronic inflammatory disease, graft rejection as well as in adverse reactions to drugs or to artificial surfaces. The book offers the present state-of-the-art compiled by leading experts in the field. Extensive literature citations offer easy access to those interested in more detail.

  • 58. Nilsson, Bo
    et al.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    The tick-over theory revisited: Is C3 a contact-activated protein?2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1106-1110Article, review/survey (Refereed)
    Abstract [en]

    The tick-over theory was first introduced in the 1970s to explain the presence of the initial C3b molecules, which are able to trigger complement activation by the alternative pathway in human plasma under physiological conditions. After the identification of the thioester, the predominant hypothesis has been that this bond is hydrolyzed at a slow but constant rate by nucleophilic attack by H2O, leading to the generation of C3(H2O). Here we put forward the hypothesis that the rate of hydrolysis of C3 to C3(H2O) may be greatly accelerated by the interaction between C3 and a number of biological and artificial interfaces, including gas bubbles, biomaterial surfaces and different lipid surfaces and complexes. We therefore propose that C3 should preferentially be regarded as a contact activated protein rather than a target for passive, random hydrolysis in the fluid phase. (C) 2012 Elsevier GmbH. All rights reserved.

  • 59.
    Nilsson, Bo
    et al.
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Korsgren, Olle
    Uppsala University.
    Control of IBMIR (Instant Blood-Mediated Inflammatory Reaction) to improve islets of Langerhans engraftement2011In: Current Opinion in Organ Transplantation, ISSN 1087-2418, E-ISSN 1531-7013, Vol. 16, no 6, p. 620-626Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review Transplantation of islets of Langerhans is an emerging treatment procedure for patients with severe type 1 diabetes, but despite recent progress the procedure is associated with massive tissue loss caused by an inflammatory reaction termed instant blood-mediated inflammatory reaction (IBMIR). This reactioninvolves activation of the complement and coagulation cascades, ultimately resulting in clot formation and infiltration of leukocytes into the islets, which leadsto disruption of islet integrity and islet destruction. Recent findings In this review we discuss basic mechanisms underlying the IBMIR and emerging strategies for therapeutic regulation of the IBMIR. These include the use ofselective inhibitors of the coagulation and complement systems, different procedures to coat the surface of the islets as well as the development ofcomposite islet-endothelial cell grafts. Summary The IBMIR is a major cause of tissue loss in clinical islet transplantation, and most likely in other cell therapies in which cells are exposed to blood. Thus, it is an obvious target for therapeutic intervention. Due to its complexity, it is necessary to use different strategies to control the IBMIR.

  • 60.
    Nilsson, Bo
    et al.
    Uppsala University.
    Teramura, Yuji
    Uppsala University;University of Tokyo.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 185-190Article, review/survey (Refereed)
    Abstract [en]

    Cell therapies in which the cells come into direct contact with blood and other body fluids are emerging treatment procedures for patients with various diseases, such as diabetes mellitus, liver insufficiency, and graft-versus-host disease. However, despite recent progress, these procedures are associated with tissue loss caused by thromboinflammatory reactions. These deleterious reactions involve the activation of the complement and coagulation cascades and platelet and leukocyte activation, ultimately resulting in clot formation and damage to the implanted cells. In this concept review, we discuss the basic mechanisms underlying the thrombininflammatory process, with special reference to the engagement of complement and emerging strategies for the therapeutic regulation of these reactions that include the use of selective systemic inhibitors and various procedures to coat the surfaces of the cells. The coating procedures may also be applied to other treatment modalities in which similar mechanisms are involved, including whole organ transplantation, treatment with biomaterials in contact with blood, and extracorporeal procedures. (C) 2014 Published by Elsevier Ltd.

  • 61.
    Nilsson Ekdahl, Kristina
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Blomberg, Carolina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Henningsson Johnsson, Anna
    Dahle, Charlotte
    Håkansson, Irene
    Sandholm, Kerstin
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Ernerudh, Jan
    Systemic and Intrathecal Complement Activation in Multiple Sclerosis and Guillan-Barré Syndrome2009In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 46, no 14, p. 2848-2848Article in journal (Refereed)
  • 62.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Davoodpour, Padideh
    Uppsala University.
    Ekstrand-Hammarström, Barbro
    Swedish Defence Research Agency, Umeå.
    Fromell, Karin
    Uppsala University.
    Hamad, Osama A
    Uppsala University.
    Hong, Jaan
    Uppsala University.
    Bucht, Anders
    Swedish Defence Research Agency, Umeå;Umeå University.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Seisenbaeva, Gulaim A
    Swedish University of Agricultural Sciences (SLU).
    Kessler, Vadim G
    Swedish University of Agricultural Sciences (SLU).
    Nilsson, Bo
    Uppsala University.
    Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles2018In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 14, no 3, p. 735-744Article in journal (Refereed)
    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.

  • 63.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Hilborn, Jöns
    Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    The innate immune response: A key factor in biocompatibility2017In: Bioresorbable Polymers for Biomedical Applications: From Fundamentals to Translational Medicine / [ed] Giuseppe Perale, Jöns Hilborn, Elsevier, 2017, p. 85-94Chapter in book (Refereed)
    Abstract [en]

    The immune system guards the body against alien substances such as microorganisms and rids the body of wastes. It also responds to a variety of medical therapeutic modalities, such as the transplantation of cells or whole organs or treatment with biomaterials. This chapter highlights the innate immune reactions that are triggered by biomaterial surfaces when they come into contact with human body fluids and tissues.

  • 64.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university, Sweden.
    Fromell, Karin
    Uppsala university, Sweden.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Teramura, Yuji
    Uppsala university, Sweden;Univ Tokyo, Japan.
    Nilsson, Bo
    Uppsala university, Sweden.
    A human whole-blood model to study the activation of innate immunity system triggered by nanoparticles as a demonstrator for toxicity2019In: Science and Technology of Advanced Materials, ISSN 1468-6996, E-ISSN 1878-5514, Vol. 20, no 1, p. 688-698Article, review/survey (Refereed)
    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] .

  • 65.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lambris, JD
    Elwing, H
    Ricklin, D
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Teramura, Y
    Nicholls, Ian A.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Innate immunity activation on biomaterial surfaces: A mechanistic model and coping strategies2011In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 63, no 12, p. 1042-1050Article, review/survey (Refereed)
    Abstract [en]

    When an artificial biomaterial (e.g., a stent or implantable pump) is exposed to blood, plasma proteins immediately adhere to the surface, creating a new interface between the biomaterial and the blood. The recognition proteins within the complement and contact activation/coagulation cascade systems of the blood will be bound to, or inserted into, this protein film and generate different mediators that will activate polymorphonuclear leukocytes and monocytes, as well as platelets. Under clinical conditions, the ultimate outcome of these processes may be thrombotic and inflammatory reactions, and consequently the composition and conformation of the proteins in the initial layer formed on the surface will to a large extent determine the outcome of a treatment involving the biomaterial, affecting both the functionality of the material and the patient's life quality. This review presents models of biomaterial-induced activation processes and describes various strategies to attenuate potential adverse reactions by conjugating bioactive molecules to surfaces or by introducing nanostructures.

  • 66.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university, Sweden.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Adler, Anna
    Uppsala university, Sweden.
    Aman, Amanda
    Uppsala university, Sweden.
    Manivel, Vivek Anand
    Uppsala university, Sweden.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Fromell, Karin
    Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Is generation of C-3(H2O) necessary for activation of the alternative pathway in real life?2019In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, p. 353-361Article in journal (Refereed)
    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.

  • 67.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Hemodialys, inflammation och det naturliga immunsystemet2018In: Vaskulär Medicin, ISSN 2000-3188, Vol. 34, no 3, p. 17-21Article, review/survey (Other academic)
    Abstract [sv]

    Hemodialys är en livräddande behandling vid kronisk njursvikt, men dialyspatienter har också en kraftigt ökad risk för kardiovaskulär sjukdom. Dialys utgör en enorm utmaning för kroppens naturliga immunsystem (”innate immunity”) eftersom patientens blod under behandlingen kommer i direkt kontakt med kroppsfrämmande ytor såsom i membran, slangar, och pumpar mm. Då sker aktivering av blodets olika protein-system: främst komplementsystemet, kontakt/kallikreinsystemet och koagulationsystemet, vilket initialt leder till en lokal inflammation i anslutning till materialytan i dialyskretsen, men också generering av inflammatoriska mediatorer, till exempel anafylatoxiner och bradykinin. Dessa substanser transporteras sedan med blodet till patienten tillsammans med aktiverade leukocyter och trombocyter som aktiverar endotelet i patientens kardiovaskulära system, som då kan förlora sina normala anti-inflammatoriska och anti-trombotiska funktioner. Sammantaget resulterar detta i en kronisk inflammation som kan leda till atherogenes och arterioskleros. Möjliga strategier att dämpa dessa reaktioner inkluderar val av antikoagulantia med högre specificitet än de typer av heparin som används idag, samt ytmodifiering av de material som ingår i dialyskretsen.

  • 68.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Persson, Barbro
    Uppsala University.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Interpretation of Serological Complement Biomarkers in Disease2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2237Article, review/survey (Refereed)
    Abstract [en]

    Complement systemaberrations have been identified as pathophysiological mechanisms in a number of diseases and pathological conditions either directly or indirectly. Examples of such conditions include infections, inflammation, autoimmune disease, as well as allogeneic and xenogenic transplantation. Both prospective and retrospective studies have demonstrated significant complement-related differences between patient groups and controls. However, due to the low degree of specificity and sensitivity of some of the assays used, it is not always possible to make predictions regarding the complement status of individual patients. Today, there are three main indications for determination of a patient's complement status: (1) complement deficiencies (acquired or inherited); (2) disorders with aberrant complement activation; and (3) C1 inhibitor deficiencies (acquired or inherited). An additional indication is to monitor patients on complement-regulating drugs, an indication which may be expected to increase in the near future since there is now a number of such drugs either under development, already in clinical trials or in clinical use. Available techniques to study complement include quantification of: (1) individual components; (2) activation products, (3) function, and (4) autoantibodies to complement proteins. In this review, we summarize the appropriate indications, techniques, and interpretations of basic serological complement analyses, exemplified by a number of clinical disorders.

  • 69.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala university.
    Teramura, Yuji
    Univ Tokyo, Japan.
    Asif, Sana
    Uppsala university.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Magnusson, Peetra
    Uppsala university.
    Nilsson, Bo
    Uppsala university.
    Thromboinflammation in therapeutic medicine2015In: Immune Responses to Biosurfaces / [ed] Lambris J., Ekdahl K., Ricklin D., Nilsson B., Springer, 2015, Vol. 865, p. 3-17Conference paper (Refereed)
    Abstract [en]

    Thromboinflammation is primarily triggered by the humoral innate immune system, which mainly consists of the cascade systems of the blood, i.e., the complement, contact/coagulation and fibrinolytic systems. Activation of these systems subsequently induces activation of endothelial cells, leukocytes and platelets, finally resulting in thrombotic and inflammatory reactions. Such reactions are triggered by a number of medical procedures, e.g., treatment with biomaterials or drug delivery devices as well as in transplantation with cells, cell clusters or whole vascularized organs. Here, we (1) describe basic mechanisms for thromboinflammation; (2) review thromboinflammatory reactions in therapeutic medicine; and (3) discuss emerging strategies to dampen thromboinflammation.

  • 70.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Teramura, Yuji
    Uppsala University;Univ Tokyo, Japan.
    Asir, Sana
    Uppsala University.
    Manell, Elin
    Swedish University of Agricultural Sciences.
    Biglarnia, Alireza
    Skåne Univ Hosp.
    Jensen-Waern, Marianne
    Swedish University of Agricultural Sciences.
    Nilsson, Bo
    Uppsala University.
    Protective role of PEG conjugated phospholipid in reducing ischemic reperfusion injury in two allogeneic pig kidney transplant models2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1184-1184Article in journal (Other academic)
  • 71.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Interactions between platelets and complement with implications for the regulation at surfaces2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Disturbances of host integrity have the potential to evoke activation of innate immunologic and hemostatic protection mechanisms in blood. Irrespective of whether the activating stimulus is typically immunogenic or thrombotic, it will generally affect both the complement system and platelets to a certain degree. The theme of this thesis is complement and platelet activity, which is intersected in all five included papers. The initial aim was to study the responses and mechanisms of the complement cascade in relation to platelet activation. The secondary aim was to use an applied approach to regulate platelets and complement on model biomaterial and cell surfaces.   

    Complement activation was found in the fluid phase in response to platelet activation in whole blood. The mechanism was traced to platelet release of stored chondroitin sulfate-A (CS-A) and classical pathway activation via C1q. C3 was detected at the platelet surface, though its binding was independent of complement activation. The inhibitors factor H and C4-binding protein (C4BP) were detected on activated platelets, and their binding was partly dependent on surface-exposed CS-A. Collectively, these results showed that platelet activation induces inflammatory complement activation in the fluid phase. CS-A was shown to be a central molecule in the complement-modulatory functions of platelets by its interaction with C1q, C4BP, and factor H.

    Platelet activation and surface adherence were successfully attenuated by conjugating an ADP-degrading apyrase on a model biomaterial. Only minor complement regulation was seen, and was therefore targeted specifically on surfaces and cells by co-immobilizing a factor H-binding peptide together with the apyrase. This combined approach led to a synchronized inhibition of both platelet and complement activation at the interface of biomaterials/xenogeneic cells and blood.

    In conclusion, here presents a novel crosstalk-mechanism for activation of complement when triggering platelets, which highlights the importance of regulating both complement and platelets to lower inflammatory events. In addition, a strategy to enhance the biocompatibility of biomaterials and cells by simultaneously targeting ADP-dependent platelet activation and the alternative complement C3-convertase is proposed.

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  • 72.
    Nilsson, Per H.
    et al.
    University of Oslo, Rikshospitalet, Norway.
    Berg, A.
    e, Stavanger University Hospital, Norway ; Hospital of Maputo, Mozambique ; University of Bergen, Norway.
    Otterdal, K.
    University of Oslo, Rikshospitalet, Norway.
    Patel, S.
    Hospital of Maputo, Mozambique.
    Gonca, M.
    Hospital of Maputo, Mozambique.
    David, C.
    Hospital of Maputo, Mozambique.
    Dalen, I.
    Stavanger University Hospital, , Norway.
    Nymo, S.
    University of Oslo, Rikshospitalet, Norway ; Research Laboratory Nordland Hospital, Norway ; University of Tromsø, Norway.
    Nilsson, M.
    University of Oslo, Rikshospitalet, Norway.
    Ueland, T.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Prato, M.
    University of Torino Medical School, Italy.
    Giribaldi, G.
    University of Torino Medical School, Italy.
    Aukrust, P.
    University of Oslo, Rikshospitalet, Norway.
    Langeland, N.
    University of Bergen, Norway.
    Mollnes, T. E.
    University of Oslo, Rikshospitalet, Norway.
    Complement-dependent inflammatory response Plasmodium-derived hemozoin in malaria2014In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, no 2, p. 230-230Article in journal (Refereed)
  • 73.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Johnson, Christina
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Fure, Hilde
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Landsem, Anne
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Haugaard-Kedström, Linda M.
    Univ Copenhagen, Denmark.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Brekke, Ole-Lars
    Nordland Hosp, Norway;Univ Tromso, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Characterization of a novel whole blood model for the study of thrombin in complement activation and inflammation2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 136-137Article in journal (Other academic)
  • 74.
    Nilsson, Per H.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Thomas, Anub Mathew
    Oslo Univ Hosp, Norway.
    Bergseth, Grethe
    Nordland Hosp, Norway.
    Gustavsen, Alice
    Oslo Univ Hosp, Norway.
    Volokhina, Elena B.
    Radboud Univ Nijmegen, Netherlands;Radboud Univ Nijmegen, Netherlands.
    van den Heuvel, Lambertus P.
    Radboud Univ Nijmegen, Netherlands;Univ Hosp Leuven, Belgium.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway.
    Mollnes, Tom E.
    Oslo Univ Hosp, Rikshosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, p. 111-114Article in journal (Refereed)
    Abstract [en]

    The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.

  • 75.
    Orrem, Hilde L.
    et al.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Natl Hosp Norway, Norway;Univ Oslo, Norway;Univ Oslo, Norway.
    Pischke, Soren E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Kleveland, Ola
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Yndestad, Arne
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Ekholt, Karin
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Damas, Jan K.
    Norwegian Univ Sci & Technol, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Bendz, Bjorn
    Natl Hosp Norway, Norway.
    Halvorsen, Bente
    Univ Oslo, Norway;Natl Hosp Norway, Norway.
    Gregersen, Ida
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Wiseth, Rune
    St Olavs Hosp, Norway;Norwegian Univ Sci & Technol, Norway.
    Andersen, Geir O.
    Oslo Univ Hosp, Norway.
    Ueland, Thor
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Gullestad, Lars
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Natl Hosp Norway, Norway.
    Aukrust, Pal
    Univ Oslo, Norway;Natl Hosp Norway, Norway;Oslo Univ Hosp, Norway.
    Barratt-Due, Andreas
    Natl Hosp Norway, Norway;Univ Oslo, Norway.
    Mollnes, Tom E.
    Natl Hosp Norway, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway;Univ Tromso, Norway.
    IL-6 Receptor Inhibition by Tocilizumab Attenuated Expression of C5a Receptor 1 and 2 in Non-ST-Elevation Myocardial Infarction2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2035Article in journal (Refereed)
    Abstract [en]

    Background: Elevated interleukin-6 (IL-6) and complement activation are associated with detrimental effects of inflammation in coronary artery disease (CAD). The complement anaphylatoxins C5a and C3a interact with their receptors; the highly inflammatory C5aR1, and the C5aR2 and C3aR. We evaluated the effect of the IL-6 receptor (IL-6R)-antagonist tocilizumab on the expression of the anaphylatoxin receptors in whole blood from non-ST-elevation myocardial infarction (NSTEMI) patients. Separately, anaphylatoxin receptor expression in peripheral blood mononuclear cells (PBMC) from patients with different entities of CAD was investigated. Materials and Methods: NSTEMI patients were randomized to one dose of tocilizumab (n = 28) or placebo (n = 32) and observed for 6 months. Whole blood samples drawn at inclusion, at day 2, 3 and after 6 months were used for mRNA isolation. Plasma was prepared for analysis of complement activation measured as sC5b-9 by ELISA. Furthermore, patients with different CAD entities comprising stable angina pectoris (SAP, n = 22), non-ST-elevation acute coronary syndrome (NSTE-ACS, n = 21) and ST-elevation myocardial infarction (STEMI, n = 20) were included. PBMC was isolated from blood samples obtained at admission to hospital and mRNA isolated. Anaphylatoxin-receptor-expression was analyzed with qPCR using mRNA from whole blood and PBMC, respectively. Results: Our main findings were (i) Tocilizumab decreased C5aR1 and C5aR2 mRNA expression significantly (p < 0.001) and substantially (> 50%) at day 2 and 3, whereas C3aR expression was unaffected. (ii) Tocilizumab did not affect complement activation. (iii) In analyzes of different CAD entities, C5aR1 expression was significantly increased in all CAD subgroups compared to controls with the highest level in the STEMI patients (p < 0.001). For C5aR2 and C3aR the expression compared to controls were more moderate with increased expression of C5aR2 in the STEMI group (p < 0.05) and C3aR in the NSTE-ACS group (p < 0.05). Conclusion: Expression of C5aR1 and C5aR2 in whole blood was significantly attenuated by IL-6R-inhibition in NSTEMI patients. These receptors were significantly upregulated in PBMC CAD patients with particularly high levels of C5aR1 in STEMI patients.

  • 76.
    Ricklin, Daniel
    et al.
    Univ Penn, USA.
    Sfyroera, Georgia
    Univ Penn, USA.
    Reis, Edimara
    Univ Penn, USA.
    Chen, Hui
    Univ Penn, USA.
    Wu, Emilia
    Univ Minnesota, USA.
    Kaznessis, Yiannis
    Univ Minnesota, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Lambris, John D.
    Univ Penn, USA.
    Rare loss-of-function mutation in C3 provides insight into molecular and pathophysiological determinants of alternative pathway activity2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 174-174Article in journal (Other academic)
  • 77.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Carlsson, Hanna
    Linköping University, Sweden;Region Kalmar county, Sweden.
    Persson, Barbro
    Uppsala University, Sweden.
    Skattum, Lillemor
    Lund University, Sweden.
    Tjernberg, Ivar
    Linköping University, Sweden;Region Kalmar county, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Discrepancies in plasma levels of complement components measured by a newly introduced commercially available magnetic bead technique compared to presently available clinical reference intervals2020In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 91, no 2, p. 1-3, article id e12831Article in journal (Refereed)
  • 78.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Henningsson, Anna J.
    Bergstrom, Sven
    Ernerudh, Jan
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Complement activation and phagocytosis in vitro of two strains of Borrelia burgdorferi S.L2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1153-1153Article in journal (Other academic)
  • 79.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Henningsson, Anna J.
    Linköping University.
    Säve, Susanne
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bergström, Sven
    Umeå University.
    Forsberg, Pia
    Linköping University.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ernerudh, Jan
    Linköping University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Early Cytokine Release in Response to Live Borrelia burgdorferi Sensu Lato Spirochetes Is Largely Complement Independent2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108013-Article in journal (Refereed)
    Abstract [en]

    Aim: Here we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78, which is resistant to complement-mediated lysis, and Borrelia garinii LU59, which is complement-sensitive. Methods: Borrelia spirochetes were incubated in hirudin plasma, or hirudin-anticoagulated whole blood. Complement activation was measured as the generation of C3a and sC5b-9. Binding of the complement components C3, factor H, C4, and C4BP to the bacterial surfaces was analyzed. The importance of complement activation on phagocytosis, and on the release of cytokines and chemokines, was investigated using inhibitors acting at different levels of the complement cascade. Results: 1) Borrelia garinii LU59 induced significantly higher complement activation than did Borrelia afzelii K78. 2) Borrelia afzelii K78 recruited higher amounts of factor H resulting in significantly lower C3 binding. 3) Both Borrelia strains were efficiently phagocytized by granulocytes and monocytes, with substantial inhibition by complement blockade at the levels of C3 and C5. 4) The release of the pro-inflammatory cytokines and chemokines IL-1 beta, IL-6, TNF, CCL20, and CXCL8, together with the anti-inflammatory IL-10, were increased the most (by>10-fold after exposure to Borrelia). 5) Both strains induced a similar release of cytokines and chemokines, which in contrast to the phagocytosis, was almost totally unaffected by complement blockade. Conclusions: Our results show that complement activation plays an important role in the process of phagocytosis but not in the subsequent cytokine release in response to live Borrelia spirochetes.

  • 80.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Persson, Barbro
    Uppsala University.
    Skattum, Lillemor
    Lund University.
    Eggertsen, Gösta
    Karolinska Institutet;Karolinska University Hospital.
    Nyman, Dag
    Aland Cent Hosp, Finland.
    Gunnarsson, Iva
    Karolinska Institutet;Karolinska University Hospital.
    Svenungson, Elisabet
    Karolinska Institutet;Karolinska University Hospital.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Evaluation of a Novel Immunoassay for Quantification of C1q for Clinical Diagnostic Use2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 7Article in journal (Refereed)
    Abstract [en]

    Objectives: C1q is a valuable biomarker of disease activity in systemic lupus erythematosus (SLE). The "gold standard" assay, rocket immunoelectrophoresis (RIE), is time-consuming, and thus a shift to soluble immune precipitation techniques such as nephelometry has occurred. However, quantification of C1q with these techniques has been questioned as a result of the antibody binding properties of C1q. In the present work, we have compared results using various techniques (RIE, nephelometry, and ELISA) and have developed and validated a new magnetic bead-based sandwich immunoassay (MBSI). Methods: C1q was quantified by nephelometry and the new sandwich immunoassay in 45 serum samples analyzed using RIE. C1q was also assessed in plasma using RIE and sandwich immunoassay in samples from SLE patients with nephritis (n = 69), SLE patients without nephritis (n = 310) as classified by BILAG score, and matched controls (n = 322). In addition, cerebrospinal fluid (CSF) samples from 31 patients, previously analyzed with ELISA, were also analyzed with the MBSI to test the behavior of this new assay in the lower detection range. Results: We found a strong correlation between the new MBSI, RIE, and ELISA, but not with nephelometry. The MBSI demonstrated lower levels of C1q in SLE patients than in matched controls (p < 0.0001), and patients with nephritis had lower levels than patients without nephritis (p < 0.01). Similarily, RIE showed significant differences between the patient groups (p < 0.0001). An association was also found between the levels of C1q and the SLE disease activity index (SLEDAI). Furthermore, there was good correlation between the values obtained by MBSI and ELISA, in both serum (r = 0.960) and CSF (r = 0.786), underscoring the ability of both techniques to measure low concentrations of C1q with high accuracy. Conclusion: The sandwich immunoassay correlated well with RIE, but soluble immune precipitation techniques, such as nephelometry, did not appear suitable alternatives, since C1q itself, and possibly anti-C1q antibodies, interfered with the measurements. The new sandwich immunoassay is therefore a good replacement for RIE in monitoring SLE disease activity.

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  • 81.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Wijkstrom, Elisabeth
    University Hospital, Uppsala.
    Skattum, Lillemor
    Lund University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Validations of assays for the evaluation of C1q in inflammatory diseases and thromboinflammation2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 176-177Article in journal (Other academic)
  • 82. Sartz, Lisa
    et al.
    Olin, Anders
    Kristoffersson, AC
    Ståhl, AL
    Johansson, ME
    Westman, K
    Fremeaux-Bacchi, V
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karpman, Diana
    A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome.2012In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 188, no 4, p. 2030-2037Article, review/survey (Refereed)
    Abstract [en]

    Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.

  • 83.
    Sfyroera, Georgia
    et al.
    Univ Penn, USA.
    Ricklin, Daniel
    Univ Penn, USA.
    Reis, Edimara
    Univ Penn, USA.
    Chen, Hui
    Univ Penn, USA.
    Wu, Emilia
    Univ Minnesota, USA.
    Kaznessis, Yannis
    Univ Minnesota, USA.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lambris, John
    Univ Penn, USA.
    Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity2015In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 194, no 7, p. 3305-3316Article in journal (Refereed)
    Abstract [en]

    The plasma protein C3 is a central element in the activation and effector functions of the complement system. A hereditary dysfunction of C3 that prevents complement activation via the alternative pathway (AP) was described previously in a Swedish family, but its genetic cause and molecular consequences have remained elusive. In this study, we provide these missing links by pinpointing the dysfunction to a point mutation in the beta-chain of C3 (c.1180T > C; p.Met(373)Thr). In the patient's plasma, AP activity was completely abolished and could only be reconstituted with the addition of normal C3. The M373T mutation was localized to the macroglobulin domain 4 of C3, which contains a binding site for the complement inhibitor compstatin and is considered critical for the interaction of C3 with the AP C3 convertase. Structural analyses suggested that the mutation disturbs the integrity of macroglobulin domain 4 and induces conformational changes that propagate into adjacent regions. Indeed, C3 M373T showed an altered binding pattern for compstatin and surface-bound C3b, and the presence of Thr(373) in either the C3 substrate or convertase-affiliated C3b impaired C3 activation and opsonization. In contrast to known gain-of-function mutations in C3, patients affected by this loss-of-function mutation did not develop familial disease, but rather showed diverse and mostly episodic symptoms. Our study therefore reveals the molecular mechanism of a relevant loss-of-function mutation in C3 and provides insight into the function of the C3 convertase, the differential involvement of C3 activity in clinical conditions, and some potential implications of therapeutic complement inhibition.

  • 84.
    Speth, Cornelia
    et al.
    Med Univ Innsbruck, Austria.
    Rambach, Guenter
    Med Univ Innsbruck, Austria.
    Wuerzner, Reinhard
    Med Univ Innsbruck, Austria.
    Lass-Floerl, Cornelia
    Med Univ Innsbruck, Austria.
    Kozarcanin, Huda
    Uppsala University.
    Hamad, Osama A.
    Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement and platelets: Mutual interference in the immune network2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 108-118Article, review/survey (Refereed)
    Abstract [en]

    In recent years, the view of platelets has changed from mere elements of hemostasis to immunological multitaskers. They are connected in manifold ways to other cellular and humoral components of the immune network, one of which is the complement system, a potent player in soluble innate immunity. Our article reviews the crucial and complex interplay between platelets and complement, focusing on mutual regulation of these two interaction partners by their respective molecular mechanisms. Furthermore, the putative relevance of these processes to infectious diseases, inflammatory conditions, and autoimmune disorders, as well as the treatment of patients with biomaterials is highlighted. (C) 2015 Elsevier Ltd. All rights reserved.

  • 85.
    Teramura, Yuji
    et al.
    University of Tokyo, Japan.
    Asif, Sana
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Cell surface engineering for regulation of immune reactions in cell therapy2015In: Immune Responses to Biosurfaces: Mechanisms and Therapeutic Interventions / [ed] John D. Lambris, Kristina Nilsson-Ekdahl, Daniel Ricklin, Bo Nilsson, Springer, 2015, p. 189-209Chapter in book (Refereed)
    Abstract [en]

    Transplantation of the pancreatic islets of Langerhans (islets) is a promising cell therapy for treating insulin-dependent type 1 diabetes mellitus. Islet transplantation is a minimally-invasive technique involving relatively simple surgery. However, after intraportal transplantation, the transplanted islets are attacked by the recipient’s immune system, because they activate a number of systems, including coagulation, complement response, inflammation, immune rejection, and recurrence of autoimmune disease. We have developed a surface modification and microencapsulation technique that protects cells and islets with biomaterials and bioactive substances, which may be useful in clinical settings. This approach employs amphiphilic polymers, which can interact with lipid bilayer membranes, without increasing cell volume. Molecules attached to these polymers can protect transplanted cells and islets from attack by the host immune system. We expect that this surface modification technique will improve graft survival in clinical islet transplantation.

  • 86. Teramura, Yuji
    et al.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Magnusson, Peetra U.
    Qu, Hongchang
    Ricklin, Daniel
    Hong, Jaan
    Lambris, John D.
    Nilsson, Bo
    Autoregulation of thromboinflammation on biomaterials and cells by a novel therapeutic coating technique2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1140-1140Article in journal (Other academic)
  • 87.
    Thomas, Anub M.
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    McAdam, Martin B.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Floisand, Yngvar
    Oslo Univ Hosp, Norway.
    Lau, Corinna
    Nordland Hosp, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Tromso, Norway.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Complement Component C5 and TLR Molecule CD14 Mediate Heme-Induced Thromboinflammation in Human Blood2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 203, no 6, p. 1571-1578Article in journal (Refereed)
    Abstract [en]

    Heme is a critical danger molecule liberated from hemeproteins in various conditions, including from hemoglobin in hemolytic diseases. Heme may cause thromboinflammatory damage by activating inflammatory and hemostatic pathways, such as complement, the TLRs, coagulation, and platelets. In this study, we explored the effect of single and dual inhibition of complement component C5 and TLR coreceptor CD14 on heme-induced thromboinflammation in an ex vivo human whole blood model. Heme induced a dose-dependent activation of complement via the alternative pathway. Single inhibition of C5 by eculizumab attenuated the release of IL-6, IL-8, TNF, MCP-1, MIP-1 alpha, IFN-gamma, LTB-4, MMP-8 and -9, and IL-1Ra with more than 60% (p < 0.05 for all) reduced the upregulation of CD11b on granulocytes and monocytes by 59 and 40%, respectively (p < 0.05), and attenuated monocytic tissue factor expression by 33% (p < 0.001). Blocking CD14 attenuated IL-6 and TNF by more than 50% (p < 0.05). In contrast to single inhibition, combined C5 and CD14 was required for a significantly attenuated prothrombin cleavage (72%, p < 0.05). Markers of thromboinflammation were also quantified in two patients admitted to the hospital with sickle cell disease (SCD) crisis. Both SCD patients had pronounced hemolysis and depleted plasma hemopexin and haptoglobin. Plasma heme and complement activation was markedly increased in one patient, a coinciding observation as demonstrated ex vivo. In conclusion, heme-induced thromboinflammation was largely attenuated by C5 inhibition alone, with a beneficial effect of adding a CD14 inhibitor to attenuate prothrombin activation. Targeting C5 has the potential to reduce thromboinflammation in SCD crisis patients.

  • 88.
    Thomas, Anub Mathew
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Gerogianni, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Barratt-Due, Andreas
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    McAdam, Martin B.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Nordland Hosp, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Complement (C5)-inhibition attenuates heme-induced inflammation in human whole blood2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 102, p. 220-220Article in journal (Other academic)
  • 89.
    Thomas, Anub Mathew
    et al.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Schjalm, Camilla
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Lindenskov, Paal H H
    Oslo University Hospital, Norway.
    Rørtveit, Runa
    Norwegian University of Life Sciences Oslo/Ås, Norway.
    Solberg, Rønnaug
    Oslo University Hospital, Norway.
    Saugstad, Ola Didrik
    Oslo University Hospital, Norway.
    Berglund, Magnus M
    Swedish Orphan Biovitrum.
    Strömberg, Patrik
    Swedish Orphan Biovitrum.
    Jansen, Johan Høgset
    Norwegian University of Life Sciences Oslo/Ås, Norway.
    Castellheim, Albert
    Queen Silvia Children's Hospital.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway;Nordland Hospital, Norway;University of Tromsø, Norway.
    Barratt-Due, Andreas
    Oslo University Hospital, Norway;University of Oslo, Norway.
    Combined inhibition of C5 and CD14 attenuates systemic inflammation in a newborn pig-model of meconium aspiration syndrome2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 166-167Article in journal (Refereed)
  • 90.
    Tjernberg, Anna Rockert
    et al.
    Region Kalmar, Sweden;Örebro University, Sweden.
    Woksepp, Hanna
    Region Kalmar, Sweden.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Johansson, Marcus
    Region Kalmar, SwedenRegion Kalmar, Sweden;Linköping University, Sweden.
    Dahle, Charlotte
    Linköping University, Sweden;Linköping University Hospital, Sweden.
    Ludvigsson, Jonas F.
    Karolinska Institutet, Sweden;Örebro University Hospital, Sweden.
    Bonnedahl, Jonas
    Linköping University, Sweden.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Oslo, Norway.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Celiac disease and complement activation in response to Streptococcus pneumoniae2020In: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076, Vol. 179, no 1, p. 133-140Article in journal (Refereed)
    Abstract [en]

    Individuals with celiac disease (CD) are at increased risk of invasive pneumococcal disease (IPD). The aim of this study was to explore whether the complement response to Streptococcus pneumoniae differed according to CD status, and could serve as an explanation for the excess risk of IPD in CD. Twenty-two children with CD and 18 controls, born 1999-2008, were included at Kalmar County Hospital, Sweden. The degree of complement activation was evaluated by comparing levels of activation products C3a and sC5b-9 in plasma incubated for 30 min with Streptococcus pneumoniae and in non-incubated plasma. Complement analyses were performed with enzyme-linked immunosorbent assay (ELISA). Pneumococcal stimulation caused a statistically significant increase in C3a as well as sC5b-9 in both children with CD and controls but there was no difference in response between the groups. After incubation, C3a increased on average 4.6 times and sC5b-9 22 times in both the CD and the control group (p = 0.497 and p = 0.724 respectively). Conclusion: Complement response to Streptococcus pneumoniae seems to be similar in children with and without CD and is thus unlikely to contribute to the increased susceptibility to invasive pneumococcal disease in CD.

  • 91.
    Toda, Shota
    et al.
    Shibaura Inst Technol, Japan.
    Fattah, Artin
    Uppsala University, Sweden.
    Asawa, Kenta
    Univ Tokyo, Japan.
    Nakamura, Naoko
    Shibaura Inst Technol, Japan.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Teramura, Yuji
    Uppsala University, Sweden;Univ Tokyo, Japan.
    Optimization of Islet Microencapsulation with Thin Polymer Membranes for Long-Term Stability2019In: Micromachines, ISSN 2072-666X, E-ISSN 2072-666X, Vol. 10, no 11, p. 1-10, article id 755Article in journal (Refereed)
    Abstract [en]

    Microencapsulation of islets can protect against immune reactions from the host immune system after transplantation. However, sufficient numbers of islets cannot be transplanted due to the increase of the size and total volume. Therefore, thin and stable polymer membranes are required for the microencapsulation. Here, we undertook the cell microencapsulation using poly(ethylene glycol)-conjugated phospholipid (PEG-lipid) and layer-by-layer membrane of multiple-arm PEG. In order to examine the membrane stability, we used different molecular weights of 4-arm PEG (10k, 20k and 40k)-Mal to examine the influence on the polymer membrane stability. We found that the polymer membrane made of 4-arm PEG(40k)-Mal showed the highest stability on the cell surface. Also, the polymer membrane did not disturb the insulin secretion from beta cells.

  • 92. Tsai, Jon A
    et al.
    Lund, Mikael
    Lundell, Lars
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    One-lung ventilation during thoracoabdominal esophagectomy elicits complement activation2009In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 152, no 2, p. 331-337Article in journal (Refereed)
    Abstract [en]

    Background. One-lung ventilation (OLV) during thoracoabdominal esophagectomy may induce an inflammatory response that can contribute to the induction and propagation of frequently occurring postoperative respiratory distress. Markers of such a response might be detected in the pulmonary as well as in the systemic circulation. Inflammation and tissue damage may be key pathogenetic pathways and we hypothesized that 1-lung ventilation may induce an inflammatory cascade reflected by markers for such a response. Materials and methods. Thirty patients with esophageal cancer were randomized to OLV (n = 16) or 2-lung ventilation (TLV; n = 14) during the thoracic part of the operation. Compounds involved in inflammation and coagulation were measured perioperatively and during the 1st, 2nd, 3rd, and 10th postoperative d. Results. During the perioperative phase, the proinflammatory cytokine interleukin-6 and thrombin, measured as thrombin-antithrombin complexes, started to increase. Thrombin, which can induce complement activation, peaked at the end of surgery and interleukin-6 at the 1st to 2nd postoperative d, but there were no differences between the OLV and TLV groups. C3a and terminal complement complex (TCC) started to increase on the 2nd postoperative d and continued to do so for the rest of the study period. The increase of TCC was significantly higher in the OLV group compared to the TLV group, whereas C3a attained similar levels in the 2 groups. Conclusions. OLV is associated with an augmented inflammatory response as reflected by the activation of the TCC. This may induce pulmonary tissue damage and recruitment of inflammatory cells.

  • 93.
    van Griensven, Martijn
    et al.
    Technical University of Munich, Germany.
    Ricklin, Daniel
    University of Pennsylvania, USA ; University of Basel, Switzerland.
    Denk, Stephanie
    University of Ulm, Germany.
    Halbgebauer, Rebecca
    University of Ulm, Germany.
    Braun, Christian K
    University of Ulm, Germany.
    Schultze, Anke
    University of Ulm, Germany.
    Hönes, Felix
    University of Ulm, Germany.
    Koutsogiannaki, Sofia
    University of Pennsylvania, USA.
    Primikyri, Alexandra
    University of Pennsylvania, USA.
    Reis, Edimara
    University of Pennsylvania, USA.
    Messerer, David
    University of Ulm, Germany.
    Hafner, Sebastian
    University of Ulm, Germany.
    Radermacher, Peter
    University of Ulm, Germany.
    Biglarnia, Ali-Reza
    Malmö University Hospital ; Lund University.
    Resuello, Ranillo R G
    Simian Conservation Breeding and Research Center (SICONBREC), Philippines.
    Tuplano, Joel V
    Simian Conservation Breeding and Research Center (SICONBREC), Philippines.
    Mayer, Benjamin
    University of Ulm, Germany.
    Nilsson Ekdahl, Kristina
    Uppsala University, Sweden.
    Nilsson, Bo
    Uppsala University, Sweden.
    Lambris, John D
    University of Pennsylvania, USA.
    Huber-Lang, Markus
    University of Ulm, Germany.
    Protective Effects of the Complement Inhibitor Compstatin CP40 in Hemorrhagic Shock2019In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 51, no 1, p. 78-87Article in journal (Refereed)
    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.

  • 94.
    Vijayaraghavan, Swetha
    et al.
    Karolinska Institutet.
    Karami, Azadeh
    Karolinska Institutet.
    Aeinehband, Shahin
    Karolinska Institutet.
    Behbahani, Homira
    Karolinska Institutet.
    Grandien, Alf
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Lindblom, Rickard P. F.
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Darreh-Shori, Taher
    Karolinska Institutet.
    Regulated Extracellular Choline Acetyltransferase Activity: The Plausible Missing Link of the Distant Action of Acetylcholine in the Cholinergic Anti-Inflammatory Pathway2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, article id e65936Article in journal (Refereed)
    Abstract [en]

    Acetylcholine (ACh), the classical neurotransmitter, also affects a variety of nonexcitable cells, such as endothelia, microglia, astrocytes and lymphocytes in both the nervous system and secondary lymphoid organs. Most of these cells are very distant from cholinergic synapses. The action of ACh on these distant cells is unlikely to occur through diffusion, given that ACh is very short-lived in the presence of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), two extremely efficient ACh-degrading enzymes abundantly present in extracellular fluids. In this study, we show compelling evidence for presence of a high concentration and activity of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT) in human cerebrospinal fluid (CSF) and plasma. We show that ChAT levels are physiologically balanced to the levels of its counteracting enzymes, AChE and BuChE in the human plasma and CSF. Equilibrium analyses show that soluble ChAT maintains a steady-state ACh level in the presence of physiological levels of fully active ACh-degrading enzymes. We show that ChAT is secreted by cultured human-brain astrocytes, and that activated spleen lymphocytes release ChAT itself rather than ACh. We further report differential CSF levels of ChAT in relation to Alzheimer's disease risk genotypes, as well as in patients with multiple sclerosis, a chronic neuroinflammatory disease, compared to controls. Interestingly, soluble CSF ChAT levels show strong correlation with soluble complement factor levels, supporting a role in inflammatory regulation. This study provides a plausible explanation for the long-distance action of ACh through continuous renewal of ACh in extracellular fluids by the soluble ChAT and thereby maintenance of steady-state equilibrium between hydrolysis and synthesis of this ubiquitous cholinergic signal substance in the brain and peripheral compartments. These findings may have important implications for the role of cholinergic signaling in states of inflammation in general and in neurodegenerative disease, such as Alzheimer's disease and multiple sclerosis in particular.

  • 95.
    Vogt, Leonie M.
    et al.
    Lund University, Sweden.
    Kwasniewicz, Ewa
    Lund University, Sweden.
    Talens, Simone
    Lund University, Sweden.
    Scavenius, Carsten
    Aarhus Univ, Denmark.
    Bielecka, Ewa
    Jagiellonian Univ, Poland.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Enghild, Jan J.
    Aarhus Univ, Denmark.
    Morgelin, Matthias
    Lund University, Sweden.
    Saxne, Tore
    Lund University, Sweden.
    Potempa, Jan
    Jagiellonian Univ, Poland;Univ Louisville, USA.
    Blom, Anna M.
    Lund University, Sweden.
    Apolipoprotein E Triggers Complement Activation in Joint Synovial Fluid of Rheumatoid Arthritis Patients by Binding C1q2020In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 204, no 10, p. 2779-2790Article in journal (Refereed)
    Abstract [en]

    We identified apolipoprotein E (ApoE) as one of the proteins that are found in complex with complement component C4d in pooled synovial fluid of rheumatoid arthritis (RA) patients. Immobilized human ApoE activated both the classical and the alternative complement pathways. In contrast, ApoE in solution demonstrated an isoform-dependent inhibition of hemolysis and complement deposition at the level of sC5b-9. Using electron microscopy imaging, we confirmed that ApoE interacts differently with C1q depending on its context; surface-bound ApoE predominantly bound C1q globular heads, whereas ApoE in a solution favored the hinge/stalk region of C1q. As a model for the lipidated state of ApoE in lipoprotein particles, we incorporated ApoE into phosphatidylcholine/phosphatidylethanolamine liposomes and found that the presence of ApoE on liposomes increased deposition of C1q and C4b from serum when analyzed using flow cytometry. In addition, posttranslational modifications associated with RA, such as citrullination and oxidation, reduced C4b deposition, whereas carbamylation enhanced C4b deposition on immobilized ApoE. Posttranslational modification of ApoE did not alter Clq interaction but affected binding of complement inhibitors factor H and C4b -binding protein. This suggests that changed ability of C4b to deposit on modified ApoE may play an important role. Our data show that posttranslational modifications of ApoE alter its interactions with complement. Moreover, ApoE may play different roles in the body depending on its solubility, and in diseased states such as RA, deposited ApoE may induce local complement activation rather than exert its typical role of inhibition.

  • 96.
    Wibroe, Peter Popp
    et al.
    Univ Copenhagen, Denmark.
    Anselmo, Aaron C
    Univ Calif Santa Barbara, USA.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Oslo, Norway ;Oslo Univ Hosp, Rikshosp, NorwayRikshospitalet.
    Sarode, Apoorva
    Univ Calif Santa Barbara, USA.
    Gupta, Vivek
    St Johns Univ, USA.
    Urbanics, Rudolf
    Semmelweis Univ, Hungary.
    Szebeni, Janos
    Semmelweis Univ, Hungary.
    Hunter, Alan Christy
    Montfort Univ, UK.
    Mitragotri, Samir
    Univ Calif Santa Barbara, USA.
    Mollnes, Tom Eirik
    University of Oslo, Norway ;Oslo Univ Hosp, Rikshosp, NorwayRikshospitalet ; Nordland Hosp, Norway ; Univ Tromso, Norway ; Norwegian Univ Sci & Technol, Norway.
    Moghimi, Seyed Moein
    Univ Copenhagen, Denmark ; Univ Durham, UK.
    Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes.2017In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 12, no 6, p. 589-594Article in journal (Refereed)
    Abstract [en]

    Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration.

  • 97.
    Wu, YQ
    et al.
    University of Pennsylvania, USA.
    Qu, H
    University of Pennsylvania, USA.
    Sfyroera, G
    University of Pennsylvania, USA.
    Tzekou, A
    University of Pennsylvania, USA.
    Kay, BK
    University of Illinois at Chicago, USA.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University Hospital.
    Ricklin, D
    University of Pennsylvania, USA.
    Lambris, JD
    University of Pennsylvania, USA.
    Protection of Nonself Surfaces from Complement Attack by Factor H-Binding Peptides: Implications for Therapeutic Medicine2011In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 7, p. 4269-4277Article in journal (Refereed)
    Abstract [en]

    Exposure of nonself surfaces such as those of biomaterials or transplanted cells and organs to host blood frequently triggers innate immune responses, thereby affecting both their functionality and tolerability. Activation of the alternative pathway of complement plays a decisive role in this unfavorable reaction. Whereas previous studies demonstrated that immobilization of physiological regulators of complement activation (RCA) can attenuate this foreign body-induced activation, simple and efficient approaches for coating artificial surfaces with intact RCA are still missing. The conjugation of small molecular entities that capture RCA with high affinity is an intriguing alternative, as this creates a surface with autoregulatory activity upon exposure to blood. We therefore screened two variable cysteine-constrained phage-displayed peptide libraries for factor H-binding peptides. We discovered three peptide classes that differed with respect to their main target binding areas. Peptides binding to the broad middle region of factor H (domains 5–18) were of particular interest, as they do not interfere with either regulatory or binding activities. One peptide in this group (5C6) was further characterized and showed high factor H-capturing activity while retaining its functional integrity. Most importantly, when 5C6 was coated to a model polystyrene surface and exposed to human lepirudin-anticoagulated plasma, the bound peptide captured factor H and substantially inhibited complement activation by the alternative pathway. Our study therefore provides a promising and novel approach to produce therapeutic materials with enhanced biocompatibility.

  • 98.
    Zeuthen, Christina M.
    et al.
    Aarhus Univ, Denmark;Sino Danish Ctr Educ & Res, Denmark;Ctr Cellular Signal Patterns CellPAT, Denmark.
    Shahrokhtash, Ali
    Aarhus Univ, Denmark;Ctr Cellular Signal Patterns CellPAT, Denmark.
    Fromell, Karin
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Mohammad-Beigi, Hossein
    Aarhus Univ, Denmark;Ctr Cellular Signal Patterns CellPAT, Denmark.
    Sutherland, Duncan S.
    Aarhus Univ, Denmark;Ctr Cellular Signal Patterns CellPAT, Denmark.
    C1q recognizes antigen-bound IgG in a curvature-dependent manner2020In: Nano Reseach, ISSN 1998-0124, E-ISSN 1998-0000, p. 1-8Article in journal (Refereed)
    Abstract [en]

    C1q is an important recognition protein in the complement system, which is a major protein cascade in the innate immune system. Upon recognition of a target by C1q, the target is marked for opsonization and destruction. C1q recognizes many pathogenic patterns directly, but an important target is the Fc domain of antibodies binding to their antigen. In this paper, the curvature-dependence of the interaction between IgG and C1q is studied by surface plasmon resonance and quartz crystal microbalance. IgG is organized in similar surface coverage densities on flat polystyrene surfaces and polystyrene nanoparticles of different sizes, and the amount of C1q binding to the IgG is investigated. Nanoparticles in solution were found to aggregate upon incubation with IgG, and therefore a new technique utilizing nanoparticles binding to antifouling polymer brush functionalized surfaces was used to prepare surfaces with nanoparticles for measurements with surface plasmon resonance. Interestingly antigen-bound IgG at the curved surface of nanoparticles showed 5.6 times lower binding of C1q compared to at matched flat surfaces. There was no significant difference between the binding at 100 and 200 nm polystyrene particles. These findings are important for designing drug delivery systems to evade the complement system.

  • 99.
    Zhao, Fei
    et al.
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Afonso, Sara
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Lindner, Susanne
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Hartmann, Andrea
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Loeschmann, Ina
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    Nilsson, Bo
    Uppsala University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linneaus Ctr Bomat Chem, Kalmar, Sweden..
    Weber, Lutz T.
    Univ Hosp Cologne, Germany.
    Habbig, Sandra
    Univ Hosp Cologne, Germany.
    Schalk, Gesa
    Univ Hosp Cologne, Germany.
    Kirschfink, Michael
    Heidelberg Univ, Germany.
    Zipfel, Peter F.
    Leibniz Inst Nat Prod Res & Infect Biol, Germany;Friedrich Schiller Univ Jena, Germany.
    Skerka, Christine
    Leibniz Inst Nat Prod Res & Infect Biol, Germany.
    C3-Glomerulopathy Autoantibodies Mediate Distinct Effects on Complement C3-and C5-Convertases2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, p. 1-14, article id 1030Article in journal (Refereed)
    Abstract [en]

    C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

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