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  • 1. Ahrenstedt, Örjan
    et al.
    Knutson, L
    Nilsson, B
    Nilsson Ekdahl, Kristina
    University Hospital, Uppsala.
    Odlind, B
    Hällgren, R
    Enhanced local production of the complement components in the small intestine in Crohn's disease1990In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 322, p. 1345-1349Article in journal (Refereed)
    Abstract [en]

    There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum.

    The mean (±SEM) jejunal-fluid C4 concentration was 2.0±0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7±0.1 mg per liter; P<0.001). The mean C3 concentration was 1.0±0.1 mg per liter in the patients and 0.7±0.1 mg per liter in the controls (P<0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4).

    We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages. 

  • 2. Alston-Smith, J
    et al.
    Boija, P O
    Ware, J
    Nilsson Ekdahl, Kristina
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Endotoxin, epinephrine, glucagon, insulin and calcium ionophore A23187 modulation of pyruvate kinase activity in cultured rat hepatocytes1990In: Acta chirurgica Scandinavica, Vol. 156, no 10, p. 677-681Article in journal (Refereed)
    Abstract [en]

    Altered glucose metabolism is one of the commonly observed sequelae of sepsis and septic shock. The present investigation was undertaken to determine the role of endotoxin (ET) upon hepatocyte glucoregulation, by measuring the activity of pyruvate kinase (PK), a key glycolytic enzyme. Hepatocytes were exposed to endotoxin concentrations known to occur in vivo during sepsis, i.e., from 1 X 10(-14) to 1 X 10(-8) g/ml. The alteration of the enzyme activities after addition of epinephrine, glucagon, insulin and calcium ionophore A23187 with and without ET preincubation were also examined. ET alone decreased the PK activity by 12% at all concentrations tested. The basal inhibition of the enzyme caused by epinephrine (-48%) was partially blocked by ET preincubation above 1 X 10(-10) g/ml. There were no ET-(glucagon, calcium ionophore, insulin) interaction. These in vitro results do not support pyruvate kinase as a site of hepatic enzyme regulation defect in endotoxaemia. 

  • 3. Alston-Smith, J
    et al.
    Ljungqvist, O
    Ware, J
    Nilsson Ekdahl, Kristina
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Regulation of rat hepatocyte fructose 1,6-diphosphatase activity during endotoxemia1991In: Surgical research communications, ISSN 0882-9233, Vol. 11, p. 67-75Article in journal (Refereed)
  • 4. Babiker, Adil A
    et al.
    Magnusson, Peetra U
    Ronquist, Gunnar
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mapping Pro- and Antiangiogenic Factors on the Surface of Prostasomes of Normal and Malignant Cell Origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis.

    METHODS. VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy.

    RESULTS. VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy.

    CONCLUSIONS. Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 5. Babiker, Adil A
    et al.
    Ronquist, Gunnar
    Nilsson, Bo
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Prostasome Involvement in the Development and of Prostate Cancer2010In: Open Prostate Cancer Journal, ISSN 1876-8229, Vol. 3, p. 1-13Article, review/survey (Refereed)
    Abstract [en]

    Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen after secretion. Even dedifferentiated prostate cancer cells have preserved their ability to produce and export prostasomes to the extracellular space. The precise physiological role of prostasomes is not known, although some of their properties assign them to important physiological and patho-physiological functions that could be exploited in prostate cancer growth and development. In this review, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes will be discussed.There are typical differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) as well as in the transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes). CD59, protein kinases and TF exhibit characteristic patterns of overexpression by malignant cell prostasomes. A high ATPase activity is recognized on seminal prostasomes with minimal activity on malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins are phosphorylated by prostasomal protein kinases, namely, complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF is identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes are demonstrated. DU145 and PC-3 cell-derived prostasomes exert a higher clotting effect on whole blood and plasma compared to LNCaP cell-derived and seminal prostasomes.In conclusion, malignant cell prostasomes show an increased ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation and inactivation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

  • 6.
    Barratt-Due, Andreas
    et al.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Pischke, Søren Erik
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway ; University of Oslo, Norway.
    Espevik, Terje
    Norwegian University of Science and Technology, Norway.
    Mollnes, Tom Eirik
    Norwegian University of Science and Technology, Norway ; Nordland Hospital, Norway ; University of Tromsø, Norway.
    Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets.2017In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 101, no 1, p. 193-204Article in journal (Refereed)
    Abstract [en]

    The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by "dual blockade" of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.

  • 7.
    Bauer, Patrik Maximilian
    et al.
    Lund University, Sweden.
    Zalis, Marina Castro
    Lund University, Sweden.
    Abdshill, Hodan
    Lund University, Sweden.
    Deierborg, Tomas
    Lund University, Sweden.
    Johansson, Fredrik
    Lund University, Sweden.
    Englund Johansson, Ulrica
    Lund University, Sweden.
    Inflamed In Vitro Retina: Cytotoxic Neuroinflammation and Galectin-3 Expression2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 9, article id e0161723Article in journal (Refereed)
    Abstract [en]

    Background Disease progression in retinal neurodegeneration is strongly correlated to immune cell activation, which may have either a neuroprotective or neurotoxic effect. Increased knowledge about the immune response profile and retinal neurodegeneration may lead to candidate targets for treatments. Therefore, we have used the explanted retina as a model to explore the immune response and expression of the immune modulator galectin-3 (Gal-3), induced by the cultivation per se and after additional immune stimulation with lipopolysaccharide (LPS), and how this correlates with retinal neurotoxicity. Methods Post-natal mouse retinas were cultured in a defined medium. One group was stimulated with LPS (100 ng/ml, 24 h). Retinal architecture, apoptotic cell death, and micro- and macroglial activity were studied at the time of cultivation (0 days in vitro (DIV)) and at 3, 4 and 7 DIV using morphological staining, biochemical- and immunohistochemical techniques. Results Our results show that sustained activation of macro- and microglia, characterized by no detectable cytokine release and limited expression of Gal-3, is not furtherinducing apoptosis additional to the axotomy-induced apoptosis in innermost nuclear layer. An elevated immune response was detected after LPS stimulation, as demonstrated primarily by release of immune mediators (i.e. interleukin 2 (IL-2), IL-6, KC/GRO (also known as CLCX1) and tumour necrosis factor-α (TNF-α)), increased numbers of microglia displaying morphologies of late activation stages as well as Gal-3 expression. This was accompanied with increased apoptosis in the two additional nuclear layers, and damage to retinal gross architecture. Conclusion We demonstrate that an immune response characterized by sustained and increased release of cytokines, along with an increase in Gal-3 expression, is accompanied by significant increased neurotoxicity in the explanted retina. Further investigations using the current setting may lead to increased understanding on the mechanisms involved in neuronal loss in retinal neurodegenerations. © 2016 Bauer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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  • 8.
    Behailu Bekele, Haimanot
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Atypisk aktivering av komplementprotein C52019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 9.
    Berg, Aase
    et al.
    Stavanger University Hospital, Norway ; University of Bergen, Norway.
    Otterdal, Kari
    Oslo University Hospital Rikshospitalet, Norway.
    Patel, Sam
    Central Hospital of Maputo, Mozambique.
    Gonca, Miguel
    Central Hospital of Maputo, Mozambique.
    David, Catarina
    Central Hospital of Maputo, Mozambique.
    Dalen, Ingvild
    Stavanger University Hospital, Norway.
    Nymo, Stig
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson, Margareta
    Oslo University Hospital Rikshospitalet, Norway.
    Nordling, Sofia
    Uppsala University.
    Magnusson, Peetra U
    Uppsala University.
    Ueland, Thor
    Oslo University Hospital Rikshospitalet, Norway.
    Prato, Mauro
    University of Torino, Italy.
    Giribaldi, Giuliana
    University of Torino, Italy.
    Mollnes, Tom Eirik
    Oslo University Hospital Rikshospitalet, Norway.
    Aukrust, Pål
    Oslo University Hospital Rikshospitalet, Norway.
    Langeland, Nina
    University of Bergen, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria.2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 11, p. 1835-1840Article in journal (Refereed)
    Abstract [en]

    The impact of complement activation and its possible relation to cytokine responses during malaria pathology was investigated in plasma samples from patients with confirmed Plasmodium falciparum malaria and in human whole-blood specimens stimulated with malaria-relevant agents ex vivo. Complement was significantly activated in the malaria cohort, compared with healthy controls, and was positively correlated with disease severity and with certain cytokines, in particular interleukin 8 (IL-8)/CXCL8. This was confirmed in ex vivo-stimulated blood specimens, in which complement inhibition significantly reduced IL-8/CXCL8 release. P. falciparum malaria is associated with systemic complement activation and complement-dependent release of inflammatory cytokines, of which IL-8/CXCL8 is particularly prominent.

  • 10.
    Bergseth, Grethe
    et al.
    Nordland Hospital, Bodø, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway.
    Thomas, Anub Mathew
    Radboud University Medical Center, The Netherlands.
    Gustavsen, Alice
    University of Oslo, Rikshospitalet, Norway.
    Volokhina, Elena B
    Radboud University Medical Center, The Netherlands.
    van den Heuvel, Lambertus P
    Radboud University Medical Center, The Netherlands.
    Barratt-Due, Andreas
    University of Oslo, Rikshospitalet, Norway.
    Mollnes, Tom E
    University of Oslo, Rikshospitalet, Norway;Nordland Hospital, Norway;University of Tromsø, Norway.
    Neoepitope based assays to detect C5a – Pitfalls and interpretations2017In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 89, no SI: EMCHD2017, p. 201-201Article in journal (Refereed)
  • 11.
    Bernhard, Stefan
    et al.
    Univ Hosp Ulm, Germany.
    Hug, Stefan
    Univ Hosp Ulm, Germany.
    Stratmann, Alexander Elias Paul
    Univ Hosp Ulm, Germany.
    Erber, Maike
    Univ Hosp Ulm, Germany.
    Vidoni, Laura
    Univ Hosp Ulm, Germany.
    Knapp, Christiane Leonie
    Univ Hosp Ulm, Germany.
    Thomass, Bertram Dietrich
    Univ Hosp Ulm, Germany.
    Fauler, Michael
    Univ Ulm, Germany.
    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.
    Foehr, Karl
    Univ Hosp Ulm, Germany.
    Braun, Christian Karl
    Univ Hosp Ulm, Germany.
    Wohlgemuth, Lisa
    Univ Hosp Ulm, Germany.
    Huber-Lang, Markus
    Univ Hosp Ulm, Germany.
    Messerer, David Alexander Christian
    Univ Hosp Ulm, Germany.
    Interleukin 8 Elicits Rapid Physiological Changes in Neutrophils That Are Altered by Inflammatory Conditions2021In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 13, p. 225-241Article in journal (Refereed)
    Abstract [en]

    A sufficient response of neutrophil granulocytes stimulated by interleukin (IL)-8 is vital during systemic inflammation, for example, in sepsis or severe trauma. Moreover, IL-8 is clinically used as biomarker of inflammatory processes. However, the effects of IL-8 on cellular key regulators of neutrophil properties such as the intracellular pH (pH(i)) in dependence of ion transport proteins and during inflammation remain to be elucidated. Therefore, we investigated in detail the fundamental changes in pH(i), cellular shape, and chemotactic activity elicited by IL-8. Using flow cytometric methods, we determined that the IL-8-induced cellular activity was largely dependent on specific ion channels and transporters, such as the sodium-proton exchanger 1 (NHE1) and non-NHE1-dependent sodium flux. Exposing neutrophils in vitro to a proinflammatory micromilieu with N-formyl-Met-Leu-Phe, LPS, or IL-8 resulted in a diminished response regarding the increase in cellular size and pH. The detailed kinetics of the reduced reactivity of the neutrophil granulocytes could be illustrated in a near-real-time flow cytometric measurement. Last, the LPS-mediated impairment of the IL-8-induced response in neutrophils was confirmed in a translational, animal-free human whole blood model. Overall, we provide novel mechanistic insights for the interaction of IL-8 with neutrophil granulocytes and report in detail about its alteration during systemic inflammation.

  • 12.
    Bexborn, Fredrik
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Engberg, Anna E.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Sandholm, Kerstin
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Mollnes, Tom Eirik
    Hong, Jaan
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Hirudin versus heparin for use in whole blood in vitro biocompatibility models2009In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 89A, no 4, p. 951-959Article in journal (Refereed)
    Abstract [en]

    Background: Heparin has traditionally been a widely used anticoagulant in blood research, but has been shown to be inappropriate for work with the complement system because of its complement-interacting properties. In this work, we have compared the effects of heparin with those of the specific thrombin inhibitor hirudin on complement and blood cells in vitro.

    Methods: Whole blood collected in the presence of hirudin (50 µg/mL) or heparin (1 IU/mL) was incubated in the slide chamber model. The plasma was analyzed for complement activation markers C3a and sC5b-9, and the polyvinylchloride test slides were stained for adhering cells. The integrity of the complement system was tested by incubating serum and hirudin-treated plasma in the presence of various activating agents.

    Results: In contrast to heparin, the addition of hirudin generally preserved the complement reactivity, and complement activation in hirudin plasma closely resembled that in normal serum. Importantly, immunochemical staining of surface-bound cells demonstrated the inducible expression of tissue factor on bound monocytes from hirudin-treated blood, an effect that was completely abolished in heparin-treated blood.

    Conclusion: Our results indicate that hirudin as an anticoagulant produces more physiological conditions than heparin, making hirudin well-suited for in vitro studies, especially those addressing the regulation of cellular processes.

  • 13.
    Blomberg, Carolina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Intrathecal and Systemic Complement Activation Studies of Multiple Sclerosis and Guillan-Barré Syndrome2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Both Multiple Sclerosis (MS) and Guillan-Barré syndrome (GBS) are neurological inflammatory demyelinating autoimmune diseases, with a probable antibody contribution. Complement proteins in both MS and GBS does play a role in inflammation and demyelination at pathogenesis, according to earlier scientific evidence. The aim of this examination project work was to investigate systemic and intrathecal complement activation in MS and GBS, to gain further knowledge that might be useful for development of future therapeutics targeting immune responses during those diseases. An additional aim was to develop a new ELISA method for detection of complement iC3.

    By using sandwich ELISA, complement proteins C1q, C4, C3, fH and C3a were measured in plasma and cerebrospinal fluid (CSF) from persons within 4 different diagnostic groups; MS, other neurological diseases (OND), GBS and controls (C). An ELISA method to detect iC3 (hydrolysed C3) was also developed, including usage of SDS-PAGE. Results based on raw data and statistical analysis show significantly elevated levels of C3a (C3a/C3) in MS and decreased C3 in plasma. In CSF low levels of C4 and C3a/C3 in MS were detected, though correlation of C3a and C1q was positive. GBS reveal high levels of all complement proteins analysed in CSF except for C3, and a positive correlation of C3a and C1q as well as C3a and fH was found.

    These results indicate that MS patients have systemic complement activation; however the activation pathway is not determined. Complement activation in MS may also occur intrathecally, with correlation analysis indicating a possible activation via the classical pathway. MS patients suffering from a more acute relapsing-remitting (RR) MS have a more prominent systemic complement activation compared to MS patients responding to beta-interferon treatment. Systemic increased C3a/C3 ratio may be a possible biomarker to distinguish more acute RR MS in an earlier step of MS pathogenesis and should be further investigated. GBS patients have an intrathecal complement activation that seems to occur via the classical pathway.

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  • 14. Boij, Roland
    et al.
    Svensson, Judit
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lindahl, Tomas
    Palonek, Elzbieta
    Garle, Mats
    Berg, Mats
    Ernerudh, Jan
    Jenmalm, Mats
    Matthiesen, Leif
    Biomarkers of coagulation, inflammation and angiogenesis are independently associated with preeclampsia2012In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 68, no 3, p. 258-270Article in journal (Refereed)
    Abstract [en]

    Problem Although preeclampsia has been associated with inflammation, coagulation, and angiogenesis, their correlation and relative contribution are unknown. Method of Study About 114 women with preeclampsia, 31 with early onset (EOP) and 83 with late onset preeclampsia (LOP), and 100 normal pregnant controls were included. A broad panel of 32 biomarkers reflecting coagulation, inflammation, and angiogenesis was analyzed. Results Preeclampsia was associated with decreased antithrombin, IL-4 and placental growth factor levels and with increased C3a, pentraxin-3, and sFlt-1 levels, with more marked differences in the EOP group. The Th1-associated chemokines CXCL10 and CXCL11 were significantly higher in the preeclampsia and EOP group than in controls, respectively. No correlations between the biomarkers were found in preeclampsia. Multivariate logistic regression tests confirmed the results. Conclusions Cytokines, chemokines and complement activation seem to be part of a Th1-like inflammatory reaction in preeclampsia, most pronounced in EOP, where chemokines may be more useful than cytokines as biomarkers. Biomarkers were not correlated suggesting partly independent or in time separated mechanisms.

  • 15. Boija, P O
    et al.
    Nilsson Ekdahl, Kristina
    Department of Medical and Physiological Chemistry, University of Uppsala.
    Nylander, G
    Ware, J
    Hemorrhagic hypotension and hepatic cell pyruvate kinase and fructose-1,6-diphosphatase activity in vivo1987In: Surgical research communications, Vol. 2, p. 119-124Article in journal (Refereed)
  • 16.
    Brandwijk, Ricardo J. M. G. E.
    et al.
    Hycult Biotechnol bv, Netherlands.
    Michels, Marloes A. H. M.
    Radboud Univ Nijmegen Med Ctr, Netherlands.
    van Rossum, Mara
    Hycult Biotechnol bv, Netherlands.
    de Nooijer, Aline H.
    Radboud Univ Nijmegen Med Ctr, Netherlands.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Univ Oslo, Norway;Oslo University Hospital Rikshospitalet, Norway.
    de Bruin, Wieke C. C.
    Hycult Biotechnol bv, Netherlands.
    Toonen, Erik J. M.
    Hycult Biotechnol bv, Netherlands.
    Pitfalls in complement analysis: A systematic literature review of assessing complement activation2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 1007102Article in journal (Refereed)
    Abstract [en]

    Background: The complement system is an essential component of our innate defense and plays a vital role in the pathogenesis of many diseases. Assessment of complement activation is critical in monitoring both disease progression and response to therapy. Complement analysis requires accurate and standardized sampling and assay procedures, which has proven to be challenging. Objective: We performed a systematic analysis of the current methods used to assess complement components and reviewed whether the identified studies performed their complement measurements according to the recommended practice regarding pre-analytical sample handling and assay technique. Results are supplemented with own data regarding the assessment of key complement biomarkers to illustrate the importance of accurate sampling and measuring of complement components. Methods: A literature search using the Pubmed/MEDLINE database was performed focusing on studies measuring the key complement components C3, C5 and/or their split products and/or the soluble variant of the terminal C5b-9 complement complex (sTCC) in human blood samples that were published between February 2017 and February 2022. The identified studies were reviewed whether they had used the correct sample type and techniques for their analyses. Results: A total of 92 out of 376 studies were selected for full-text analysis. Forty-five studies (49%) were identified as using the correct sample type and techniques for their complement analyses, while 25 studies (27%) did not use the correct sample type or technique. For 22 studies (24%), it was not specified which sample type was used. Conclusion: A substantial part of the reviewed studies did not use the appropriate sample type for assessing complement activation or did not mention which sample type was used. This deviation from the standardized procedure can lead to misinterpretation of complement biomarker levels and hampers proper comparison of complement measurements between studies. Therefore, this study underlines the necessity of general guidelines for accurate and standardized complement analysis

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  • 17. Bäck, Jennie
    et al.
    Sanchez, Javier
    Elgue, Graciela
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Activated human platelets induce factor XIIa-mediated contact activation2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 391, no 1, p. 11-17Article in journal (Refereed)
    Abstract [en]

    Earlier studies have shown that isolated platelets in buffer systems can promote activation of FXII or amplify contact activation. in the presence of it negatively charge Substance or material Still proof is lacking that FXII is activated by platelets in a more physiological environment In this study we investigate if activated platelets can induce FXII-mediated contact activation and whether this activation affects clot formation in human blood.

    Human platelets were activated with a thrombin receptor-activating peptide, SFLLRN-amide, in platelet-rich plasma or in whole blood. FXIIa and FXIa in complex with preferentially antithrombin (AT) and to some extent C1-inhibitor (C1INH) were generated in response to TRAP stimulation. This contact activation was independent of surface-mediated contact activation, tissue factor pathway or thiombin. In clotting whole blood FXIIa-AT and FXIa-AT complexes were specifically formed. demonstrating that AT is a potent inhibitor of FXIIa and FXIa generated by platelet activation Contact activation proteins were analyzed by flow cytometry and FXII, FXI, high-molecular weight kininogen, and prekallikrein were detected oil activated platelets Using chromogenic assays, enzymatic activity of platelet-associated FXIIa, FXIa, and kallikrein were demonstrated Inhibition of FXIIa in non-anticoagulated blood also prolonged the clotting time.

    We conclude that platelet activation triggers FXII-mediated contact activation oil the Surface and in the vicinity of activated platelets This leads specifically to generation of FXIIa-AT and FXIa-AT complexes, and contributes to clot formation Activated platelets may thereby constitute an intravascular locus for contact activation, which may explain the recently reported importance of FXII in thrombus formation (C) 2009 Published by Elsevier Inc.

  • 18.
    Chaban, Viktoriia
    et al.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    de Boer, Eline
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    McAdam, Karin E.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Vaage, Jarle
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp, 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.
    Piscike, Soren Erik
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Islam, Rakibul
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Escherichia coli-induced inflammatory responses are temperature-dependent in human whole blood ex vivo2023In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 157, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Systemic inflammatory conditions are often associated with hypothermia or hyperthermia. Therapeutic hypothermia is used in post-cardiac arrest and some other acute diseases. There is a need for more knowledge concerning the effect of various temperatures on the acute inflammatory response. The complement system plays a crucial role in initiating the inflammatory response. We hypothesized that temperatures above and below the physiologic 37 & DEG;C affect complement activation and cytokine production ex vivo. Lepirudin-anticoagulated human whole blood from 10 healthy donors was incubated in the presence or absence of Escherichia coli at different temperatures (4 & DEG;C, 12 & DEG;C, 20 & DEG;C, 33 & DEG;C, 37 & DEG;C, 39 & DEG;C, and 41 & DEG;C). Complement activation was assessed by the terminal C5b-9 complement complex (TCC) and the alternative convertase C3bBbP using ELISA. Cytokines were measured using a 27-plex assay. Granulocyte and monocyte activation was evaluated by CD11b surface expression using flow cytometry. A consistent increase in complement activation was observed with rising temperature, reaching a maximum at 41 & DEG;C, both in the absence (C3bBbP p < 0.05) and presence (C3bBbP p < 0.05 and TCC p < 0.05) of E. coli. Temperature alone did not affect cytokine production, whereas incubation with E. coli significantly increased cytokine levels of IL-18, IL-2, IL-6, IL-8, IFN-& gamma;, and TNF at temperatures > 20 & DEG;C. Maximum increase occurred at 39 & DEG;C. However, a consistent decrease was observed at 41 & DEG;C, significant for IL-18 (p = 0.003). Granulocyte CD11b displayed the same temperature-dependent pattern as cytokines, with a corresponding increase in endothelial cell apoptosis and necrosis. Thus, blood temperature differentially determines the degree of complement activation and cytokine release.

  • 19.
    Christensen, Kjeld
    et al.
    Örebro University Hospital.
    Kozarcanin, Huda
    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.
    Evidence of contact activation in patients suffering from ST-elevation myocardial infarction2016In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 141, p. 158-162Article in journal (Refereed)
    Abstract [en]

    Introduction: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. Methods and patients: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3 days post-percutaneous intervention (PCI) and, in one-third of the patients, 3 months after PCI. In order to investigate the degree of Factor XII (FXII) activation, changes in FXIIa/AT and FXIIa/C1INH complex levels were quantified by ELISA. Results: FXIIa/AT levels at admission (0.89 +/- 0.50; p < 0.01) were significantly higher than those in normal individuals (0.39 +/- 0.28), but the levels after 1-3 days (0.33 +/- 0.33; p < 0.05) were essentially normalized. In contrast, the FXII/C1INH levels at admission (1.40 +/- 0.72; p < 0.001) and after 1-3 days (0.83 +/- 0.59; p < 0.001) were both significantly higher than those in normal individuals (0.40 +/- 0.30). FXIIa/AT and FXIIa/C1INH complexes at admission (p < 0.001; p < 0.001) and after 1-3 days (p < 0.02; p < 0.001) were significantly different from those at 3 months. No significant differences were observed when the data were stratified for patency (open/closed culprit lesions). Conclusion: Both FXIIa/AT and FXIIa/C1INH complexes were significantly increased and reflected the activation of FXII in STEMI patients at admission. In particular, FXIIa/AT complex elevations support the hypothesis that clot propagation-mediated FXII activation had occurred, and this activation may be a target for anticoagulation in patients with cardiac infarction. Based on previous studies, the FXIIa/C1INH complex levels were primarily interpreted to reflex endothelial cell activation. (C) 2016 Published by Elsevier Ltd.

  • 20.
    Davidsson, Rebecca
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Effektivitet och säkerhet av anti-amyloid-β antikroppar för behandling av Alzheimers sjukdom: En litteraturstudie2023Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Alzheimer’s disease is a neurodegenerative disease that is caused by accumulation of amyloid-β (Aβ) in the brain. The prevalence of Alzheimer’s disease is increasing, and symptoms of the disease include memory loss, anxiety, depression, confusion, impaired judgment and disorientation. Age and genetic variants are the two main risk factors for developing Alzheimer’s disease. There are two models which describe the development of the disease, 1) the amyloid hypothesis which describes how the deposition of Aβ leads to increased aggregation of the protein tau, which causes neuronal cell death and neurodegeneration, and 2) the cholinergic hypothesis which describes that Aβ plaques decrease the production of acetylcholine, this causes less activity in cholinergic neurons. The two areas in the brain which are mainly affected by neurodegeneration are the entorhinal cortex and the hippocampus. Diagnosing Alzheimer’s disease is done by medicinal and neurological assessments and by using standardized tests/instruments. Currently only symptomatic treatments for Alzheimer’s disease are available; acetylcholine esterase inhibitors and memantine. Another treatment method is using monoclonal antibodies against Aβ to decrease the Aβ load in the brain. To assess the effectiveness of these drugs assessment methods based on cognitive and functional tests can be used. 

    Aim: This study aimed to analyse the efficacy and safety of anti-Aβ antibodies as a treatment for Alzheimer’s disease, which was done by analysing cognitive ability, biomarkers and adverse events. 

    Method: This literature study was based on 5 clinical randomized controlled trials which were obtained from the PubMed database. Keywords that were used in the searches were “aducanumab”, “lecanemab”, “donanemab”, “crenezumab” and “bapineuzumab”. 

    Results: High-dose aducanumab in the study EMERGE and lecanemab showed statistically significant differences on all endpoints, and analysis of biomarkers showed a decrease in amyloid load in the brain. Donanemab showed statistically significant differences on the primary endpoint and analysis of biomarkers but results on secondary endpoints were not statistically significant. Crenezumab only showed statistically significant change on the primary endpoint in CREAD2. Bapineuzumab did not show statistically significant differences on any endpoint or on changes in levels of biomarkers. Statistically significant results on primary and secondary endpoints indicated decreased cognitive impairment among the patients. ARIA was a common adverse event in all drugs, with exception of crenezumab, but the occurrence of ARIA was in most cases mild to moderate. Other common adverse events were infusion-related reactions, headaches and falls. 

    Conclusion: With consideration of the results of this paper a conclusion can be drawn that aducanumab, lecanemab and donanemab have been shown to be effective on primary endpoints and analysis of biomarkers. The drugs that seem the most promising are aducanumab and lecanemab, mainly because they showed efficacy on both primary and secondary endpoints, and biomarkers and because of the FDA’s recent approval of both drugs in the US. The occurrence of ARIA is something that affects the safety of these drugs and because of this more studies are needed to further assess their safety. 

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  • 21.
    de Boer, Eline
    et al.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Sokolova, Marina
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Quach, Huy Q.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    McAdam, Karin E.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Gotz, Maximilian P.
    Univ Copenhagen, Denmark.
    Chaban, Viktoriia
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Vaage, Jarle
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Fagerang, Beatrice
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Woodruff, Trent M.
    Univ Queensland, Australia.
    Garred, Peter
    Univ Copenhagen, Denmark.
    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 E.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway;Nordland Hosp Bodo, Norway;Univ Tromso, Norway;Norwegian Univ Sci & Technol, Norway.
    Pischke, Soren E.
    Univ Oslo, Norway;Oslo Univ Hosp, Norway.
    Synthetic Oligodeoxynucleotide CpG Motifs Activate Human Complement through Their Backbone Structure and Induce Complement-Dependent Cytokine Release2022In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 209, no 9, p. 1760-1767Article in journal (Refereed)
    Abstract [en]

    Bacterial and mitochondrial DNA, sharing an evolutionary origin, act as danger-associated molecular patterns in infectious and sterile inflammation. They both contain immunomodulatory CpG motifs. Interactions between CpG motifs and the complement system are sparsely described, and mechanisms of complement activation by CpG remain unclear. Lepirudin-anticoagulated human whole blood and plasma were incubated with increasing concentrations of three classes of synthetic CpGs: CpG-A, -B, and -C oligodeoxynucleotides and their GpC sequence controls. Complement activation products were analyzed by immunoassays. Cytokine levels were determined via 27-plex beads-based immunoassay, and CpG interactions with individual complement proteins were evaluated using magnetic beads coated with CpG-B. In whole blood and plasma, CpG-B and CpG-C (p < 0.05 for both), but not CpG-A (p > 0.8 for all), led to time- and dose-dependent increase of soluble C5b-9, the alternative complement convertase C3bBbP, and the C3 cleavage product C3bc. GpC-A, -B, and -C changed soluble fluid-phase C5b-9, C3bBbP, and C3bc to the same extent as CpG-A, -B, and -C, indicating a DNA backbone-dependent effect. Dose-dependent CpG-B binding was found to C1q (r = 0.83; p 5 0.006) and factor H (r = 0.93; p < 0.001). The stimulatory complement effect was partly preserved in C2-deficient plasma and completely preserved in MASP-2-deficient serum. CpG-B increased levels of IL-1 beta, IL-2, IL-6, IL-8, MCP-1, and TNF in whole blood, which were completely abolished by inhibition of C5 and C5aR1 (p < 0.05 for all). In conclusion, synthetic analogs of bacterial and mitochondrial DNA activate the complement system via the DNA backbone. We suggest that CpG-B interacts directly with classical and alternative pathway components, resulting in complement-C5aR1-dependent cytokine release.

  • 22. Demirel, Isak
    et al.
    Vumma, Ravi
    Mohlin, Camilla
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Svensson, Lovisa
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Säve, Susanne
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Persson, Katarina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nitric Oxide Activates IL-6 Production and Expression in Human Renal Epithelial Cells2012In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 36, no 6, p. 524-530Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Increased nitric oxide (NO) production or inducible form of NO synthase activity have been documented in patients suffering from urinary tract infection (UTI), but the role of NO in this infection is unclear. We investigated whether NO can affect the host response in human renal epithelial cells by modulating IL-6 production and mRNA expression. Methods: The human renal epithelial cell line A498 was infected with a uropathogenic Escherichia coli (UPEC) strain and/or the NO donor DETA/NO. The IL-6 production and mRNA expression were evaluated by ELISA and real-time RT-PCR. IL-6 mRNA stability was evaluated by analyzing mRNA degradation by real-time RT-PCR. Results: DETA/NO caused a significant (p < 0.05) increase in IL-6 production. Inhibitors of p38 MAPK and ERK1/2 signaling, but not JNK, were shown to significantly suppress DETA/NO-induced IL-6 production. UPEC-induced IL-6 production was further increased (by 73 +/- 23%, p < 0.05) in the presence of DETA/NO. The IL-6 mRNA expression increased 2.1 +/- 0.17-fold in response to DETA/NO, while the UPEC-evoked increase was pronounced (20 +/- 4.5-fold). A synergistic effect of DETA/NO on UPEC-induced IL-6 expression was found (33 +/- 7.2-fold increase). The IL-6 mRNA stability studies showed that DETA/NO partially attenuated UPEC-induced degradation of IL-6 mRNA. Conclusions: NO was found to stimulate IL-6 in renal epithelial cells through p38 MAPK and ERK1/2 signaling pathways and also to increase IL-6 mRNA stability in UPEC-infected cells. This study proposes a new role for NO in the host response during UTI by modulating the transcription and production of the cytokine IL-6. Copyright (C) 2012 S. Karger AG, Basel

  • 23.
    Engberg, Anna E.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Biomaterials and Hemocompatibility2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biomaterials are commonly used in the medical clinic today; however, artificial materials can activate the cascade systems in the blood (complement-, coagulation-, contact- and fibrinolytic systems) as well as the platelets to various degrees. When an artificial surface comes in contact with blood, plasma proteins will be adsorbed to the surface within seconds. The composition of the layer of proteins differs between materials and is crucial for the hemocompatibility of the material.

    This thesis includes five projects.

    In Paper I the anticoagulants heparin and the thrombin inhibitor hirudin were evaluated in a whole blood model. Hirudin was found to be superior to low dose heparin since it did not affect the activation of the complement system nor the leukocytes. The most interesting observation was that expression of TF was seen on surface-attached monocytes in hirudin- treated blood but not heparin blood.

    In Paper II peptides from the streptococcal M-protein, which has affinity for the human complement inhibitor C4BP, were attached to a polymeric surface. When being exposed to blood the endogenous complement regulator was enriched at the surface of the material, via the M-peptides. With this new approach we created a self-regulatory surface, showing significant lowered material-induced complement activation.

    In Paper III apyrase, an enzyme which hydrolyzes nucleoside ATP and ADP, was immobilized on a polymer surface. Lower platelet activation and platelet-induced coagulation activation was seen for the apyrase-coated surface compared to control surfaces after exposure to whole human blood, due to the enzymes capability to degrade ADP released from activated platelets.

    In Paper IV and V we synthesized an array of polymeric materials which were characterized regarding physical-chemical properties, adsorption of plasma proteins, and hemocompatibility. The polymers showed widely heterogeneous protein adsorption. Furthermore, when the polymers were exposed to whole blood, two of the materials showed superior hemocompatibility (monitored as complement- and coagulation activation), compared to the reference poly(vinyl chloride).

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  • 24.
    Engberg, Anna E.
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren-Holmberg, Jenny P
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nilsson, Per H.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Bäck,
    Department of Oncology, Radiology and Clinical Immunology, Section of Clinical Immunology, Rudbeck Laboratory C5, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
    Mollnes, Tom Eirik
    Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway,Research Laboratory, Nordland Hospital, Bodø, and University of Tromsø, Norway.
    Nicholls, Ian A.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nilsson, Bo
    Department of Oncology, Radiology and Clinical Immunology, Section of Clinical Immunology, Rudbeck Laboratory C5, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
    Nilsson Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    EVALUATION OF THE HEMOCOMPATIBILITY OF NOVEL POLYMERIC MATERIALSManuscript (preprint) (Other academic)
    Abstract [en]

    When a biomaterial surface comes in contact with blood an immediate adsorption of plasma proteins to the surface will occur, and the cascade systems in the blood, such as the complement, coagulation and contact system, will be activated to various degrees. The intensity of this reaction will determine the hemocompatibility of the materials. Here we present an evaluation of the link between the composition, the physico-chemical properties and the protein adsorption properties of six newly synthesized polymers (P1-P6) and the hemocompatibility.The hemocompatibility of the polymeric surfaces was evaluated in human blood plasma and whole blood. Commercially available polyvinylchloride (PVC) was used as reference material. The hemocompatibility of the polymeric surfaces was evaluated with regard to complement activation (C3a and sC5-9 generation) and coagulation activation (platelet loss and TAT-formation) and cytokine productions (27 analytes in multiplex assay) after contact with whole blood. Contact activation was quantified by analyses of FXIIa-C1INH, FXIa-C1INH, and kallikrein-C1INH complexes.Polymers P2 (p<0.05 for C3a), P3, P5 and P6 showed less complement activation, and polymers P1 and P4 (p<0.05 for platelet loss), as well as P5 and P6 showed less coagulation activation compared with reference PVC. Polymers P1-P3 induced activation of the contact system, P3 being the most potent. Secretion of 17 cytokines including chemokines and growth factors were differentially influenced by the polymers, P1 and P3 being significantly (p<0.05) more compatible for five of the analytes.Collectively these data demonstrate that the composition of the polymers clearly leads to different biological properties as a consequence of distinctive physico-chemical properties and protein adsorption patterns.1

  • 25.
    Engberg, Anna
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Rosengren-Holmberg, Jenny
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Chen, Hui
    Department of Pathology, University of Pennsylvania, 401 Stellar Chance, Philadelphia, PA 19104, USA.
    Lambris, John
    Department of Pathology, University of Pennsylvania, 401 Stellar Chance, Philadelphia, PA 19104, USA.
    Nicholls, Ian
    University of Kalmar, School of Pure and Applied Natural Sciences.
    N. Ekdahl, Kristina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    BLOOD PROTEIN-POLYMER ADSORPTION FINGERPRINTING:IMPLICATIONS FOR UNDERSTANDING HEMOCOMPATIBILITYAND FOR BIOMATERIAL DESIGNManuscript (preprint) (Other academic)
    Abstract [en]

    Within seconds after an artificial material has been implanted into the blood thesurface will be covered by adsorbed plasma proteins. The composition of theprotein layer is determined by the physical-chemical properties of the surface. Asthe layer itself will become the new interface between the material and blood, itis of major importance for the hemocompatibility. In this project we have studiedthe adsorption of proteins to a model material (polystyrene, PS) with the peptidemass fingerprint technique (PMF) analyzed on a Matrix Assisted LaserDesorption/Ionization Time-of-Flight (MALDI-TOF). To further be able to studythe adsorption of plasma proteins to polymer surfaces, we have synthesized 33new polymer compositions with variable surface properties. Six of thosepolymers were selected and their protein binding ability was determined as wellas quantification of adsorption of 20 plasma proteins to the surface of thepolymers. Our results showed that fourteen high abundant plasma proteins werepositively identified on the PS-surface by MALDI-TOF. Further, the resultsshowed that the synthesized polymers had very distinctive adsorption patterns,with enrichment of different proteins after incubation in plasma and serum. Oneof the polymers was shown to adsorb large amounts of the complementactivating recognition protein C1q, which makes this polymer to a potentialactivating surface. Two of the polymers showed a clear enrichment of thecomplement regulating protein vitronectin as well as two apolipoproteins (AI andAIV) to the surface of the polymers, while some of the polymers bound proteinsapproximately in correlation to the concentration found in plasma.

  • 26.
    Evanson, Thea
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Preventiv behandling mot Diabetes Mellitus typ I: En jämförande litteraturstudie mellan Coxsackievirus-B-vaccin och behandling med GAD-alum2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Diabetes Mellitus type I is a global health issue, causing numerous deaths each year and also influencing the quality of life of those affected. Type I diabetes is an autoimmune disease where the individuals own immune system causes destruction of insulin producing beta cells in the endocrine islets of pancreas. Main immunological features include, autoantibodies directed towards glutamic acid decarboxylase 65, and autoreactive T-cells. Diagnosis is generally based on elevated levels of plasma glucose and stimulated C-peptide, together disclosing the status of the beta cell function. The lack of endogen insulin causes disturbances in the glucose metabolism which leads to prevailing tissue damage in cells and organs of the diabetic individual’s body. Furthermore, insufficient control of plasma glucose is related to development of diabetes complications. Diabetic complications are known to be a major cause of death in diabetic patients. Diabetes and diabetic complications caused 4,2 million deaths in 2019. Insufficient adherence to treatment regimen during a long period of time is known to increase the risk for some common diabetes complications. Administration of exogenous insulin is the only current treatment available for type I diabetes, albeit recurrent attempts to find a cure or successful preventive treatment for diabetes mellitus type I. Recent promising research on diabetes preventive treatment includes the autoantigen glutamic acid decarboxylase-65 and vaccine against coxsackievirus B. Aim: The purpose of this literature study was to examine prospective possibilities for diabetes preventive treatments. Further, the purpose was to compare the promising preventive treatments of GAD65-vaccine and CVB-vaccine concerning effect and prospective treatment regimens. Methods: The thesis is a literature study based on articles found by searching the database PubMed. Clinical studies examining the effect of GAD-treatment was found by using key words such as ”type 1 diabetes”, ”diabetes mellitus”, ”type 1”, ”GAD” and ”vaccine”. Studies examining the effect of CVB and CVB-vaccines was primarily preclinical and prospective cohort studies, found by searching for the key words ”type 1 diabetes”, ”vaccine” and ”coxsackievirus”. Results: Clinical studies of GAD-treatment does not demonstrate a statistically significant difference between treatment with GAD-alum compared to placebo in full group analysis. Stratified groups occasionally prove significant differences in quantity of stimulated C-peptide or progression to clinical diabetes by age, gender or amount of risk factors for example. The prospective cohort study examining the incidence of diabetes, demonstrates that CVB is a risk factor for type I diabetes in humans. Furthermore, the preclinical studies detect a significant decrease in diabetes incidence in CVB-vaccinated mice compared with placebo. Conclusion: Neither treatment with GAD-alum nor CVB-vaccine is currently ready for use. However, the studies show a promising prospective possibility for CVB-vaccine as a primary prevention and GAD-alum as a secondary or tertiary prevention of type I diabetes.

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  • 27.
    Faqiri, Ariana
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Har vitamin-D skyddande effekt mot luftvägsinfektion?2022Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: The respiratory tract includes several different parts including; nose, sinuses, pharynx, larynx, trachea and lungs. The respiratory tract can be infected by viruses or bacteria, which can lead to inflammation. The respiratory infection can be caused by rhinovirus, influenza virus, coronavirus or bacteria, such as streptococci or pneumococci. A variant of the coronavirus with the name, SARS-CoV-2 caused outbreaks over the entire world and was declared as a pandemic on 11th March 2020. On average, adults get a respiratory infection about 2-4 times a year, while children get sick more often, approximately 6-8 times a year. The immune system consists of components that work together to attack bacteria, fungi and viruses to protect the body against infections. Vitamin D has a significant effect on the innate and adaptive immune system. The body can absorb vitamin D through diet and from UV-radiation from the sun. Vitamin D has an effect on the immune system, which leads to upregulation of the immune system´s essential components and helps to fight infections as well as damaging cell membrane of microbes. 

    Objective: The purpose of the study was to investigate whether vitamin D has a protective effect in the fight against respiratory infections. 

    Method: The following literature study was based on five scientific articles from the databasePubMed. The following keywords were “vitamin d” and “respiratory infection”.Results: All five studies showed that vitamin D supplementation reduced the incidence of respiratory infections and the course of the disease was shortened. In study 5, the probability of covid-19 patients with vitamin D supplementation to be placed in intensive care decreased. There was a significant difference in the dosage of vitamin D in study 2, where higher dose was compared to a recommended dose. 

    Conclusion: All studies show that vitamin D has a certain protective effect against respiratory infections and helps shorten the course of the disease by strengthening the immune system. The results of the studies have varied depending on different aims and treatment approaches. Therefore it has been difficult to draw concrete conclusions. The dosages where well tolerated and didn’t cause serious side effects that could be linked to the treatment. Further studies are needed to determine the protective effects of vitamin D on respiratory tract infections and also toinvestigate whether there are individual differences in vitamin D uptake and metabolismthereby being able to draw concrete and general conclusions. 

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    Har vitamin-D skyddande effekt mot luftvägsinfektion?
  • 28.
    Fernández Sjödin, Susana
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    I fotspåren av forskarnas jakt efter lösningen på gåtan: sambandet mellan narkolepsi och influensavaccinet Pandemrix2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 29.
    Fretland, Asmund Avdem
    et al.
    The Intervention Centre, Oslo University Hospital, Norway.
    Sokolov, Andrey
    Oslo University Hospital, Norway.
    Postriganova, Nadya
    Intervention Centre, Oslo University Hospital, Norway.
    Kazaryan, Airazat M
    Intervention Centre, Oslo University Hospital, Norway.
    Pischke, Soren E
    Intervention Centre, Oslo University Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital, Norway.
    Rognes, Ingrid Nygren
    Oslo University Hospital, Norway.
    Bjornbeth, Bjorn Atle
    Oslo University Hospital, Norway.
    Fagerland, Morten Wang
    Oslo University Hospital, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital, Norway.
    Edwin, Bjorn
    Intervention Centre, Oslo University Hospital, Norway.
    Inflammatory Response After Laparoscopic Versus Open Resection of Colorectal Liver Metastases: Data From the Oslo-CoMet Trial.2015In: Medicine, ISSN 0025-7974, E-ISSN 1536-5964, Vol. 94, no 42, p. 1-7, article id e1786Article in journal (Refereed)
    Abstract [en]

    Laparoscopic and open liver resection have not been compared in randomized trials. The aim of the current study was to compare the inflammatory response after laparoscopic and open resection of colorectal liver metastases (CLM) in a randomized controlled trial.This was a predefined exploratory substudy within the Oslo CoMet-study. Forty-five patients with CLM were randomized to laparoscopic (n = 23) or open (n = 22) resection. Ethylenediaminetetraacetic acid-plasma samples were collected preoperatively and at defined time points during and after surgery and snap frozen at -80 C. A total of 25 markers were examined using luminex and enzyme-linked immunosorbent assay techniques: high-mobility box group 1(HMGB-1), cell-free DNA (cfDNA), cytokines, and terminal C5b-9 complement complex complement activation.Eight inflammatory markers increased significantly from baseline: HMGB-1, cfDNA, interleukin (IL)-6, C-reactive protein, macrophage inflammatory protein -1β, monocyte chemotactic protein -1, IL-10, and terminal C5b-9 complement complex. Peak levels were reached at the end of or shortly after surgery. Five markers, HMGB-1, cfDNA, IL-6, C-reactive protein, and macrophage inflammatory protein -1β, showed significantly higher levels in the open surgery group compared with the laparoscopic surgery group.Laparoscopic resection of CLM reduced the inflammatory response compared with open resection. The lower level of HMGB-1 is interesting because of the known association with oncogenesis.

  • 30.
    Gerogianni, Alexandra
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Baas, Laura M.
    Radboud Univ Nijmegen, Netherlands;Amalia Children’s Hospital, Netherlands.
    Sjöström, Dick J.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    van de Kar, Nicole C. A. J.
    Radboud Univ Nijmegen, Netherlands;Amalia Children’s Hospital, Netherlands.
    Pullen, Marit
    Radboud Univ Nijmegen, Netherlands.
    van de Peppel, Siem J.
    Radboud Univ Nijmegen, Netherlands;Amalia Children’s Hospital, Netherlands.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    van den Heuvel, Lambertus P.
    Radboud Univ Nijmegen, Netherlands;;Amalia Children’s Hospital, Netherlands;Univ Hosp Leuven, Belgium.
    Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1279612Article in journal (Refereed)
    Abstract [en]

    Factor I (FI) is an essential regulator of the complement system. Together with co-factors, FI degrades C3b, which inhibits further complement activation. Genetic mutations in FI are associated with pathological conditions like age-related macular degeneration and atypical hemolytic uremic syndome. Here, we evaluated eight recombinant FI genetic variants found in patients. We assessed FI's co-factor activity in the presence of two co-factors; Factor H and soluble CR1. Different analytical assays were employed; SDS-PAGE to evaluate the degradation of C3b, ELISA to measure the generation of fluid phase iC3b and the degradation of surface-bound C3b using a novel Luminex bead-based assay. We demonstrate that mutations in the FIMAC and SP domains of FI led to significantly reduced protease activity, whereas the two analyzed mutations in the LDLRA2 domain did not result in any profound changes in FI's function. The different assays employed displayed a strong positive correlation, but differences in the activity of the genetic variants Ile55Phe and Gly261Asp could only be observed by combining different methods and co-factors for evaluating FI activity. In conclusion, our results provide a new perspective regarding available diagnostic tools for assessing the impact of mutations in FI.

  • 31.
    Gustafson, Elisabet
    et al.
    Uppsala University Hospital, Sweden.
    Asif, Sana
    Uppsala University, Sweden.
    Kozarcanin, Huda
    Uppsala University, Sweden.
    Elgue, Graciela
    Uppsala University, Sweden.
    Meurling, Staffan
    Uppsala University Hospital, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University, Sweden.
    Control of IBMIR Induced by Fresh and Cryopreserved Hepatocytes by Low Molecular Weight Dextran Sulfate Versus Heparin2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 1, p. 71-81Article in journal (Refereed)
    Abstract [en]

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

  • 32.
    Hamad, Osama
    et al.
    Uppsala University.
    Bäck, Jennie
    Uppsala University.
    Nilsson, Per H.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Platelets, Complement, and Contact Activation: Partners in inflammation and thrombosis2012In: Current Topics in Innate Immunity II / [ed] John D. Lambris &George Hajishengallis, Springer, 2012, Vol. 946, no Current Topics in Innate Immunity II. J. D. Lambris, G. Hajishengallis (eds.), p. 185-205Conference paper (Refereed)
    Abstract [en]

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

  • 33.
    Harboe, M.
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Johnson, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nymo, S.
    Nordland Hospital, Norway.
    Ekholt, K.
    Oslo University Hospital Rikshospitalet, Norway.
    Schjalm, C.
    Oslo University Hospital Rikshospitalet, Norway.
    Lindstad, J. K.
    Oslo University Hospital Rikshospitalet, Norway.
    Pharo, A.
    Oslo University Hospital Rikshospitalet, Norway.
    Hellerud, B. C.
    Oslo University Hospital Rikshospitalet, Norway.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Mollnes, T. E.
    Oslo University Hospital Rikshospitalet, Norway ; Nordland Hospital, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway.
    Molecular modelling showed optimal fit between TSR5 in trimeric properdin and C345C in the C3b moiety for stabilization of the alternative convertase, whereas binding to molecular patterns in myeloperoxidase, endothelial cells and Neisseria meningitides was indirectly mediated by initial C3 activation2016In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 221, no 10, p. 1205-1205Article in journal (Refereed)
  • 34.
    Harboe, M.
    et al.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Nilsson, Per H.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Johnson, C.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Lindstad, J. K.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Pharo, A.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Hellerud, B. C.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway.
    Nymo, S.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway ; University of Tromsö, Norway.
    Mollnes, T. E.
    University of Oslo, Rikshospitalet, Norway ; University of Oslo, Norway ; University of Tromsö, Norway.
    Binding of properdin to myeloperoxidase and Neisseria meningitidis is C3-dependent2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, Special Issue, p. 142-142, article id 067Article in journal (Refereed)
  • 35.
    Holt, Margrethe Flesvig
    et al.
    Oslo Univ Hosp, Norway;Oslo University Hospital Rikshospitalet, Norway.
    Michelsen, Annika E.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Shahini, Negar
    Oslo Univ Hosp, Norway.
    Bjorkelund, Elisabeth
    Oslo University Hospital Rikshospitalet, Norway.
    Bendz, Christina Holt
    Oslo University Hospital Rikshospitalet, Norway.
    Massey, Richard J.
    Oslo University Hospital Rikshospitalet, Norway;Univ Oslo, Norway.
    Schjalm, Camilla
    Oslo University Hospital Rikshospitalet, Norway;Univ Oslo, Norway.
    Halvorsen, Bente
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Broch, Kaspar
    Oslo University Hospital Rikshospitalet, Norway;Univ Oslo, Norway.
    Ueland, Thor
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;The Arctic University of Norway, Norway.
    Gullestad, Lars
    Oslo University Hospital Rikshospitalet, Norway;Univ Oslo, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Oslo University Hospital Rikshospitalet, Norway;University of Oslo, Norway.
    Aukrust, Pål
    Oslo University Hospital Rikshospitalet, Norway;University of Oslo, Norway.
    Mollnes, Tom Eirik
    Oslo University Hospital Rikshospitalet, Norway;University of Oslo, Norway;The Arctic University of Norway, Norway;Nordland Hospital, Norway;Norwegian University of Science and Technology, Norway.
    Louwe, Mieke C.
    Oslo University Hospital, Norway.
    The Alternative Complement Pathway Is Activated Without a Corresponding Terminal Pathway Activation in Patients With Heart Failure2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 800978Article in journal (Refereed)
    Abstract [en]

    Objective: Dysregulation of the complement system has been described in patients with heart failure (HF). However, data on the alternative pathway are scarce and it is unknown if levels of factor B (FB) and the C3 convertase C3bBbP are elevated in these patients. We hypothesized that plasma levels of FB and C3bBbP would be associated with disease severity and survival in patients with HF. Methods: We analyzed plasma levels of FB, C3bBbP, and terminal C5b-9 complement complex (TCC) in 343 HF patients and 27 healthy controls. Results: Compared with controls, patients with HF had elevated levels of circulating FB (1.6-fold, p < 0.001) and C3bBbP (1.3-fold, p < 0.001). In contrast, TCC, reflecting the terminal pathway, was not significantly increased (p = 0.15 vs controls). FB was associated with NT-proBNP, troponin, eGFR, and i.e., C-reactive protein. FB, C3bBbP and TCC were not associated with mortality in HF during a mean follow up of 4.3 years. Conclusion: Our findings suggest that in patients with HF, the alternative pathway is activated. However, this is not accompanied by activation of the terminal pathway.

  • 36.
    Huang, Shan
    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.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Anders
    Gambro Lundia AB.
    Wieslander, Anders
    Gambro Lundia AB.
    Grundström, Gunilla
    Gambro Lundia AB.
    Hancock, Viktoria
    Gambro Lundia AB.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood2015In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 37.
    Håkansson, Irene
    et al.
    Linköping University, Sweden.
    Ernerudh, Jan
    Linköping University, Sweden.
    Vrethem, Magnus
    Linköping University, Sweden.
    Dahle, Charlotte
    Linköping University, Sweden.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University, Sweden.
    Complement activation in cerebrospinal fluid in clinically isolated syndrome and early stages of relapsing remitting multiple sclerosis2020In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 340, p. 1-8, article id 577147Article in journal (Refereed)
    Abstract [en]

    To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p <= .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information.

  • 38.
    Islam, Rakibul
    et al.
    Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Islam, Mohammad Mirazul
    Massachusetts Eye & Ear, USA;Schepens Eye Res Inst, USA;Harvard Med Sch, USA.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Oslo Univ Hosp, Norway;Univ Oslo, Norway.
    Mohlin, Camilla
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hagen, Kjersti Thorvaldsen
    Univ Oslo, Norway.
    Paschalis, Eleftherios, I
    Schepens Eye Res Inst, USA;Harvard Med Sch, USA.
    Woods, Russell L.
    Schepens Eye Res Inst, USA;Harvard Med Sch, USA.
    Bhowmick, Sabuj Chandra
    Univ Oslo, Norway.
    Dohlman, Claes H.
    Massachusetts Eye & Ear, USA;Harvard Med Sch, USA.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Chodosh, James
    Massachusetts Eye & Ear, USA;Harvard Med Sch, USA.
    Gonzalez-Andrades, Miguel
    Massachusetts Eye & Ear, USA;Schepens Eye Res Inst, USA;Harvard Med Sch, USA;Reina Sofia Univ Hosp, Spain;Univ Cordoba, Spain.
    Mollnes, Tom Eirik
    Oslo Univ Hosp, Norway;Univ Oslo, Norway;Norwegian Univ Sci & Technol, Norway;Nordland Hosp, Norway;Univ Tromso, Norway.
    Combined blockade of complement C5 and TLR co-receptor CD14 synergistically inhibits pig-to-human corneal xenograft induced innate inflammatory responses2021In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 127, p. 169-179Article in journal (Refereed)
    Abstract [en]

    Inadequate supplies of donor corneas have evoked an escalating interest in corneal xenotransplantation. However, innate immune responses contribute significantly to the mechanism of xenograft rejection. We hypothesized that complement component C5 and TLR co-receptor CD14 inhibition would inhibit porcine cornea induced innate immune responses. Therefore, we measured cytokine release in human blood, induced by three forms of corneal xenografts with or without inhibitors. Native porcine cornea (NPC) induced interleukins (IL-1 beta, IL-2, IL-6, IL-8, IL-1ra), chemokines (MCP-1, MIP-1 alpha, MIP-1 beta) and other cytokines (TNF, G-CSF, INF-gamma, FGF-basic). Decellularized (DPC) and gamma-irradiated cornea (g-DPC) elevated the release of those cytokines. C5-blockade by eculizumab inhibited all the cytokines except G-CSF when induced by NPC. However, C5-blockade failed to reduce DPC and g-DPC induced cytokines. Blockade of CD14 inhibited DPC-induced cytokines except for IL-8, MCP-1, MIP-1 alpha, and G-CSF, while it inhibited all of them when induced by g-DPC. Combined blockade of C5 and CD14 inhibited the maximum number of cytokines regardless of the xenograft type. Finally, by using the TLR4 specific inhibitor Eritoran, we showed that TLR4 activation was the basis for the CD14 effect. Thus, blockade of C5, when combined with TLR4 inhibition, may have therapeutic potential in pig-to-human corneal xenotransplantation. Statement of significance Bio-engineered corneal xenografts are on the verge of becoming a viable alternative to allogenic human donor-cornea, but the host's innate immune response is still a critical barrier for graft acceptance. By overruling this barrier, limited graft availability would no longer be an issue for treating corneal diseases. We showed that the xenograft induced inflammation is initiated by the complement system and toll-like receptor activation. Intriguingly, the inflammatory response was efficiently blocked by simultaneously targeting bottleneck molecules in the complement system (C5) and the TLR co-receptor CD14 with pharmaceutical inhibitors. We postulate that a combination of C5 and CD14 inhibition could have a great therapeutic potential to overcome the immunologic barrier in pig-to-human corneal xenotransplantation. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of Acta Materialia Inc.

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  • 39.
    Johansson, Emilia
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences.
    Larsson, Amanda
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences.
    När det ofarliga blir farligt: En enkätstudie om hur frekvent matöverkänslighet är bland människor i åldern 18-28 år i Sverige2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: Att definiera matöverkänslighet är ännu idag inte fastställt, det råder delade meningar om denna definition. Författarna har valt att inrikta sig på matöverkänslighet som definieras matallergi och matintolerans. Flera av matallergierna kan utlösa en allergisk chock, denna typ av chock som även kallas anafylaktisk chock kan vara livshotande om inte behandling sätts in direkt. Idag lider var tredje person i Sverige av någon typ av allergi, vanligt förekommande matöverkänsligheter är komjölksallergi, laktosintolerans, äggallergi och nötallergi.

    Syfte: Syftet är att undersöka hur många människor i åldern 18-28 år som lider utav matöverkänslighet och om allergimedicin bärs med dagligen.

    Metod: En empirisk enkätstudie låg till grund för studiens resultat. Författarna valde att göra en kvantitativ studie för att kunna samla in data systematiskt och sedan sammanfatta dessa i statistisk form. Studien var ute efter ett större antal deltagare utspridda på olika platser så därför passade kvantitativ metod in med en enkätstudie. Det blev en prospektiv tvärsnittsstudie då studien undersöker hur något såg ut vid ett specifikt tillfälle.

    Resultat: Studiens resultat visar att drygt en tredjedel utav deltagarna lider utav någon form utav matöverkänslighet, allergi eller intolerans. Ytterligare 20 % har någon gång reagerat på ett livsmedel, men använder idag ingen medicin mot sina besvär. De vanligaste livsmedlen att reagera emot är mjölk- laktos, frukt, nötter och vete.

    Slutsatser: Knappt hälften av de personerna som deltagit i denna studie har någon gång reagerat på ett livsmedel. Sedan har drygt 35 % utav deltagarna uppgett att de använder någon form utav allergimedicin mot livsmedel. Det innebär att människor i västvärlden är mer matöverkänsliga nu än någonsin och trenden fortsätter att eskalera. Renlighet och matvanor är troligen orsaker till detta växande hälsoproblem. 

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  • 40.
    Johnson, Christina
    et al.
    Univ Oslo, Norway;RIKEN Oslo Univ Hosp, Norway.
    Quach, Huy Quang
    Univ Oslo, Norway;RIKEN Oslo Univ Hosp, Norway.
    Lau, Corinna
    Nordland Hosp, Norway.
    Ekholt, Karin
    Univ Oslo, Norway;RIKEN Oslo Univ Hosp, Norway.
    Espevik, Terje
    Norwegian Univ Sci & Technol, Norway.
    Woodruff, Trent M.
    Univ Queensland, Australia.
    Pischke, Soren Erik
    Univ Oslo, Norway;RIKEN Oslo Univ Hosp, Norway.
    Mollnes, Tom Eirik
    Univ Oslo, Norway;RIKEN Oslo Univ Hosp, Norway;Nordland Hosp, Norway;Norwegian Univ Sci & Technol, Norway;Univ Tromso, Norway.
    Nilsson, Per H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Univ Oslo, Norway;RIKEN Oslo Univ Hosp, Norway.
    Thrombin Differentially Modulates the Acute Inflammatory Response to Escherichia coli and Staphylococcus aureus in Human Whole Blood2022In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 208, no 12, p. 2771-2778Article in journal (Refereed)
    Abstract [en]

    Thrombin plays a central role in thromboinflammatory responses, but its activity is blocked in the common ex vivo human whole blood models, making an ex vivo study of thrombin effects on thromboinflammatory responses unfeasible. In this study, we exploited the anticoagulant peptide Gly-Pro-Arg-Pro (GPRP) that blocks fibrin polymerization to study the effects of thrombin on acute inflammation in response to Escherichia coli and Staphylococcus aureus. Human blood was anticoagulated with either GPRP or the thrombin inhibitor lepirudin and incubated with either E. coli or S. aureus for up to 4 h at 37 degrees C. In GPRP-anticoagulated blood, there were spontaneous elevations in thrombin levels and platelet activation, which further increased in the presence of bacteria. Complement activation and the expression of activation markers on monocytes and granulocytes increased to the same extent in both blood models in response to bacteria. Most cytokines were not elevated in response to thrombin alone, but thrombin presence substantially and heterogeneously modulated several cytokines that increased in response to bacterial incubations. Bacterial-induced releases of IL-8, MIP-1 alpha, and mip-1 beta were potentiated in the thrombin-active GPRP model, whereas the levels of IP-10, TNF, IL-6, and IL-1 beta were elevated in the thrombin-inactive lepirudin model. Complement CS-blockade, combined with CD14 inhibition, reduced the overall cytokine release significantly, both in thrombin-active and thrombin-inactive models. Our data support that thrombin itself marginally induces leukocyte-dependent cytokine release in this isolated human whole blood but is a significant modulator of bacteria-induced inflammation by a differential effect on cytokine patterns.

  • 41.
    Kokelj, Spela
    et al.
    University of Gothenburg, Sweden.
    Ostling, Jorgen
    PExA AB, Sweden.
    Fromell, Karin
    Uppsala University, Sweden.
    Vanfleteren, Lowie E. G. W.
    Sahlgrenska University Hospital, Sweden;University of Gothenburg, Sweden.
    Olsson, Henric K.
    AstraZeneca, Sweden.
    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.
    Olin, Anna-Carin
    University of Gothenburg, Sweden.
    Activation of the Complement and Coagulation Systems in the Small Airways in Asthma2023In: Respiration, ISSN 0025-7931, E-ISSN 1423-0356, Vol. 102, no 8, p. 621-631Article in journal (Refereed)
    Abstract [en]

    Background: Several studies have shown the importance of the complement and coagulation systems in the pathogenesis of asthma. Objectives: We explored whether we could detect differentially abundant complement and coagulation proteins in the samples obtained from the small airway lining fluid by collection of exhaled particles in patients with asthma and whether these proteins are associated with small airway dysfunction and asthma control. Method: Exhaled particles were obtained from 20 subjects with asthma and 10 healthy controls (HC) with the PExA method and analysed with the SOMAscan proteomics platform. Lung function was assessed by nitrogen multiple breath washout test and spirometry. Results: 53 proteins associated with the complement and coagulation systems were included in the analysis. Nine of those proteins were differentially abundant in subjects with asthma as compared to HC, and C3 was significantly higher in inadequately controlled asthma as compared to well-controlled asthma. Several proteins were associated with physiological tests assessing small airways. Conclusions: The study highlights the role of the local activation of the complement and coagulation systems in the small airway lining fluid in asthma and their association with both asthma control and small airway dysfunction. The findings highlight the potential of complement factors as biomarkers to identify different sub-groups among patients with asthma that could potentially benefit from a therapeutic approach targeting the complement system.

  • 42.
    Kozarcanin, H.
    et al.
    Uppsala University.
    Lood, C.
    Skåne University Hospital;Lund University.
    Munthe-Fog, L.
    University of Copenhagen, Denmark.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hamad, O. A.
    Uppsala University.
    Bengtsson, A. A.
    Skåne University Hospital;Lund University.
    Skjoedt, M. -O
    University of Copenhagen, Denmark.
    Huber-Lang, M.
    University Hospital of Ulm, Germany.
    Garred, P.
    University of Copenhagen, Denmark.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 3, p. 531-545Article in journal (Refereed)
    Abstract [en]

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

  • 43. Kruse, Robert
    et al.
    Säve, Susanne
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Persson, Katarina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Adenosine Triphosphate Induced P2Y(2) Receptor Activation Induces Proinflammatory Cytokine Release in Uroepithelial Cells.2012In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 188, no 6, p. 2419-2425Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We characterized and identified the uroepithelial P2 receptor responsible for adenosine triphosphate mediated release of the cytokines interleukin-8 and 6.

    MATERIALS AND METHODS: The human renal epithelial cell line A498 (ATCC™) was cultured and stimulated with different purinergic agonists with or without prior inhibition with different antagonists or signaling pathway inhibitors. Supernatant was analyzed for interleukin-8 and 6 by enzyme-linked immunosorbent assay. P2 receptor mRNA expression was assessed by real-time reverse transcriptase-polymerase chain reaction. The candidate receptor was knocked down with siRNA technology. Interleukin-8 and 6 responses were measured after purinergic stimulation of knocked down cells.

    RESULTS: ATP and ATP-γ-S (Roche Diagnostics, Mannheim, Germany) were equipotent as inducers of interleukin-8 and 6 release. Agonist profile experiments using different P2 receptor agonists indicated that P2Y(2) was the main contributor to this release, although P2Y(11) and P2X(7) activation could not be excluded. Signaling pathway experiments showed that interleukin-8 release involved phospholipase C and inositol trisphosphate mediated signaling, indicating a P2Y receptor subtype. Antagonist experiments indicated P2Y(2) as the responsible receptor. Gene expression analysis of P2 receptors showed that strong expression of P2Y(2) receptor and subsequent knockdown of P2Y(2) receptor mRNA for 72 and 96 hours abrogated interleukin-8 and 6 release after purinergic stimulation with adenosine triphosphate-γ-S.

    CONCLUSIONS: Interleukin-8 and 6 release after purinergic stimulation in uroepithelial A498 cells is mediated through P2Y(2) receptor activation.

  • 44. Kuraya, M
    et al.
    Nilsson, B
    Nilsson Ekdahl, Kristina
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Klein, E
    C3d-mediated negative and positive signals on the proliferation of human B cells separated from blood1990In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 26, no 1, p. 51-58Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 45. Lavö, B
    et al.
    Nilsson, B
    Lööf, L
    Nilsson, U R
    Nilsson Ekdahl, Kristina
    Department of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala.
    Fc receptor function and circulating immune complexes in gluten sensitive enteropathy - possible significance of serum IgA1991In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 32, p. 876-880Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Lidén, Pauline
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kan selentillskott behandla autoimmun tyreoidit?: En litteraturstudie2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Introduction. Autoimmune thyroiditis (AITD) is a chronic autoimmune disease in which the immune system's antibodies (ab) attack the thyroid proteins thyroid peroxidase (TPO) and/or thyroglobulin (TG). Studies show that selenium supplementation in patients with AITD can reduce thyroid antibodies and the size and number of nodules in an enlarged thyroid. The purpose of this study was to investigate how selenium supplementation affects the serum levels of thyroid peroxidase antibodies (TPOab) and thyroid hormone levels in autoimmune thyroiditis.

    Method. This is a literature study and therefore the method has been to gather relevant literature through searches on PubMed such as "selenium autoimmune thyroiditis", "selenium thyroid" and "autoimmune thyroiditis". Among the search results, nine articles were selected based on quality, publication year and relevance. Among the articles, measured levels of TPOab and thyroid hormone levels were examined and compiled, and were chosen as an indication of the effect of selenium supplementation.

    Results. The results were inconsistent. The majority of the studies (7 of 9) suggest that oral administration of selenium supplements effectively reduced serum concentrations of TPOab in patients with AITD in all age groups. The studies that resulted in the largest decrease in TPOab lasted for 3-12 months. Out of the 9 examined studies, only one study did not report any positive clinical effect in patients. Two of the studies showed that the selenium prevents further impairment of thyroid echogenicity, suggesting that selenium can inhibit the inflammatory process but not reverse the pre-existing thyroid damage it’s caused. The majority of studies (7 out of 9) show that selenium supplementation does not produce significant changes in the thyroid hormones: TSH, fT4 and fT3.

    Discussion. Why AITD-patients respond differently to selenium administration is still unknown, but it may be due to the duration of selenium treatment, the patients' intrathyroid levels of selenium at the onset of the study, the presence of iodine deficiency, as well as the age and disease progression of the patients.

    Conclusion. Having adequate physiological levels of selenium is of great importance in preserving thyroid health and preventing thyroid-related diseases. The majority of the studies show that selenium supplementation can reduce the number of TPOab. Selenium supplementation may also have immune related benefits but does not appear to affect the thyroid hormone levels. No adverse effects were observed during selenium supplementation, which makes its administration safe. However, more studies are needed to determine the effectiveness of selenium supplementation for AITD.

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    1. Examensarbete Pauline
  • 47.
    Lindblom, Rickard P. F.
    et al.
    Karolinska Institutet;Uppsala University.
    Aeinehband, Shainn
    Karolinska Institutet.
    Ström, Mikael
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Khademi, Mohsen
    Karolinska Institutet.
    Nilsson, Bo
    Uppsala University.
    Piehl, Fredrik
    Karolinska Institutet.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Complement receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function2016In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 166, p. 89-95Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 48.
    Lindblom, Rickard P. F.
    et al.
    Karolinska Institutet;Univ Uppsala Hosp;Karolinska Univ Hosp.
    Berg, Alexander
    Karolinska Institutet.
    Ström, Mikael
    Karolinska Institutet.
    Aeinehband, Shahin
    Karolinska Institutet.
    Dominguez, Cecilia A.
    Karolinska Institutet.
    Al Nimer, Faiez
    Karolinska Institutet.
    Abdelmagid, Nada
    Karolinska Institutet.
    Heinig, Matthias
    Max Delbruck Ctr Mol Med, Germany.
    Zelano, Johan
    Karolinska Institutet.
    Harnesk, Karin
    Karolinska Institutet.
    Hubner, Norbert
    Max Delbruck Ctr Mol Med, Germany.
    Nilsson, Bo
    Uppsala University.
    Nilsson Ekdahl, Kristina
    Uppsala University.
    Diez, Margarita
    Karolinska Institutet.
    Cullheim, Staffan
    Karolinska Institutet.
    Piehl, Fredrik
    Karolinska Institutet.
    Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response2015In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 12, article id 192Article in journal (Refereed)
    Abstract [en]

    Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.

  • 49.
    Lindelöf, Linnea
    et al.
    Uppsala University, Sweden.
    Dahlqvist, Solbritt Rantapää
    Umeå University, Sweden.
    Lundtoft, Christian
    Uppsala University, Sweden.
    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.
    Gunnarsson, Iva
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Svenungsson, Elisabet
    Karolinska Institutet, Sweden;Karolinska University Hospital, Sweden.
    Eriksson, Oskar
    62 Acquired ficolin-3 deficiency in patients with Systemic Lupus Erythematosus2023In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 228, no 5, p. 152515-152515, article id 62Article in journal (Refereed)
    Abstract [en]

    Background: Ficolin-3 is the main initiator of the lectin pathway in humans. Case reports of ficolin-3 deficient patients have suggested that ficolin-3 deficiency may be enriched in patients with Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease where complement plays an important role. Therefore, this study aimed to investigate the activity levels of ficolin-3 and to identify potential ficolin-3 deficient individuals in two Swedish SLE cohorts.

    Methods: Serum or plasma samples from SLE patients (n=810) and matched controls (n=566) were collected from the Karolinska Institute (KI) and Umeå University Hospital. The ficolin-3 activity levels were measured by an in-house developed functional ELISA with a pooled normal human serum sample as a reference. Serial samples were analyzed for ficolin-3 deficient patients when available. Sequencing data were analyzed for FCN3 frame-shift mutation +1637delC (rs532781899) and other potential loss-of-function (LoF) variants.

    Results: This screening revealed that the level of ficolin-3 activity varies largely in patients with SLE. The activity levels also show that SLE patients seem to generally have elevated ficolin-3 activity compared to the control group (p<0.0001). Out of 810 patients with SLE, four patients were determined to be ficolin-3 deficient. For two of these patients, the ficolin-3 activity was at normal levels at the time of diagnosis and thereafter depleted over time, indicating an acquired deficiency. For deficient patients, no or very low ficolin-3 protein levels and no lectin pathway-dependent complement activation could be detected. Autoantibodies against ficolin-3 were not detectable. No patients were homozygous for the +1637delC frameshift mutation, whereas in total 10 patients were determined to be heterozygous carriers. These heterozygous patients displayed lower levels of ficolin-3 activity but did not include the deficient patients. Additional possible LoF variants were analyzed but none were enriched in either patients or controls.

    Conclusions: Contrary to the classical pathway of the complement system we show that genetic ficolin-3 deficiency is not a risk factor for SLE. Instead, acquired ficolin-3 deficiency was observed in a subgroup of SLE patients, possibly due to a potent activation of the lectin pathway that depleted ficolin-3 plasma levels in these individuals.

  • 50. Lundgren, Brita A
    et al.
    Rorsman, Fredrik
    Portela-Gomes, G
    Grimelius, Lars
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Nilsson, Bo
    Ekwall, Olof
    Identification of complement C3 as an autoantigen in inflammatory bowel disease2010In: Journal of Gastroenterology and Hepatology, ISSN 0815-9319, E-ISSN 1440-1746, Vol. 2, no 4, p. 429-436Article in journal (Refereed)
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